Reworking the Spine

Motivation: During medical school, when I told a notable surgeon that I intended to enter neurology, he smirked while trying to suction clotted blood and then said, "If you like banging your head against a wall, then go to neurology."  The implication being, of course, that neurologists have few cures.  While I disagree with the surgeon's assessment of neurology, even I was surprised by a remarkable article in Lancet this year that demonstrated for the first time recovery of ability to stand after complete spinal cord motor injury.  And, this experiment did not even use stem cells.

The theory driving this experiment is rooted in the observation that mammalian spinal cords can generate locomotor output even in absence of central input.  The hypothesis is that if these spinal circuits can be stimulated, then people with spinal cord injury may be able to stand once more.

Paper: Harkema, S., Gerasimenko, Y., Hodes, J., et. al. "Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study." Lancet (2011); 377: 1938-47.

Method: This case study examined a single subject: a 23 year old man who was paraplegic from C7-T1 subluxation after a motor vehicle accident in 2006.  He had no contraction of trunk or leg muscles and only weak movements of hand muscles.  He retained, however, light-touch and pinprick sensation in lower extremities.  From 2007 to 2009, patient received 108 hours of step training and 54 hours of stand training during rehab with no clinical improvement.  An epidural spinal cord stimulation unit was then placed on the patient to stimulate the lumbosacral epidural region at location T11-L1 (to control spinal cord segments L1-S1).

Results:
Standing: Epidural stimulation (15 Hz, 8V) of the L5-S1 segment along with extension of legs resulted in the patient being able to stand in sustained posture with full weight bearing for more than four minutes.  Interestingly, the sustained standing posture was triggered by loading weight onto the legs.  Simultaneous EMG showed coordinated contraction of both flexors and extensors.  Of note, during standing, spontaneous postural changes occurred in response to shifts in center of gravity sagitally.

Walking: Epidural stimulation at 30-40 Hz and sensory cues (such as manually positioned stepping posture) generated walking-like motor patterns.  Without stimulation, manual positioning elicited no motor response.

Function Recovery: After 80 training sessions with epidural simulation over seven months, patient recovered voluntary movement of toe extension and ankle and leg stimulation while receiving spinal stimulation.  During epidural stimulation, patient also recovered bladder function with minimal post void residuals.  He also recovered function of other autonomic nervous system processes and gained weight by 18%.

Discussion: This paper is not only a potential paradigm changing case report in the field of spinal cord injury but also illustrates concepts that affect our understanding of the nervous system.  First, traditionally in our mind's eye, we view the sensory system and motor system as fairly indpendent pieces - one traveling up the dorsal part of the spinal cord and the other descending down the ventral part.  This paper shows that for basic tasks like standing, integration of sensory input and motor output occurs at multiple levels beginning with the spinal cord. So, while evaluating patients with gait difficulty, sensory deficits must be considered along with weakness.  Secondly, this paper extends the trend in our understanding that complex motions like walking occur as a result of interactions between multiple centers in the nervous system.  Clearly, part of the coordination process occur in the spinal cord itself.  Encouragingly, this distributive process may help us recover from seemingly "irremediable" defects such as complete motor spinal cord injury with the help of prosthetic electrical devices.

While encouraging, this paper obviously has many limitations.  Before epidural stimulation becomes the next glamorous procedure, this finding has to be replicated in more than the one case report.  Also, the patient in this case report is a healthy man in his 20s who had an accident.  It is unclear how this result generalizes to older nervous systems of patients in their 70s.  Nonetheless, for the final post of the year, this paper shows how seemingly impossible medical advances keep happening.

Aortic Stenosis - How Bad?

Motivation: If you listen closely enough, you will hear a murmur.  That has been my feeling about listening to murmurs over the aortic valve.  Almost everyone has a "soft ejection murmur."  The question, of course, is how tight is the aortic valve.  We have all heard cautionary tales about the lack of correlation of murmur intensity with aortic valve area.  During morning rounds, an attending suggested using the physical exam sign of "brachioradial delay" as a measure of severity of aortic stenosis.  How good is the sign?

For background, brachioradial delay is assessed by gently palpating the brachial and radial pulses simultaneously.  If there is a palpable delay between the brachial and radial pulses, then "brachioradial delay" is present.  From a pathophysiology viewpoint, the quicker the upstroke of the arterial pulse the quicker the pulse pressure wavefront spreads through the arterial tree.  In aortic stenosis, the upstroke of the arterial pulse is slower allowing some of the energy to be absorbed by circumferential stretch of the arteries.  Consequently, with a slow upstroke, there is a palpable delay in the spread of the pulse upstroke between proximal and distal arteries.

Paper: Leach, R.M. and McBrien, D.J. "Brachioradial delay: a new clinical indicator of the severity of aortic stenosis." Lancet (1990); 335: 1199-201.

Methods: Patients presenting at echocardiography clinic at Worthington Hospital (U.K.) were prospectively assessed by four clinicians about the presence of brachioradial delay.  Subjects were not preselected by any diagnosis.  The sign was counted positive if all four clinicians agreed.  Subsequently, for all the patients, the delay between the brachial and radial pulses was timed, and echocardiography was done in all patients.  In the paper, severe aortic stenosis was defined as aortic valve area of 0.5-0.75 sqcm.

Results:
Patient selection: Among the patients assessed, there were 33 patients with aortic stenosis and 25 patients with other heart diseases (9 heart failure, 4 MR, 3 post MI, 3 HOCM, 2 aortic regurg, 2 afib, 1 bicuspid aortic valve, 1 heart transplant).  Of the 33 patients with aortic stenosis, 17 had severe aortic stenosis (valve area between 0.5-0.75 sqcm).  The authors also reported on 27 controls without heart disease who were age and sex matched.

Control Subjects: For none of the 27 control subjects was a brachioradial delay palpable.  On measurement by pressure transducers,  the mean brachioradial delay was 24.3 msec below age 55 and 21.7 msec for those over age 75.  None of these delays were palpable.

Aortic Stenosis: In the 17 patients with "severe" aortic stenosis (valve area 0.5-0.75 sqcm), the brachioradial delay was palpable in all patients.  For 16 patients with mild aortic stenosis (valve area > 0.75 sqcm), brachioradial delay was palpable in only 6 out of 16 patients.

Other Heart Conditions: In 25 patients with other heart conditions, brachioradial delay was palpable in one patient with hypertrophic obstructive cardiomyopathy.  In no other patient was brachioradial delay palpable.

Discussion: This paper is remarkable in many ways.  I was surprised to see a novel physical exam sign for aortic stenosis described in the relatively recent past (1990).  Also surprising is the 100% sensitivity of this sign for aortic stenosis with valve area <0.75 sqcm.  The physical exam sign is also good because to determine a positive sign, you do not need to have many years of experience examining normal subjects.   The sign is a relative palpable delay between brachial and radial arteries.  Of note, the sensitivity of the sign falls off rapidly as the valve area increases above 0.75 sqcm (only 6/16 positive).

The paper, however, also has many weaknesses.  First of all, there are relatively few subjects examined.  Secondly, the specificity of the sign is very poorly established.  The group with "other" heart diseases was heterogeneous with few representatives of each type of cardiac pathology.  Finally, of note, what is called "severe" aortic stenosis (valve area <0.75 sqcm) would likely be termed critical aortic stenosis now (at least in the U.S.) while the mild aortic stenosis in the paper would be severe aortic stenosis at present (valve area 0.75 to 1 sqcm).  Despite these weakness, I think that the brachioradial delay is a good test to assess for critical AS in a patient with classic AS murmur.

DVT Prophylaxis - Surprising Truths

Motivation: Frankly, DVT prophylaxis seems like a lot of voodoo to me.  Most patients who become hospitalized have probably been sick in bed at home for some days, and many continue to be bed-bound after discharge.  During the few days of hospitalization, I often wonder what difference is made by daily stabs in the stomach with heparin.  Yet, there is increasing institutional push to remember to use heparin prophylaxis.  I was browsing for some evidence for DVT prophylaxis when I came across American College of Physician systematic review about this very topic published this year.  The results are surprising.

Paper: Qaseem, A., Chou, R., Humphrey, L., et. al. "Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline from the American College of Physicians."  Ann. Intern Med. (2011) 155: 625-632.

Methods: Systematic review of published randomized trials from 1950 to 2011.  Primary outcome was total mortality 120 days after randomization.  Secondary outcomes were symptomatic DVT, all PE, fatal PE, all bleeding, and major bleeding.  The review separated analysis for patients with and without acute stroke.

Results:
Effect of heparin prophylaxis versus no prophylaxis:
Medical patients without stroke - The review found ten trials (total of 20,717 patients) of patients without stroke.  There was NO significant effect on mortality at 120 days (RR: 0.94, CI: 0.84-1.04).  Heparin was associated with reduced risk for PE (RR: 0.69, CI: 0.52-0.90) but also increased risk of any bleeding (RR: 1.34, CI: 1.08-1.66). The differences in major bleeding and symptomatic DVT were not significant. In summary, heparin use prevents 4 PE per 1000 treated but causes 9 events of any bleeding per 1000 treated.
Acute Stroke - Review found 8 trials (total of 15,405 patients).  Pooled results showed NO significant reduction in mortality, PE, or symptomatic DVT. Prophylaxis was associated with increased risk for major bleeding (RR: 1.66, CI: 1.20-2.28). Pooled data was, however, pretty heterogenous in findings (wide spread in data).  The largest randomized trial with acute stroke had 14,578 patients and found NO reduction in mortality or PE.  However, a significant reduction in recurrent ischemic stroke was detected (RR: 0.65, CI: 0.54-0.80) at the risk of increased risk of hemorrhagic stroke or serious extracranial hemorrhage (RR: 1.73, CI: 1.22-2.46).

