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.