Do we need alpha blockade?

Traditionally, patients with pheo are treated with medications to block the alpha adrenergic receptor (alpha blockade) before surgical resection for longer than 2 weeks. alpha blockade has worked very well in the past 50 years to prepare patients for surgery. On the other hand, whether alpha blockade is really needed has been questioned for many years. Do we need alpha blockade?

Indeed, there has not been a randomized clinical trial comparing alpha blockade and another regimen without alpha blockade. Strictly speaking, the answer to the question whether we need alpha blockage is unknown. I believe in alpha blockade based on the long history of effective use, successful personal experience, and some evidence that alpha blockade reverses pheo-induced cardiomyopathy. In addition, I find 2 important flaws in the arguments against alpha blockade.

Flaw 1: Other medications control blood pressure just as well. As I explained in earlier posts, the goal of preoperative preparation is not just to control blood pressure but to treat and prevent pheo-induced cardiomyopathy. The most devastating complications of pheo are cardiovascular catastrophes such as congestive heart failure, cardiac arrest, severe arrhythmia, myocardial infarction, ventricular thrombosis, and stroke. Most patients who present with those complications have no history of hypertension but they are the ones who most need preoperative preparation.

Flaw 2: Nobody dies of pheo resection, regardless of the preoperative preparation regimen. Perioperative mortality is the wrong criterion for the success of pheo management. I have witnessed cases where omission of preoperative alpha blockade in normotensive patients led to severe postoperative complications and prolonged hospital stay. Postoperative length of stay, complications, and quality of life are much more meaningful criteria for the success of pheo medical management.

There is also a common issue in the arguments for and against alpha blockade. Both sides seem to consider all the pheos and the patients with pheo are the same. In reality, there is clear heterogeneity of pheo and the patients with this tumor. A 2-cm incidentally identified pheo is certainly different from a 7-cm one causing cardiac arrest. Likewise, a 30-year-old, otherwise healthy patient is obviously different from an 80-year-old patient with multiple comorbidities. Patients with low-risk pheo (< 3-cm) who are otherwise healthy and non-pregnant may probably undergo adrenalectomy safely without specific medical management. For the majority of patients with intermediate- and high-risk pheo, alpha blockade is probably the best initial treatment, until a randomized clinically trial demonstrates otherwise.

Dr. Pheo

Biochemical growth speed of pheo

A few years ago, I wrote on the growth speed of pheo. Pheo, contrary to conventional wisdom, grows slowly, at an average speed of one tenth of an inch (0.2 cm) every year. Recently, a study showed that the biochemical markers of pheo appear to also rise slowly. This study is interesting in a few aspects. It was based on the Department of Defense Serum Repository (DoDSR). The DoDSR is a large serum bank of all members of the US military forces and boasts of 50 million specimens. The specimens were collected on annual physicals. The authors used a smart research strategy. They identified people who had ever served in the US military and been diagnosed with pheo. They then tracked down the patients’ serum specimens and measured the metanephrine and normetanephrine levels in the specimens. For example, a person could be enrolled in military service at age 20 and diagnosed with pheo at age 40. All his serum specimens since he (most of the subjects were men, as expected) joined the military were available for testing. The authors actually picked only 3 specimens for testing.

The authors found out that the serum metanephrine or normetanephrine levels began to be elevated years before diagnosis. For example, the levels turned abnormal about 6 years before pheo diagnosis and were 3-fold elevated about 4 years before diagnosis. The average time of doubling of the marker levels was about 3 years. Individual patients had very wide differences in the rise of marker levels. For example, some patients had a doubling time less than 1 and half years, while some others had a doubling time more than 8 years. The authors thus concluded that a steady and slow rise of pheo marker levels is very suggestive of pheo. Because there were no imaging data, we don’t know if the rise of pheo marker levels is related to tumor growth, which is a limit of the study. Other studies do show parallel increase in pheo marker levels and tumor burden AFTER diagnosis.

Dr. Pheo

Seasonal variations not found in a third study

I wrote 2 years ago on the seasonal variations of plasma normetanephrine levels in patients without pheo. In early 2014, a paper reported that the normetanephrine levels are 20% higher in wintertime than in summertime in the Netherlands and Germany, and a second study showed that normetanephrine levels are 40% higher in wintertime than in summertime in Los Angeles, USA. As the Netherlands and Germany have temperate climate and Los Angeles has Mediterranean climate, higher normetanephrine levels in wintertime seem to be pretty universal. At that time, I suggested a similar study in a tropical area like Hawaii with minimal temperature differences throughout the year. One would predict that the plasma normetanephrine levels in people without pheo remain unchanged throughout the year in Hawaii.

A third study is indeed done, although not in Hawaii, and published recently. It is done in the West of Ireland. Ireland has a temperate oceanic climate. The average summertime and wintertime temperatures are 14.3 and 5.8 °C respectively in the West of Ireland. The temperature difference of 8.4 °C in the West of Ireland is very similar to that in Los Angeles (8.6 °C), although it is generally much cooler in the West of Ireland (average Los Angeles summertime and wintertime temperatures are 23.2 and 14.6 °C respectively). The seasonal temperature differences are much smaller in the West of Ireland and Los Angeles than those in the Netherlands and Germany (17 °C). Unlike in Los Angeles, there is, however, no difference in the plasma normetanephrine levels between the summertime and wintertime in the West of Ireland.

There could be multiple potential explanations of the different result obtained from the third study. An obvious issue is that all three studies are retrospective ones which can lead to certain biases. The most important lesson, however, is that medical studies need to be reproduced in different settings. We cannot assume that results from a previous study should be readily applied to another setting.

Dr. Pheo