Low-Molecular Weight Heparin versus Unfractionated Heparin:
Medical patients without acute stroke: NO statistical difference in mortality, PE, or major bleeding events.
Acute Stroke: NO statistical difference in mortality, PE, or bleeding events.

Compression Stockings versus no stockings:
Sparse data (three trials, 2518 patients) making separation of general medical patients from patients with acute stroke difficult.  Overall, compression stockings did NOT reduce mortality, symptomatic DVT, or PE.  Risk for lower extremity skin damage was significantly increased among patients wearing stockings (RR: 4.02, CI: 2.34-6.91) conferring risk of 39 events per 1000 treated.

Discussion: To me, the most surpirsing part of the review was that despite the large pooled cohort size (>20,000 patients), there was no mortality benefit with heparin prophylaxis four months post-randomization.  The reduction in PE risk by about 30% presumably involves decreased risk of small PE.  As expected, the cost of reducing PE is increased bleeding events.  Amazingly, acute stroke patients did not have similar PE risk reduction despite a large cohort size.  Heparin use in acute stroke is a different balance between reduction in recurrent stroke (reduction by about 35%) compared to increased risk of major bleeds, including intracranial bleeds.  The review also helped clarify a couple of other misconceptions that I had.  Overall, low molecular weight heparin is no better than unfractionated heparin other than once a day dosing versus three times daily dosing.  I had thought that LMWH was better than unfractionated heparin.  Also, compression stockings proved to be pretty useless.  There is no demonstrable benefit while incurring increased risk of lower extremity skin damage.  On balance, there appears to be increased harm.  The review did not cover pneumatic compression devices.

One caveat to keep in mind in these large systematic reviews is that by pooling data, a lot of granular differences among subgroups are lost.  For example, ICU patients may have different risks and benefits.  There are also number of other cohorts such as patients with cirrhosis or kidney disease who may benefit variably with heparin.  When evaluating 30,000 patients, only effects that are consistent across entire groups are apparent.  One way in which this paper changes my perspective on DVT prophylaxis is that I will be less hesitant to hold prophylaxis in patients at risk for bleeding (after all, not saving lives with heparin).  And, I will stop pushing for stockings - good for Christmas but probably not for preventing PE.

Valves of the Right Stuff

Motivation: Morning rounds with a cardiologist is like going from room to room and trying to be a human echo machines.  Is there a valvular problem? The safe answer is almost always yes.  You may not be able to hear it, but the attending can.  Although human beings have refined their ears to distinguish harsh, blowing, and soft transvalvular flow sounds, the ability to fix valvular disease has lagged behind.  Artifical valves have major problems.  Mechanical valves require life long anti-coagulation, and dead tissue valves have finite lifespan.  A surgeon recently showed me the third way: growing valves out of your own tissue.  Sounds like fiction, but the patient did just fine after the tricuspid valve repair operation.  Here is a case series from Italy that demonstrates the magic.

Paper: Quarti, A. et. al. "Preliminary experience in the use of an extracellular matrix to repair congenital heart diseases." Interactive Cardiovascular and Thoracic Surgery (2011) article in press.

Methods: Between 2009 and 2011, 26 patients with congenital heart defect underwent surgery using an extracellular matrix patch (manufactured by CorMatrix).  The matrix was constructed from porcine small intestinal submucosa with expectation that native heart tissue would grow over the matrix.  The immediate post-operative course was reported.

Results:
Patients: Surgery was performed in 26 patients (mean age 6.4 years, range of 8 days to 32 years):

• 10 for pulmonary patch arterioplasty
• 9 for valve leaflet repair (including tricuspid, pulmonary, aortic, and mitral valves)
• 4 for ascending aortic patch aortoplasty
• 3 for aortic arch reconstruction
• 1 for right ventricular outflow tract obstruction

Results: There were no deaths in the peri-operative period.  At follow-up (mean 13.2 months, range 4-25 months), there was no evidence of thrombosis, disruption, shrinkage, leakage, or patch calcification on echo and CXR. 

For the patients with valve repair, follow-up echo only showed trivial to mild regurgitation.  No valve repair required reoperation.  Intial followup of the valve repair cohort (mean of 12.5 months) did not show evidence of progression of regurgitation. 

For cases in which extracellular matrix was used as vascular patch (18 cases), two had pulmonary artery stenosis distal to the patch.  One required operative repair.

Discussion: This paper may be part of the intial foundations of a marked change in valve repair surgery.  If the results eventually hold up in larger study, many of the long-term complications of valve repair surgery such as anti-coagulation, thrombogenic risk, and risk of endocarditis will be significantly decreased.  At present, however, this paper probably generates more questions than answers.  First of all, the follow-up is short, and questions about long-term viability of the ECM repair remain.  Also, most of the subjects were children, and older adults may repopulate the matrix at a different rate than children making extension of the results to adults problematic.  This paper probably lays the groundwork for larger randomized trials.  Finally, the paper does not mention the funding source.  In subsequent trials, it would be preferable if CorMatrix is not part of the trials.

Regrowing the Heart

Motivation: With the recent AHA conference, a flurry of new findings has been released.  Although there have been many negative findings, there was one recent trial in particular that caught my attention.  Wouldn't it be nice if we could somehow regrow heart cells in patients with heart failure? People have tried it in the past and failed.  But, there was a recent report of success!

Paper:   Bolli, R. et. al. "Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial" Lancet (2011) epub.

Methods: The full trial consisted of an early safety analysis and then a randomized portion.  Given low recruitment so far, the reported results combine the results of the whole experience.  The trial included patients of (1) less than 75 who were (2) undergoing CABG with (3) LVEF <= 40% and (4) history of previous MI.  Initial screening occurred at time of CABG during which the right atrial appendage was harvested and cardiac stem cells bearing cell surface marker c-kit were isolated.  At a mean of 113 days after CABG, the cardiac stem cells were infused into the infarcted territory using a balloon catheter.

Results:
Subjects: In total, 16 patients received stem cells while there were seven patients in the control group.  The two groups were overall similar in terms of age, gender, and comorbidities though the number of patients in each group is obviously very small.

Treatment Effect: At four month follow-up, the left ventricular ejection fraction (LVEF) increased from mean of 30.3% to 38.5% (p = 0.001).  By contrast, in the controls, the LVEF remained unchanged from mean of 30.1% to 30.2%.  The authors had injected the stem cells into the infarcted territory of previous MI.  In the infused territory, the regional wall motion score improved significantly (1.97 to 1.78, p = 0.007), with lower scores indicating less wall motion defect.  The regional wall motion score did not change in the control group.

Cardiac MRI: Seven patients treated with cardiac stem cells underwent cardiac MRI to assess mean infarct weight.  In the seven patients, the mean infarct weight decreased by 7.8 g (standard error, 1.7 g) at four months.  A reduction in infarct size was also noted.

Functional Data:  In the stem cell treated patient, the NYHA functional class decreased from mean of 2.19 to 1.63 four months after infusion.  The NYHA class of control patients stayed identical. 

Adverse effects: No serious adverse effects occurred more frequently in the treatment group including MI, arrhythmia, new tumor, or stroke.

Discussion: The trial is pretty exciting because it shows that a one-time procedure of stem cell infusion can generate long-lasting benefits including ejection fraction increase and functional benefit in terms NYHA heart failure severity.  This trial, however, must be taken in the context of a proof-of-concept safety analysis trial.  The number of patients in each group is pretty small.  Also, the entire trial was not randomized, and there may have been non-obvious differences in the two cohorts.  Despite media hype about this trial, both of these are strong limitations in extending stem cell infusions to routine practice just now.  Nonetheless, this trial provides hope that rather than just thinking about slowing down the pace of heart failure progression, we may actually in the future think about reversing heart failure.  Perhaps, in the future, standard therapy for STEMI will be PCI with stem cell infusion.  There is much more to come from this field!

Parkinson's Disease Prevention

Motivation: Lately, I have been meeting too many people with Parkinson's Disease - one of those random streaks of fate.  Controllable at first, the disease is pretty disabling as it progresses.  I was wondering about causes of this "idiopathic" disease and whether there are protective factors like say eating a salmon each day.  During this search, I came across some rumors that calcium channel blockers may be protective against Parkinson's Disease.  And, the data?

Paper: Ritz, B. et. al. "L-Type Calcium Channel Blockers and Parkinson Disease in Denmark." Ann. Neurol. (2010) 67: 600-606.

Methods: A case-control study in Denmark using the Denmark National Health Service registry that covers medical service for all citizens.  Authors identified initial diagnoses of Parkinson's Disease (PD) between 2001-2006.  Cases were identified either by first coded diagnosis of PD or first prescription of PD medication.  Controls were chosen after matching for birth year and sex.  Patients with any type of dementia or cerebrovascular disease before diagnosis of PD were excluded (along with matched controls).  Also excluded were patients with PD who were not prescribed any PD drugs.

Results:
Subjects: In total, the authors identified 1931 cases of PD with 9651 matched controls.  Five years prior to the index date of PD, the general health of cases and matched controls as measured by the Charson index was similar. 

