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!