Non-dihydropyridine Calcium Channel Blockers: Authors looked at prescription drug use two years prior to diagnosis of PD to account for the pre-clinical phase and risk factors for developing PD.  For non-dihydropyridine calcium channel blockers (verapamil and diltiazem), no association with PD was found. 

Dihydropyridine CCB: For dihydropyridine calcium channel blockers (such as amlodipine or felodipine), authors separated analysis for amlodipine, which has low central nervous system penetrance, and other members of this class, which have higher CNS availability.  For amlodipine, no protective effects were found.  For other members of dihydropyridine CCB, use was associated with protective effects: odds ratio of 0.70, adjusted confidence interval (0.52-0.94).  Of note, there were 55 patients with PD and 368 controls using medications of this class.

Discussion: The paper shows that use of non-hydropyridine calcium channel blockers (excepting amlodipine) was associated with about 30% decreased risk of PD diagnosis.  While this paper is a case-control study, the results have some biological plausability.  Non-CNS penetrant drugs did not show any effect while CNS penetrant calcium channel blockers had some protective effects.  It is plausible that blocking calcium influx into oxidatively stressed cells may provide some degree of protection.  On the other hand, the association observed may be indirect indicators of some other condition that is protective.  In the study, not much information was provided about details of comorbidities and how comorbidities were different between cases and controls.  This study is suggestive but far from definitive in using calcium channel blockers in the clinic.  As usual, more rigorous study is needed.

Prolonged QTc and Torsades de Pointes

Motivation: In the past few months, the most common EKG abnormality I have observed has been "nonspecific" ST-T wave changes.  Second to that has been mildly prolonged QT interval.  I often don't quite know what to do with a QT interval of 470 msec.  Does this mean that the patient does not get ondansetron? Or, should this QT interval lead to the reflex of K>4 and Mg>2?  The feared consequence of prolonged QTc is Torsades de Pointes.  What is the association between the degree of QTc prolongation and Torsades de Pointes?  The issue is complicated further by the fact that there is no good consensus on the definition of "normal." Conventionally, upper limit of normal for QTc is 450 msec for men and 470 msec for women.

This question turned out to be a lot harder to answer than anticipated.  There are not great prospective studies, but there have been reviews which have compiled cases of Torsades de Pointes and associated QTc intervals.

Paper:  Bednar, M.M. et. al. "The QT Interval" Progress in Cardiovascular Diseases. 43 (2001): 1-45 (supplement)

Methods: Data collected from 202 reports of Torsades de Pointes and prolonged QT interval.  Corrected QT interval was by Bazett formula.

Results:

QTc (ms)               TdP Cases (% of total cases)
<500                     9  (7.8)
500-549               13 (11.2)
550-599               24 (20.7)
600-649               36 (31.0)
650-699               21 (18.1)
>700                    13 (11.2)

Discussion: The results illustrate that while Torsades de Pointes from prolonged QTc is uncommon with QTc less than 500, the risk is not zero with mildly prolonged QTc (<500 msec).  The most commonly associated QTc interval with TdP is between 600-649 msec.  The patients who experienced QTc in the lowest QTc interval (<500 msec) may have had some inherited propensity for ventricular ectopy that was enhanced with mildly prolonged QTc.  Another explanation could be that the Bazett formula probably did not adequately correct the QT interval.  The Bazett formula overcorrects at faster heart rates and undercorrects at low heart rates.  Interestingly, Bazett proposed the formula after only examining 39 healthy patients.  An alternative way to calculate QTc is using an empirically derived formula from the Framingham study which used a much larger number of subjects (Pubmed ID: 1519533).  Anyway, in the future, I will think a little bit about risk of TdP in patients with QTc<500 and a lot more when QTc>500.

Eating during Times of Obstruction

Motivation: I used to believe in the maxim, "For SBO, keep NPO" meaning that for patient with small bowel obstruction, eating was forbidden. In fact, for decompression, the stomach should be suctioned out with an NG tube. Last month, while caring for patients with bowel obstruction, I came across papers that challenged this hegemony. They suggested that laxatives might even be beneficial in some cases of partial SBO. I asked around. Nobody uses laxatives in SBO. But, should we be changing out ideas?

Paper: Chen, S-C. et. al. "Specific oral medications decrease the need for surgery in adhesive partial small-bowel obstruction." Surgery (2006) 139: 312-316.

Methods: A randomized controlled trial in Taiwan comparing standard vs. novel treatment in patients with partial adhesive small bowel obstruction, defined by (1) history of intra-abdominal operation, (2) clinical signs and symptoms of SBO, and (3) passage of contrast to colon within 24 hours of administration. Standard treatment consisted of IV hydration, NG tube decompression, and NPO. Novel treatment was IV hydration, NG tube decompression, and oral solution containing magnesium oxide (laxative), Lactobacillus acidophilus (digestant), and simethicone (defoaming agent). The primary outcome tracked was success of non-operative management.

Results:
Patients: Total of 236 patients were randomized. Both groups were similar in terms of age, gender, and presenting symptoms (abdominal pain, distension, constipation, vomiting).

Comparison of treatments: Non-operative management success rates were less with standard approach (77%) compared to treatment with oral therapy (90%, p<0.01). In other words, more patients kept NPO required surgery. The complication and recurrence rates were not different between the two treatment arms.

Discussion: This randomized study challenges the traditional assumption that bowel rest is the best treatment for any type of small bowel obstruction. One important flaw in the study is that while the attending surgeon was blinded to allocation, the rest of the staff was not blinded. This may have introduced some bias into the decision making process. Otherwise, the study contradicts the main fear that giving PO during obstruction leads to excess complications. In fact, giving the oral regimen significantly improved chances of non-operative management success. Importantly, this study only examined partial SBO from adhesions (the most common cause of SBO). It is unclear whether diseases like Crohn's have different benefits from bowel rest. The next time I see partial SBO from adhesions, I will try to convince my attending to give this regimen a try!

From Heart Failure to Renal Failure - The Myth

Motivation: Ever since the week on heart failure in second year of medical school, I have been thinking about congestive heart failure (CHF) as consisting of "backup" symptoms like dyspnea and edema or "forward flow" symptoms like somnolence and fatigue.  One of the CHF exacerbation symptoms that I usually categorize under forward flow  is renal failure.  The presumed explanation for renal failure is relative renal hypoperfusion from decreased cardiac output in acute CHF exacerbation.  Recently, I learnt about some trials that challenged this view.  Here is one of the trials:

Paper: Nohria, A., et. al. Cardiorenal Interactions: Insights From the ESCAPE Trial. J. Am. Coll. Cardiol.(2008) 51: 1268-74.  http://content.onlinejacc.org/cgi/content/full/51/13/1268

Methods: The ESCAPE trial was a randomized trial comparing pulmonary artery catheter versus clinical volume assessment based treatment for acute heart failure exacerbation.  Included patients had LVEF<30% with SBP<125 mmHg with signs and symptoms of acute heart failure.  Patients with baseline creatinine >3.5 mg/dL  were excluded.  The current paper was an ad hoc analysis of baseline hemodynamic parameters from pulmonary artery catheter measurements and serum creatinine.

Results:
Subjects: In general, the mean age of the patient group was 56 with serum creatinine of 1.5.  Most of the patients were getting an ACE-I/ARB and beta-blocker.

Hemodyamic Correlation: There was no correlation between baseline serum creatinine or estimated GFR and cardiac index, systemic vascular resistance, or wedge pressure!  There was a weak but significant correlation between baseline serum creatinine and right atrial pressure (r = 0.165, p = 0.03).  Similar correlation was found between baseline estimated GFR and right atrial pressure (r = -0.195, p = 0.01), meaning higher right atrial pressures were correlated with decreased GFR.

Discussion: This paper clearly calls into question the assumption that renal dysfunction from acute heart failure is directly linked to renal hypoperfusion.  Renal failure seen in acute heart failure is being increasingly called the "cardiorenal syndrome" in recognition of the more complex pathophysiology.  Rather than renal arterial hypoperfusion, this trial along with other evidence suggests that elevated venous pressures may directly compromise renal function.  One of the problems in extrapolating from trials like this is the complexity of interacting factors.  The patients in this trial were sick and being treated with multiple agents like beta-blockers and ACE-I/ARB that also affect the renal vasculature.  But, these pharmacologic confounders would be expected to affect vascular tone, and no correlation was found between  systemic vascular resistance and renal dysfunction either.  Besides the effects of elevated venous pressure, other possible explanations for renal dysfunction include undefined direct toxic effects of therapeutic agents.  Also, many processes that worsen CHF, like HTN and diabetes, also have pathologic effects on the kidneys.  In the coming years, we will likely learn more about the complex pathophysiology of cardiorenal syndrome!  

Maddrey, Lille, and Alcohol

Motivation: Compared to hospitals in Baltimore, hospitals in Boston - in my brief experience- appear to get fewer patients with poly-drug abuse but just about the same number of patients with alcohol abuse.  In particular, over the past few months, I have met many patients with alcoholic hepatitis.  Some have died while others have walked out of the hospital against medical advice to the nearest bar.  To distinguish who is likely to get very ill, the Maddrey's Discriminant Function is generally used with severe alcoholic hepatitis defined as a score more than 32 or presence of encephalopathy.  Patients with severe alcoholic hepatitis have significant mortality benefit from early steroid treatment.  Recently, a French group developed a scoring system called the Lille Model, which seeks to better identify patients with poor prognosis even after steroid treatment.  How good is the French system?

Paper: Louvet, A. et. al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology (2007) 45: 1348-54.

Methods: To identify prognosis in patients with severe alcoholic hepatitis, the study was carried out in two stages.  In the "exploratory" stage, patients with severe alcoholic hepatitis were treated with prednisone 40 mg or IV 32 mg methylprednisolone for 28 days and followed for 6 months.  Severe alcoholic hepatitis was defined as discriminant function [4.6*(pt's PT-control PT) + Tbili] >=32 or presence of encephalopathy.  The derived model was verified on another "validation" cohort with severe alcoholic hepatitis treated with steroids.

Results:
Survival: In total, 320 patients with severe alcoholic hepatitis were included in the "exploratory" cohort.  Survival at one, two, and six months were 86%, 77%, and 65%.  The mean Maddrey Discriminant Function score was 47.5.

Relevant Parameters: In univariate analysis, parameters which are predictive of worse survival outcome after six months are: 1) Age (lower is better), 2) albumin (higher is better), 3) renal insufficiency, 4) difference in bilirubin levels between day 0 and day 7 of treatment, 5) PT time, 6) bilirubin at day 0.  These parameters were then incorporated into a complicated formula called the Lille Model that gives a score between 0 and 1 with higher scores indicating increased probability of death.

Validation and Comparison: 118 patients with severe alcoholic hepatitis requiring corticosteroids were enrolled and followed.  The validity of the model was measured in terms of area under the receiver operating characteristic (AUROC), which is a measure of the performance of the test (basically tests sensitivity versus specificity under varying cutoff scores).  The Lille Model, when compared to other models as indicator of survival at six months, was a better predictor of survival than Discriminant Function or MELD score at presentation.

Number to Remember: The authors next identified a Lille Model score that had the most predictive value for death at six months (optimum balance between sensitivity and specificity).  The optimum value is obtained at Lille Model score of 0.45. Patient with Lille score more than 0.45 had average 6 month survival of 25% compared to average six month survival of 85% for those with scores under 0.45.

Discussion: The Lille Model takes the prediction algorithms one step further.  Currently, the discriminant function just identifies who has severe alcoholic hepatitis and who does not.  With the Lille Model, the likely clinical trajectory of the patient can be more accurately predicted.  Patients with Lille scores above 0.45 have a very high mortality rate that is at times hard to recognize early on!  Hopefully, adjunctive therapies in these patients (like pentoxyfillene) can make a difference.   To me, the most important lesson from the paper is that patients with severe alcoholic hepatitis are potentially very sick.  Even with corticosteroid treatment, about a third will die in six months.  So, recognition of the disease severity and timely treatment are key. 

SIADH and Uric Acid

Motivation: In my brief experience as an intern, most patients predictably have two conditions.  One is a mild anemia (which implies, of course, that you need to have ordered iron, ferritin, folate, and B12 before morning rounds).  The second condition is hyponatremia.  I am not talking about sodium level of 120 but rather about the sodium level of 131.  Since the causes of hyponatremia are so many, there is often no good reflex testing to click.  I was recently told that uric acid is often low in hyponatremia from SIADH.  How sensitive is hypourecemia for hyponatremia?

Paper: Beck, Laurence, "Hypouricemia in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone".  NEJM (1979) 301: 528-30.

Methods: A single person review of records of patients examined by the author (in the grand old tradition).  Over a period of 18 months, patients with hyponatremia (defined as less than 130 mM) without renal failure (Cr<2.0) and not on diuretics were included in the study.  Patients were labeled as having SIADH if they had serum osmolality less than 270 mOsm with urine osmolality greater than 250 mOsm.  Also excluded were patients who were overtly hypervolemic (judged by edema), hypovolemic, or had signs of glucocorticoid deficiency.

Results:
Subjects: In the 18 month period, 49 patients were evaluated for hyponatremia. 19 patients were excluded for lack of uric acid measurement. Seventeen patients met criteria for SIADH wile the remaining 13 patients had euvolemic hyponatremia without SIADH.

Uric Acid Levels: The mean uric acid level in patients with SIADH was 2.9 mg/dL while the patients in the other group had mean level of 7.7 mg/dL (p<0.001).  Only one patient with SIADH had uric acid level greater than 4 mg/dL.  All patients without SIADH had uric acid concentration greater than 5 mg/dL.  In seven patients with SIADH, when fluid restricted, uric acid levels rose to a mean level of 5.2 mg/dL from previous mean of 2.8 mg/dL.

Clearance of Uric Acid: In three patients, clearance of uric acid was measured by 24 hour urine collection.  During periods of hyponatremia from SIADH, the uric acid clearance was increased compared to period after water restriction indicating that overexcretion rather than underproduction was the cause of hypouricemia.

Discussion: The paper is old with many weaknesses like few subjects and lack of testing for hypothyroidism, but this is one of the original papers showing the utility of uric acid measurement in distinguishing SIADH.  One of the key points is that in both hypovolemic and hypervolemic hyponatremia, uric acid is generally expected to be normal or higher than normal.  This paper showed that in euvolemic hyponatremia, SIADH can generally be distinguished from other causes (the paper does not investigate the "other" etiologies) by measuring uric acid levels.  What was so remarkable was the degree of difference in mean uric acid levels among patients with SIADH (mean of 2.9 mg/dL) and those with other causes (7.7 mg/dL).  These findings have been replicated in some subsequent studies (though none have very large number of subjects).  From now on, I think that uric acid level is a great test to send overnight to investigate euvolemic hyponatremia.  

Beta-Blockers in Acute Heart Failure

Motivation: When a patient is admitted with acute heart failure and laboring to breathe, I often debate whether or not to continue the home metoprolol.  In chronic heart failure, I understand the bit about beta-blockade having protective effects.  But, acutely, beta-blockers decrease heart inotropy resulting in decreased cardiac output and elevated left ventricular filling pressures - effects that are not helpful in acute heart failure.  Like so many things in cardiology, it turns out that there has been a randomized trial with a nice acronym (B-CONVINCED) that examines this issue.

Paper:  "B-CONVINCED: Beta-blocker CONtinuation Vs. INterruption in patients with Congestive heart failue hospitalizED for a decompensation episode." Jondeau, G. et. al. European Heart Journal (2009) 30: 2186-2192.

Methods: Randomized, controlled, open-labelled trial conducted in 36 centres in France.  Eligible patients were older than 18 on chronic beta-blocker therapy hospitalized for acute heart failure (including pulmonary edema) with left ventricular ejection fraction less than 40%.  Patients were excluded if found to have STEMI, bradycardia, or second-third degree heart block.  Patients who were initially judged to need dobutamine therapy were also excluded.  Intervention was continuation of home-dose beta-blocker therapy or discontinuation of beta-blocker for at least 3 days.  Primary endpoint was the general health and dyspnea at 3 days of hospitalization. 

Results:
Subjects: Analysis was performed in 147 patients (69 on BB therapy and 78 without BB).  There were no significant differences between groups including age, etiology (ischemic vs non-ischemic), ejection fraction, prevalence of atrial fibrillation, or home CHF treatment regimen.  The most common cause for acute exacerbation was non-adherence to therapy.  The beta-blockers most commonly used were bisoprolol (beta-1 blocker) 70%, carvedilol 11%, and atenolol 10%.  In the group on beta-blocker therapy, beta-blockers were stopped in four patients (three needed dobutamine and one had bronchospasm).

Hospital Courses: There were no significant differences in clinical features of heart failure (dyspnea, pulmonary rales, lower extremity edema, JVD, hepatomegaly) on the first 8 days of hospitalization (including day 3) between the two groups.  Patients without BB had higher heart rates :)  There were no differences in blood pressure during the course of hospitalization in the two groups.  No differences were observed in BNP levels either.  One death occurred in the BB group while two deaths occurred in the BB stopped group (difference not significant).

Long-term Follow-up: At 3 months, death rate and re-hospitalization rate were similar in both groups.  After 3 months, patients who were continued on beta-blockers were more likely to be receiving beta-blockers (90%) than those who had beta-blockers stopped (76%, p=0.04). 

Discussion: This paper shows that even during acute heart failure exacerbations, beta-blockers can be safely continued without adversely affecting rate of recovery.  On the other side of the fence, one can also say that this paper shows beta-blockers can be discontinued during hospitalization without affecting rate of recovery.  Between these two varying viewpoints, I would favor continuing beta-blockers since beta-blockers decrease myocardial ischemia and have proven anti-arrhythmic effect.  Also, as shown in the paper, once beta-blockers are discontinued upon hospitalization, the risk of beta-blockers not being restarted upon discharge increases.

While the paper demonstrates non-inferiority of continuing beta-blockers during acute heart failure, this trial has some important limitations.  First, the study was underpowered to detect potential benefit of beta-blockers in preventing arrhythmias during heart failure.  That part of the benefit of beta-blockers in acute heart failure remains speculative.  Also, in the study, the beta-blocker dosage was not standardized.  It is unclear if beta-blocker titrated to, for example, heart rate is beneficial in one dosage but detrimental at higher doses.   

Azithromycin for COPD

Motivation: During the first couple of months of internship, I have often taken care of patients with COPD, and in the morning presentations, the conversation inevitably turns towards the benefits of adding an antibiotic to the steroid regimen.  Macrolide antibiotics are thought to have additional anti-inflammatory benefits beyond the standard anti-microbial effects.  Recently, this hypothesis was extended further to test for beneficial effects of azithromycin in COPD patients as a standing drug in-between flares.

Paper: "Azithromycin for Prevention of Exacerbations of COPD", Albert, R.K. et. al. NEJM (2011) 365: 689-698.

Methods: A multi-centered, randomized controlled trial.  The trial included patients over 40 with a history of COPD (>10 pack year of smoking, FEV1/FVC<70%, and FEV1<80% of predicted value).  To the included in the study, the patients had to have either used systemic steroids or required ED/hospital care in the past 12 months.  Patients could also be included if using home oxygen.  The exclusion criteria were tachycardia, prolonged QTc, and hearing impairment.  The intervention was daily dose of 250 mg of azithromycin.  The primary outcome was the time to first acute exacerbation of COPD.  The follow-up period was one year.

Results: 
Patient Recruitment: Overall, 558 patients were in the treatment arm, and 559 patients were in the placebo group.  The completion rate was 89% in the treatment arm and 90% in the placebo group.  The treatment and placebo group did not differ significantly in terms of age, gender, race, disease severity, or home treatment regimens.

COPD Exacerbation: The median time to acute exacerbation was 266 days in the azithromycin group vs. 174 days in the placebo group (p<0.001).  A total of 741 exacerbations among 558 patients occurred in the azithromycin group while 900 exacerbations occurred in the placebo group (p=0.01).  The number needed to treat to prevent one acute exacerbation of COPD was 2.86.

Secondary Outcomes: There was not a statistically significant difference between the azithromycin and placebo groups in hospitalizations related to COPD (156 vs. 200, p =0.15), exacerbations requiring intubations (11 vs. 16, p=0.56), or hospitalization for any cause (323 vs. 329, p=0.52).  There was a trend towards decreased ED or urgent care visit (199 vs 257, p=0.09).

Adverse Effects: The rate of death was 3% in the azithromycin group and 4% in the placebo group (difference not significant).  The only adverse effect that occurred more frequently in the azithromycin group was audiogram confirmed hearing decrease (25% vs 20%, p=0.04).  At the end of the one year study, patients receiving azithromycin were also more likely to be colonized in the nasopharynx with azithromycin resistant organisms.

Discussion: The trial demonstrates that a daily standing regimen of azithromycin results in decreased number of total exacerbations.  While there is evidence that increased number of exacerbations results in increased morbidity and mortality, the trial was not sufficiently powered and did not have a long-enough follow-up time to demonstrate mortality benefits or decreased hospitalizations.  I think that showing a mortality benefit or showing decreased hospital stays would have made this trial much more significant.  There was an interesting side effect of increased hearing loss in a sizable minority of patients.  The data presented in the paper though is unclear about the magnitude of hearing loss.  A little bit might be tolerable while total deafness is likely not.

In summary, if a patient keeps coming back with repeated exacerbations of COPD, a standing regimen of azithromycin might be the next medicine for them!

Magnesium for Torsades

Motivation: The standard ACLS catechism is that: "If you see torsades de pointes, give magnesium."  During the ACLS protocol, torsades is, I think, the only point where magnesium enters into the algorithm.  While supplementing someone with mag the other day, I wondered what the evidence was for use of magnesium in torsades and other rhythms.  I was a bit surprised to learn that the ACLS guideline for torsades is based mostly on two (quoted from the official ACLS publication) observational studies.  The major study in Circulation appeared in 1988 and is reviewed here:

Paper: "Treatment of torsade de pointes with magnesium sulfate" Tzivoni, D. et. al. Circulation (1988), 77: 392-397.

Methods: An unblinded, uncontrolled study in which 12 consecutive patients who developed torsades de pointes (TdP) with QT prolongation were treated with magnesium (2g IV bolus over 1 to 2 minutes followed in most patients with a continuous infusion).  Five additional patients with polymorphic ventricular tachycardia with normal QT interval were also treated with magnesium.

Results:
Patients: Of 12 patients with TdP (10 men and 2 women) and prolonged QT, six had ischemic heart disease, two had valvular rheumatic heart disease, two had atrial arrhythmia, and two did not have known heart disease.  Nine of the twelve patients were also on antiarrhythmic therapy.  The mean corrected QTc was 640 msec.  The five patients with polymorphic VT with normal QT interval who received magnesium all had chronic ischemic heart disease.

Patients with prolonged QTc: In nine of the twelve patients, a single bolus of magnesium stopped TdP.  In the other three patients, TdP was stopped after second Mag bolus.  In eight of 12 patients, potassium levels were below 3.5, which was repleted with oral and intravenous potassium.  The mean QTc did not change after magnesium bolus.  Magnesium levels were available in eight patients, and all were normal.

Patients without prolonged QTc: In the five patients with polymorphic ventricular tachycardia, none responded to multiple boluses of magnesium.

Discussion: One of the major points of the paper for me is that sometimes amazing results trump poorly designed studies.  Most of the patients had multiple confounders, including hypokalemia and concurrent anti-arrhythmic administration, but achieving a 100% response rate really makes this paper landmark.  And, really since the publication of the paper, magnesium has become the standard therapy of choice for TdP.  There were a couple of other interesting points in the paper as well.  The first is that not every polymorphic ventricular tachycardia responds to magnesium - only polymorphic v-tach in patient with prolonged QTc can be properly called TdP.  Also, while magnesium bolus is key, the precipitating factor for TdP is not hypomagnesemia since magnesium levels were normal.  Finally, repleting potassium and other electrolytes are pretty important too! 

The Flutter-Fibrillation Spectrum

Motivation: Every time I encounter a patient with atrial flutter and hard to control ventricular rates, I wonder why the patient is on the floor and not in an electrophysiology suite. I mean, why should we spend time titrating diltiazem when the ablation procedure (ablation of cavo-tricuspid isthmus) has more than 90% success rate.  In fact, general guidelines state that in contrast to a-fib, for patients with recurrent atrial flutter, ablation should be the first-line approach rather than rate control.  Ablation, however, is not a good long-term fix if patients with atrial flutter also develop atrial fibrillation, which does not respond well to ablation.  I have at times heard of the "flutter fibrillation spectrum." But, how often do patients with atrial flutter actually develop atrial fibrillation in the future?

Paper: "Risk of Stroke in Patients with Atrial Flutter", Biblo, L.A. et. al. Am. J. of Card. (2001) 87: 346-349.  http://www.ncbi.nlm.nih.gov/pubmed?term=11165976%20

Methods: In this large retrospective study, the authors scanned Medicare inpatient files in 1984 for patients older than 65 who were diagnosed with atrial flutter or atrial fibrillation without stroke.  For control, a 5% random sample of other hospitalized patients were chosen without atrial flutter or fibrillation.  Patients were followed for 8 years.  The primary endpoints assessed were incidence of stroke and incidence of atrial fibrillation in patients with atrial flutter.

Results:
Subjects: The study followed 17,413 patients with atrial flutter, 337,428 with atrial fibrillation, and 395,147 controls.

Atrial Flutter to Fibrillation Incidence: Patients with atrial flutter developed atrial fibrillation in an almost linear fashion over the 8 year follow-up period.  By about 6.5 years of follow-up, half of the initial group of patients with atrial flutter had developed an episode of atrial fibrillation.  The top three factors which predicted which patients would develop fibrillation were rheumatic heart disease (Risk Ratio: 1.464, CI: 1.250-1.715)., systemic hypertension (RR: 1.333, CI: 1.267-1.402), and congestive heart failure (RR: 1.243, CI: 1.174-1.316).

Stroke Risk: After adjusting for known risk factors like hypertension, CHF, rheumatic heart disease, DM, and MI, the stroke risk in patients with atrial flutter was greater than controls (RR: 1.406, p < 0.0001).  The adjusted stroke risk in patients with atrial fibrillation (RR: 1.642, p < 0.0001) was greater than those with atrial flutter.  Importantly, the stroke risk for patients initially with atrial flutter with new onset atrial fibrillation was not significantly different from the stroke risk in patients with atrial fibrillation.

Discussion: I think that this paper nicely illustrates why it is hard to manage atrial flutter.  Patients with atrial flutter are at significant risk for atrial fibrillation (about half have atrial fibrillation by about 6.5 years of follow-up).  In these patients, going through ablation is questionable since a-fib requires rate-control and anti-coagulation regardless.  On the other hand, for the half of patients who do not develop a-fib by seven years, conversion to sinus rhythm through ablation would save them many years of hazards of warfarin anti-coagulation.  I think that it is still unclear exactly which subgroup benefits most from ablation.  Likely as suggested by the paper, patients with additional risk factors like HTN, CHF, and rheumatic heart disease are likely to go on to develop a-fib.  Another point underscored by the paper is that while both atrial flutter and fibrillation have elevated stroke risk, patients with atrial fibrillation are at higher risk than those with flutter.   Finally, while the paper is impressive in the large number of subjects tracked, the paper is retrospective in nature and only examines patients older than 65.   Also, I have some doubts about how accurately atrial flutter/fibrillation is coded during hospitalizations (!).

Looking for Tall P Waves

Sorry for the delayed post. Internship was a bit busy last week, but I will post more regularly.  Contributions also welcome!


Motivation: "Right is height" - this is a phrase often used to describe the EKG changes caused by right atrial enlargement.  But, late last week, while listening to a lecture on EKG and description of P pulmonale, I wondered just how reliable is this sign.  Or, are there other better signs of RA enlargement? For background, right atrial enlargement is classically characterized on the EKG by "P pulmonale" or P wave height greater than 2.5 mm in lead II.

Paper: Evaluation of Electrocardiographic Criteria for Right Atrial Enlargement by Quantitative Two-Dimensional Echocardiography. Kaplan, J. D. et. al. J Am. Coll. Cardiol. (1994); 23:747-52. http://www.ncbi.nlm.nih.gov/pubmed?term=8113560%20

Methods: EKGs of hospitalized patient with mild to severe right atrial enlargement on echo were randomly selected and compared against EKGs of age and gender matched healthy controls.  There were 100 patients with right atrial enlargement and 25 control patients.  EKG were interpreted independently by two cardiologists using calipers and magnifying glasses.

Results:

Cohorts: Of the patients with right atrial enlargement, 52 were in sinus rhythm, 41 were in atrial fibrillation, 5 were in atrial flutter, and 2 in ectopic atrial rhythm.  All controls were in sinus rhythm.  Right atrial enlargement was most commonly associated with tricuspid regurgitation (30%), pulmonary hypertension (28%), and cardiomyopathy (14%).

EKG criteria:

1. P wave height>2.5 mm in lead II (P pulmonale), sensitivity: 6%, specificity: 100%
2. QRS axis > 90 degrees, sensitivity: 34%, specificity: 100%
3. P wave height>1.5 mm in lead V2, sensitivity: 33%, specificity: 100%
4. P wave height>1.5 mm in lead V1, sensitivity: 17%, specificity: 100%
5. R/S ratio > 1 in lead V1 (without RBBB), sensitivity: 24%, specificity: 100%
6. QRS amplitude <6 mm in lead V1, sensitivity: 33%, specificity: 92%

Discussion: The most interesting result of the paper, I thought, was the finding that P pulmonale is very insensitive finding though quite specific.  In fact, with the same specificity, we can look with better sensitivity at the P wave height in V2 to determine right atrial enlargement.  Another interesting finding was that often the most sensitive findings relate more to right ventricular enlargement (like QRS axis > 90 or R/S ratio >1 in V1).  Surprisingly, the specificity of this finding, was quite high meaning that almost all people with right ventricular hypertrophy have right atrial enlargement.  Thus, RV enlargement is a surrogate marker for RA enlargement.

This paper, however, has some important limitations.  First, there were 25 controls to match against 100 patients.  A few more controls would have been more desirable to capture the full range of normal.  A higher number of controls would likely have driven down the "100%" specificity of some of the findings.  Secondly, of the 100 patients with right atrial enlargement, only 52 were in sinus rhythm.  So, for findings relating to P wave morphology, the number of subjects was limited.  Overall, I think that the main points to take away are that P pulmonale has low sensitivity and RV hypertrophy can be used as a surrogate marker for RA enlargement.

The Nitro Cure

Motivation: In my first week of internship, I have seen more urinary tract infections than just about anything else.  The first treatment response for uncomplicated UTI is a three day course of Bactrim, but what happens when the patient either is allergic to Bactrim or has resistant bacteria? The second choice has been ciprofloxacin.  But, flipping open UpToDate the other day, I read to my surprise that nitrofurantoin is the recommended first line agent after Bactrim.  The issue got even more complicated when the venerable Goodman & Gilman's claimed that nitrofurantoin should be a second line agent.  So, what are the data and recommendations?

Paper: Trestioreanu, Z. et. al. Antimicrobial agents for treating uncomplicated urinary tract infection in women. Cochrane Database Syst. Rev. (2010) 10:CD007182. http://www.ncbi.nlm.nih.gov/pubmed/20927755

Methods: A meta-analysis of randomized trials with the objective of comparing the efficacy and safety of different empiric antibacterial treatments for acute, uncomplicated UTI in healthy women aged 16-65 years.  The primary outcomes were short (2 weeks) and long term (8 weeks) symptomatic cures.

Results:
Fluoroquinolone vs Bactrim: Both fluoroquinolones and Bactrim are equally effective as empiric therapy for UTI  in the short (CI: 0.97-1.03) and long term (CI: 0.94-1.05) .  Overall, there is no difference in adverse effects among the two agents, but patients treated with fluoroquinolones are less likely to develop rash (CI: 0.01-0.43).

Nitrofurantoin vs Bactrim: Both nitrofurantoin and Bactrim are equally effective for UTI treatment in the short (CI: 0.95-1.05) and long term (CI: 0.94-1.09).  Overall, no difference in adverse effects for the two agents, but patients treated with nitrofurantoin were less likely to develop rash (0.04-0.76).

The meta-analysis did not find sufficient studies to compare nitrofurantoin to fluroquinolone head-to-head.  The analysis went on to further describe efficacies of beta-lactams (which are not summarized here).

Discussion: The surprising fact of the matter is that there are generally no differences in efficacy when treating UTI empirically with fluoroquinolone, Bactrim, or nitrofurantoin.  The decision to promote Bactrim stems more from a public health perspective since resistance to fluoroquinolones is increasing.  Decreased prescription of fluoroquinolones would presumably decrease generation of resistant bacteria.  In empiric treatment of uncomplicated UTI, nitrofurantoin is an excellent alternative to Bactrim and less likely to generate the adverse effect of rashes.  Overall, both Bactrim and nitrofurantoin have equivalent severity of side-effects and equivalent efficacy.  Of note, however, this meta-analysis examined uncomplicated UTI in unhospitalized patients, and the data might be different in hospitalized patients with Foley catheters in place!

Treating a Hiccup

Motivation: Last Sunday evening, I was crouching before a window in a dim room watching the dying sun and tracing uneasy thoughts about end of summer break and impending residency.  My solemn reverie was suddenly interrupted by high pitched sounds.  My brother had been struck by a bout of hiccups - incessant hiccups.  I called out for him to stop or restrain himself.  He shot back that since I was now a doctor, I could at least tell him how to stop hiccups.  I did not know.  I lost the argument.  Well, how do you treat hiccups?

As background, a hiccup - or the medical term singultus - is a sudden inspiration ending with sudden glottic closure.  There is no known physiological reason for hiccup!  The most common cause of hiccups is gastric distension.  The hiccup reflex arc has afferent nerve pathways of phrenic and vagus nerves, central mediator in the brainstem, and efferent pathways involving the phrenic nerve.  Thus, irritation at any point in the pathway from thoraco-abdominal pathology to CNS neoplasms can give rise to hiccups.  Hiccups lasting more than 48 hours are termed persistent while hiccups lasting longer than a month are called intractable.  Traditional pharmacotherapy of hiccups involves the antipsychotic chlorpromazine though the literature is thin on evidence.  But, given the side effects of chlorpromazine, alternative therapy is needed.  Recently, gabapentin was tried.

Paper: Porzio, G. et. al. Gabapentin in the Treatment of Hiccups in Patients With Advanced Cancer: A 5-Year Experience.  Clinical Neuropharmacology (2010) 33: 179-180.  http://www.ncbi.nlm.nih.gov/pubmed/20414106

Methods: This study was conducted in Italy on patients with advanced cancer in two settings: (1) a palliative in-patient care unit and (2) home comfort care service.  Patients were assessed for presence of persistent (>48 hours) hiccups that were rated at least 7 out of 10 in the patient's subjective assessment of severity of hiccups (10 means worst hiccups of life).  These patients were treated with gabapentin (300 mg thrice daily) with titration according to response.

Results:
Patients:  In the palliative in-hospital service, 37 of 944 patients (3.9%) had severe hiccups.  In the home care setting, 6 of 134 patients (4.5%) had severe hiccups.  Most patients (31/43) had advanced abdominal cancers.  The rest had advanced cancers from other locations.

Gabapentin result: After gabapentin administration, of the 37 inpatients, 31 experienced complete resolution while 4 had improvements.  Two end-stage patients on midazolam therapy experienced worsening of hiccups.  Among the 6 home care patients, 4 had complete resolution while the other 2 had improvement.  The maximum used dose of gabapentin was 1200 mg/day.  The most common side-effect was transient drowsiness.

Discussion: The paper in its design and power has many limitations, but it does demonstrate some remarkable results.  Among the 37 in-patients with severe hiccups, 35 (>90%) had improvements in hiccups, and the majority experienced complete resolution!  Another benefit of gabapentin over current therapy with chlorpromazine is that the only major side effect of gabapentin (in this trial) is transient drowsiness.  The paper, of course, has many limitations.  There was no placebo arm to the intervention, and the trial was unblinded.  So, the observed effect could be entirely a placebo response or an observer bias.

Despite the fact that about 4% of patients with advanced cancers are afflicted with severe hiccups decreasing quality of life, there have not been large randomized trials conducted for treatment of hiccups.  The future for hiccups trials does not appear too bright either.  This prospective design may be the level of the quality of data that is going to be available for some time.  So, if I had to treat hiccups, I would probably try gabapentin first given the tolerable side-effect profile of the drug.

To Salt and Death

Motivation: Last week, I eavesdropped on the subway.  Two old men were joking about their health when one man remembered recently hearing on the news that eating less salt kills you.  The other guy did not believe him. I did not believe him.  But, after flipping out my phone, a quick search of Google News revealed many recent articles stating exactly that.  Also, the articles cited a May issue of the authoritative journal JAMA.  We know that eating more salt results in increased blood pressure in the short term but does eating less salt really kill you in the long run?

Paper: Fatal and Nonfatal Outcomes, Incidence of Hypertension, and Blood Pressure Changes in Relation to Urinary Sodium Excretion.  Stolarz-Skrzypek et. al. JAMA (2011) 305: 1777-1785.  http://jama.ama-assn.org/content/305/17/1777.abstract

Methods: In this prospective study, European patients older than age 20 were recruited who did not have diagnosed cardiovascular disease at baseline.  On initial exam, a 24-hour urinary sample was collected for sodium excretion measurement (to reflect total sodium consumption).  Baseline measurements were obtained in 3681 patients, who were followed for mortality and morbidity.  A smaller subset of 2856 patients agreed to undergo follow-up exams.  Of these patients, a cohort of 2096 patients were followed for development of hypertension (760 already had hypertension at baseline).  A third cohort of 1499 patients were followed with serial urinary sodium measurements to establish a relationship between blood pressure and urinary sodium excretion - these patients were untreated with any antihypertensive medications.

Results:
Patient selection: Overall, the cohort had 52.7% women, and all participants were white.  The mean age was 40.9 years with smoking rate of 28.4% and alcohol intake (>5g/day) rate of 24.1% .  At baseline, average BP was 124.7/76.3 and total cholesterol was 209 mg/dL.

Salt and Death: The authors divided the patients into three groups based on urinary sodium excretion: low sodium excretion (1220 patients), medium (1250), and high (1211).  In the cohort, 219 patients died.  After adjusting for other variables like age, sex, smoking, drinking, diabetes, cholesterol, and educational attainment, the hazard ratios for all mortality in the three groups (from low to high) were: 1.14, 0.94, and 1.06 (p = 0.10).  For cardiovascular deaths, there were 84 events.  The adjusted hazard ratio in the three groups from low sodium to high sodium were: 1.56 (CI: 1.02-2.36), 1.05 (0.72-1.53), and 0.95 (0.66-1.38), p = 0.02.  The trend for non-cardiovascular deaths were not significant.

Cardiovascular Events:  The rates of coronary events, strokes, and all cardiovascular events across the three sodium groups were not significantly different.

Incidence of Hypertension: The baseline levels of urinary sodium levels were not predictive of incidence of hypertension.  Incidence of hypertension was about 25% in all groups.

Sodium to Blood Pressure Levels: Systolic blood pressure was positively correlated with 24 hour urinary sodium excretion.  A 100 mEq/L increase in sodium excretion resulted in only 1.14 mm Hg increase in systolic blood pressure (!).  Diastolic pressure was unaffected by sodium excretion levels.

Discussion: In summary, I think that this paper is an excellent example of data that ought to be consumed with caution and probably not fit for broad sweeping popular media coverage.  This study has several important limitations.  First, the study design is prospective meaning that while we may see associations between urinary sodium levels (and presumably sodium consumption) and medical endpoints, it would be hard to infer causality.  For example, why do some people consume less sodium?  Other than trying to be healthy, the people eating less sodium may have been poorer or may have other habits like strenuous jobs that prevented them from eating.  The study did not really adjust for socioeconomic status.  Also, the study population was relatively young (average age 40.9 years).  In a younger cohort, other factors like genetics may be more important than dietary habits.  Finally, many patients (259) were lost to follow-up.

The most provocative point in the paper is the weak association shown between decreased sodium consumption and increased cardiovascular mortality.  The association is weak with a few events (10 events in the high sodium excretion group).  While the point is interesting, I think that it would be a stretch to say that decreased sodium consumption increases mortality.  There are many confounding variables that could affect the result, and this study probably calls for a randomized intervention trial.  Finally, the other point that I found interesting is that the incidence of hypertension did not differ among groups with varying sodium consumption.  This may suggest that while sodium consumption affects blood pressure, primary hypertension may not be caused by sodium indiscretion.

PS:  In case you are still reading, there have been some items in the news that were reviewed in this blog.  1) Fidaxomicin was recently approved by FDA as a new drug for treating C. difficile.  The drug was reviewed by Haoming here.  2) There has been a lot of buzz recently about cell phones and cancer.  The topic was reviewed in this blog here by me last year.

NSF - how real?

Motivation: A few months ago, I was lounging in the neurology office when someone called to ask about the possibility of brain MRI with contrast in a patient with kidney disease.  The resident answered, "Of course, not!"  After all, gadolinium based agents have been implicated in nephrogenic systemic fibrosis (NSF).  When the resident placed the phone on the cradle, a fellow in the room smirked and remarked that our fear of NSF is overblown.  He explained that cases of NSF occur rarely and that fear of litigation probably drove our prohibition.  Well, just how common is nephrogenic systemic fibrosis after gadolinium contrast exposure?

For background, nephrogenic systemic fibrosis was first described in 2000 and is clinically characterized by thickening and hardening of skin with "brawny" hyperpigmentation especially of the extremities.  Patients experience neuropathic pain in affected areas and suffer from flexion contractures and pressure ulcers.

Paper: Association of Gadolinium Based Magnetic Resonance Imaging Contrast Agents and Nephrogenic Systemic Fibrosis.  Bhave, G. et. al. The Journal of Urology (2008) 180: 830-835. http://www.jurology.com/article/S0022-5347(08)01225-1/abstract

Results: 
Number of known cases: The largest case registry for NSF (Yale NSF case registry) contains about 200 cases. Adding all other reported cases, at the end of 2006, there were at most 400-500 cases of NSF worldwide.

Relation to Kidney Disease: No case of NSF has been described for GFR greater than 30 mL/min.  Cases which seemingly involved patients with GFR > 30 mL/min are likely due to calculation error since in acute kidney failure, serum creatinine levels do not instantaneously reach steady state and give rise to errors in GFR estimation.

Link with Gadolinium Exposure: More than 95% of known cases of NSF have had gadolinium exposure in the weeks to months prior to presentation.  A very small minority of putative NSF cases have not had gadolinium exposure.  The upper limits of lag times from gadolinium exposure to NSF are about 1-2 years.

Incidence after Gadolinium Exposure: In single center cohorts, the proportion of patients with kidney failure developing NSF after gadolinium exposure is about 2-5%.  The authors challenge this assumption based on a simple calculation.  Before 2000, there were no restrictions on gadolinium administration.  In the ten prior years, there were 50 million MRI contrast studies, and given the 0.1% prevalence of end stage renal disesaes (ESRD) in the U.S., there have been conservatively about 50,000 MRI contrast studies performed in patients on ESRD.  Given that there are at most 500 known cases of NSF, the incidence is likely no more than 1% after gadolinium exposure in patients in ESRD.


Discussion: In summary, NSF is a rare but real danger.  What I thought was an especially valuable point to keep in mind is that in cases of acute kidney failure, the serum creatinine level is an imperfect measure, and the working assumption ought to be perhaps that gadolinium is contraindicated despite seemingly permissive creatinine levels.  On the flip side, radiologists are hesitant to administer gadolinium in patients with GFR<60 mL/min but greater than 30 mL/min.  There have been no reported cases of NSF in this group, and this cautious approach may be excessive and needs to be reevaluated. 


Finally, is there any way to prevent NSF? From a pathophysiology viewpoint, gadolinium ion is toxic to human beings, and contrast agents consist of gadolinium chelated to other molecules to facilitate excretion and limit exposure of tissue to gadolinium ions.  In renal failure, with prolonged exposure, gadolinium is lost from chelation and produces toxic effects.  In the future, the thought is that with stronger chelating molecules, we may be able to further limit gadolinium loss from chelation and prevent toxic effects before excretion through dialysis or urination.

New Weapon in the Fight Against C.Diff

Introduction

Throughout my medical school career, there are many things, both good and bad which I will never forget, among them is the pungent odor of a C.difficile infection. Its an unmistakable stink which brings back memories of awkwardly trying to write a note or perform a physical exam while wearing one of those big yellow isolation gowns. C. diff's unshakable presence in our hospitals is only expected to get worse as our careless over-use of antibiotics creates more opportunities for c.diff to out compete the normal colonic flora.

Traditionally, C.diff infections have been treated with Flagyl firstline and Vancomycin for those who failed Flagyl or have fulminant disease. However, due to increasing resistance to Flagyl, Vancomycin is rapidly becoming the only effective drug for many patients. However, even Vancomycin sometimes cannot eliminate this nasty critter causing patients to relapse almost as soon as they leave the hospital. The result is chronic, uncontrollable malodorous diarrhea that can destroy a patient's quality of life and create nightmares for hospital infection control and cost billions of dollars for our health care system.

However, hope is on the horizon with a new antibiotic -Fidaxomicin, which has recently completed phase 3 trials. Fidaxomicin is a macrolide antibiotic produced by Optimer Pharma which has shown higher in vitro activity against c.diff than vancomycin. In an article published in February of 2011 in the NEJM, Louie et al. present results from a phase III trial involving 629 patients.

Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364(5):422-31.Methods: Patients were selected whom had diarrhea for 24 hours and either c.diff toxin A or B.

Patients could have received up to 4 doses of Flagyl or Vanc but no other therapy in the 24 hrs before randomization. Patients with fulminant c.diff or >1 recurrence of c.diff in the past 3 month were excluded. Patients were randomized to a 10 day course of either 200mg of Fidaxomicin q12h or 125mg of Vanc q6h. Patients were stratified according to whether this is their first or second episode of c.diff. All patients were followed for at least 28 days following the end of treatment.

Outcomes measured were:

1. clinical cure defined as cessation of diarrhea and no need for additional treatment.

2. Treatment failure was defined as continuation of diarrhea or need for additional therapy.

3. Global cure was defined as no recurrence within the 28 day follow up after end of therapy.

Patients were analyzed as modified intention to treat if they took at least one dose of medication.

Results:

A total of 596 patients were analyzed in the modified intention to treat analysis of which 92% actually adhered to the protocol. They did not differ in baseline characteristics.

Figure 1. mITT=modified intention to treat, PP=per protocol.

As shown in figure 1. Fidaxomicin was as equally efficacious as vancomycin in achieving clinical cure (resolution of diarrhea, no need for additional Rx). However, it achieved a 40% relative reduction in recurrence compared to vancomycin (absolute rate reduction of recurrence from 25% to 15%) (p=0.005).

s shown in Figure 2, in subgroup analysis, Fidaxomicin was superior to or as equally efficacious as Vancomycin at controlling C.diff recurrence in almost every subgroup save for 1. This subgroup comprised of patients with a certain genotype of c.diff known as NAP1/B1/027. For this group, fewer patients had relapse of c.diff after vancomycin treatment (21%) compared to fidaxomicin (27%) however this difference was not statistically significant.

Figure 2.

Safety wise, the rate of adverse and serious adverse reaction was similar in patients treated with Fidaxomicin or Vancomycin.

Discussion:

C.diff is a particularly difficult disease to treat (hence the name) because it is resistant to so many different antibiotics and because even successfully treated patients recur as much as 30% of the time within 60 days. More worryingly, strains of c.diff are becoming resistant to our two current standards of care: Vanc and Flagyl.

Louie et al. show in this study that Fidaxomicin is as efficacious and safe as vancomycin in treating acute infections of c.diff and perhaps more effective at eliminating recurrences. In addition, Fidaxomicin was previously shown to have poor system absorption through the GI tract, a positive attribute because it increases the concentration of the drug which actually reaches the colon after oral administration and also decreases systemic side effects.

The only wrinkle in all of this good news is that the 36% of patients with an aggressive strain of c.diff BI/NAP1/027 do not seem to obtain any additional reduction in recurrence with Fidaxomicin as compared to vanc. This is worrying because patients with this strain of c.diff is the most in need of a better treatment option.

Overall however, fidaxomicin represents an important addition to our current inventory of Flagyl and Vancomycin for the treatment of c.diff.

Diagnosing PE by Blood Gas

Motivation: On an early morning at 5:30 am last winter, I was huddling with my surgery team waiting for our chief to arrive and start rounding.  In the haze of early morning stupor, I heard one of the residents mention that overnight someone was short of breath.  He had called one of his fellow surgical residents, who had advised him to draw a blood gas to rule out pulmonary embolism (PE).  One of the other members of the team was about to say something when the chief arrived, and we cut short our talk to begin marching to the patient rooms.  But, I wondered how sensitive is an ABG with its characteristic signs of hypoxemia and hypocapnia in ruling out PE?

Paper: Diagnostic Value of Arterial Blood Gas Measurement in Suspected Pulmonary Embolism.  Rodger, M., et. al. Am. J. Respir. Crit. Care Med. (2000) 162: 2105-2108.  http://ajrccm.atsjournals.org/cgi/content/full/162/6/2105

Methods: For a 30 month period, consecutive patients (inpatient and outpatient) suspected of PE were subjected to a blood gas and D-dimer test.  Referring clinicians were then asked to provide a clinical gestalt of the likelihood of PE.  Subsequently, all patients underwent V/Q scanning.  For low probability V/Q scan with high clinical probability of PE or high probability V/Q scan with low clinical probability, patients were referred for pulmonary angiogram at the clinician's discretion.  Inclusion criteria for patients were essentially greater than 18 years of age with capacity for informed consent and physiological capability to undergo pulmonary angiogram if necessary.

Results: 
Patient Selection: In total, 246 patients were considered for PE.  In 49 patients, PE was accepted as the final diagnosis and ruled out in 163 other patients.  In 34 patients, the final diagnosis was unclassified.  These patients were not referred for angiogram by their clinicians but had either low probability V/Q scan with high pre-test likelihood or high probability V/Q scan with low pre-test likelihood.  The patients deemed unclassified were removed from further analysis.

Blood Gas Measurements: The clinical variable PaO2<80 mm Hg was present in 57.9% of patients with PE and 46.6% of patients without PE.  The clinical variable PaCO2<36 mm Hg was present in 44.4% of patients with PE and 39.7% of patients without PE.  Other clinical rule results are as follows:

• Abnormal (A-a) gradient- Sensitivity: 84.2%, Specificity: 27.4%, PPV: 27.4%, NPV: 84.2%
• D-dimer positive - Sensitivity: 83.0%, Specificity: 57.6%, PPV: 39%, NPV: 91.2%
• PaO2<80 mm Hg or D-dimer positive - Sensitivity: 91.9%, Specificity: 32.4%, PPV: 32.4%, NPV: 91.9%
• PaO2<80 mm Hg or D-dimer positive or Respiratory Rate>20 breaths/min - Sensitivity: 96.9%, Specificity: 21.3%, PPV: 30.7%, NPV: 95.0%
• PaCO2<36 mm Hg or Abnormal (A-a) O2 gradient - Sensitivity: 91.9%, Specificity: 14.7%, PPV: 25.6%, NPV: 85.0%

Discussion: To rule out PE, we ideally want clinical criteria with high sensitivity.  Individually, hypoxemia and hypocapnia have really poor sensitivities at 57.9% and 44.4%!  Calculating an abnormal alveolar-arterial gradient is a more sensitive indicator for PE, but the negative predictive value (84.2%) is still unacceptably low.  While evaluating the results, I was surprised to see that a D-dimer test was no more sensitive than an abnormal A-a gradient.  The D-dimer has the advantage of specificity rather than sensitivity over the A-a gradient.  If I were stuck on an island without radiology, I would choose the rule of PaO2<80 or D-dimer positive criteria to start ruling out PE though we would miss about 8% of pulmonary embolism cases.  With an estimated untreated mortality of 30%, such an approach would still be dangerous.  This study shows that at present, radiology remains an integral part of ruling out PE.

This study has some limitations.  Of the 246 patients originally included in the study, the diagnosis remained indeterminate in 34 patients.  Often these patients are the most troubling because they have a mismatch in the clinical probability and probability provided by V/Q scan.  A very interesting question is whether blood gas results could be used to further stratify risk status in these patients with intermediate risk status.  Pulmonary angiogram studies or at least further clinical follow-up history would be useful.

EKG - Sensitive for MI?

Motivation: During my final clerkship in medicine, I was plagued by chest pain.  Almost every day, a patient complained of chest pain, and the usual reflex was to order a 12-lead EKG.  Most of the time, the EKG was unchanged, but I did not know what to make of the normal result.  Could this person still be having a myocardial infarction?  The answer was, after all, yes.  At the same time, an unchanged EKG presumably decreased the likelihood of the patient suffering an MI.  So, how sensitive is EKG or serial EKGs for MI?

Paper: Usefulness of Automated Serial 12-Lead ECG Monitoring During the Initial Emergency Department Evaluation of Patients With Chest Pain. Fesmire, F. et. al. Annals of Emergency Medicine (1998), (31): 3-11.

Methods: A prospective observational study in 1000 patients with chest pain admitted at an academic center.  Patients received an initial ECG and automated sequential ECG 20 minutes apart.  The ECG information was compared against the final diagnosis at discharge.  Acute myocardial infarction was diagnosed on the basis of cardiac enzymes, new Q-wave formation, or death within 24 hours of presentation.  Unstable angina was diagnosed if the in-hospital attending diagnosed the chest pain as likely ischemia related.  Investigators examining the ECG were blinded to final diagnoses.  Exclusion criteria for patients included cocaine use, tachyrhythmia, presence of pacemaker, and discharge from ED.

Results:
Acute Myocardial Infarction: Among patients with final diagnoses of acute MI, the initial ECG had a sensitivity of 55.4%.  Serial ECG twenty minutes apart had sensitivity of 68.1%.  The difference in sensitivity between serial ECG and initial ECG was statistically significant (p < 0.001).  The specificity of initial ECG and serial ECG monitoring for acute MI were comparable (94.6% vs. 94.8%, difference not significant).
Acute Coronary Syndrome (ACS): For patients with final diagnoses of ACS (which consisted of MI plus unstable angina), the sensitivity of an initial ECG was 27.5% while the sensitivity of serial ECG was 34.2% (difference statistically significant with p < 0.001).  Serial ECG had higher specificity at 99.4% compared to 97.1% for initial ECG (p < 0.01). 
Mortality: In the study, 17 patients died (8 with initial diagnosis of acute MI, 8 with initial diagnosis of unstable angina, and one patient from non-ACS causes).  17.6% of deaths occurred in patients with no changes in serial ECG.

Discussion: Overall, a one-time ECG is a pretty insensitive tool for detecting acute myocardial infarction (sensitivity of 55.4%) and an even poorer tool for diagnosing ACS (sensitivity of 27.5%).  Serial ECG had higher sensitivities, but the difference to me was not overwhelming.  Rather, I think that the study highlights that if ACS is a real concern, the diagnoses still hinges on a good story and cardiac enzyme monitoring.  The ECG can be used as a triage tool to identify patients with STEMI, but for all patients with ACS in hosptial, the ECG is not an appropriate tool to rule out concern.

Some of the methodological deficiencies in the study may have inflated the calculated sensitivity of ECG.  The study only considered patients admitted to the hospital, but it is known that myocardial infarctions are often missed in the emergency department.  So, it is possible that some patients with MI and normal ECG were discharged.  With inclusion of these patients, the sensitivity would be even lower.