CPC COH2018 | Case 1 | Case of Paroxysmal Hypertension associated with Presyncope
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CPC COH2018 | Case 1 | Case of Paroxysmal Hypertension associated with Presyncope

September 9, 2019

– The physician who referred this patient asked that we see her
urgently and you can see why. She was a 62 year old woman who had had mild hypertension in the past but then the last month or so had developed increasing
blood pressure readings and also her blood pressure
became labile as well and the referral was initiated when her physician found the blood pressure at the top of the cuff at 300 millimeters of mercury systolic and this was despite her being on this anti hypertensive regimen that you see. She was on no other new medications and in particular she
was not taking NSAID’s. Her blood pressure in the mornings were often quite low as you
see a 496 systolic pressure and this would resolve
if she was lying down but she had presyncopal symptoms
frequently in the morning. In the evening her blood
pressure was quite high and this was associated
with some visual difficulty. Blood pressure in the range systolic of 190 to 200 and this might
be associated with tachycardia as well and at this time she often had symptoms and a hot feeling in the head, throbbing headaches often accompanied these elevations in
pressure and in particular she described a black curtain coming down over her eyes with this. Her husband and other observers noted that she looked ashen,
she appeared like a ghost but on one occasion when she was described as being intensely red
in the face so flushing. We were fortunate in that
her husband was trained as an accountant so he came to the clinic with her blood pressures
recorded on Excel spreadsheet which he had frequently documented during the day and this is what his data showed. as you can see her blood pressure went up during the day, and reaching a peak here in the early evening
and it was this point she had symptomatology
such as visual disturbance. However the following morning her pressure would be down again and then that would be repeated again the following day and she had orthostatic hypotension with symptoms on this
third day of observation. So this was her clinical state and with these elevations
in blood pressure at the peak you can see that
she had some tachycardia and this pretty well correlated
with her blood pressure up to levels maybe 160. She had mild hypertension, mild diabetes which wasn’t to being
treated, she was hypo thyroid, she complained of chronic low back pain and also spasms in pain in her neck, and was anxious. The medications are as you have seen for hypertension she was
also on Losartan, Tizanidine, and Levothyroxine, and her
TSH levels were normal. She was not a smoker, her alcohol intake was not excessive and she
was not taking cocaine. She had no family history
of endocrine tumors, on exam her systolic pressure
was quite elevated, 186. She was mildly obese, on
endoscopic examination revealed some copper
wiring and AV nicking. Her exam was otherwise normal it was no regular thermal pulse delay. Her potassium was normal, she had no left ventricular hypertrophy on electro cardiogram and no
re polarization abnormality. So these were the
principle considerations of when she arrived,
pheochromocytoma, baro receptor failure such as one can see after a section of para
gangliomas in the neck, presented this way, autonomic dysfunction is a possibility, sympathicomimetic drugs, maybe seen either factitious or patient unaware of the fact that they were inducing their hypertension and withdrawal from Clonidine. She had no evidence of
primary aldosteronism, her plasma and norepinephrine was 799, her normetanephrine was 902 in the urine. Notably her plasma
epinephrine and metanephrine were well within the normal range. Her data are super imposed on the data presented by Eisenhoffer showing that her norepinephrine is not high normal or low feel range,
epinephrine is totally normal. And the right hand panel
her normetanephrine is well up at the top of what
one sees in normal individual. So one question would be
could pheochromocytoma be associated with
symptomatic hypotension. I’ll put that out to
he audience to discuss. – Okay, we’ve got Bob Carey
coming to the microphone please. – The answer to the question is yes. Hypotension and postural hypotension can be associated with pheochromocytoma. You would expect that if
it were a straightforward pheochromocytoma that
the hypotensive episodes might be related to
epinephrine release by itself and particularly in the absence
of a norepinephrine surge. I’ve seen several patients who had purely epinephrine creating pheochromocytoma and their symptoms and signs were they developed sever
episodic hypotension and they turned ashen gray
similar to the history of this case during those episodes. So with this case though, with the metanephrine
and epinephrine levels being normal we have to
think that something else might be going on and we have to keep in mind that pheochromocytomas
have the capability of secreting many various neuro peptides and vaso active peptides. So there might be a concurrent
release of these peptides with some of the catecholamine surges. – Okay and another comment.
– Thank you, Dr. Carey. – One more comment please. – Alright yes, I was quite
struck by the circadian variation that you described and so one of the questions that I would ask of the husband and of the patient is whether there was a
pressure natriuresis at night. What was the frequency of nocturia and could she have been
volume depleted in the morning accounting for her morning hypotension. And I also was struck
by Dr. Otto Kushell’s description of some fields
that produce dopamine leading to this type
of labile hypertension with periods of hypotension. So those are my two thoughts thus far. – Okay would you like to answer. I perhaps want to add to
this amazing regularity of up and down the pheos that I have seen and I have seen many
have been characterized by irregular behavior, that regularity it’s always down in the morning and up in the evening, very unusual. – Yes unless there’s a particular trigger that’s happening each day. Could I ask what time of day the catecholamine measurements were made in relation to the blood pressure. – When the blood pressure was high. And her husband did not put any urinary measurements on the urinary volume measurements on his spreadsheet so we don’t know about nocturnal diuresis. – [Man] No night time blood
pressure is higher I imagine. – The question was night
time blood pressures, have they been measured. – We only have the
first morning pressures. – [Man] What time of the
day did she take the– – Can you come to the microphone, we’re filming this. Please please don’t spoil our film. – I’ll be sure to yell. What is the time of the day that she takes the Tizanidine? – It was in the evening. – In the evening. Will you be discussing that, okay. (laughter) – So could a pheochromocytoma present with flushing, Dr. Carey alluded to the fact that these tumors can also produce other
substances including neuro peptides it would be vaso dilator and while this is quite rare there is a beautiful
picture in Ray Gifford’s book on pheochromocytoma of a patient with a brilliant red flush and some periorbital edema, looks very much like kind of flush that I’ve
seen with broncho carcinoid. So but the exception proves the rule. Would you like to see further
studies evaluating pheo? – Yes please. – Okay, she had imaging
of her abdomen and pelvis CT with and without contrast and there were no adrenal
or periotic masses seen. This point I’d like to ask my co presenter to pick up the discussion. – One point is this is
extremely mild hypertension with systolic bouncing up to 300 and then way down into the 80s and it occurs suddenly and it really reminds one of baro receptor reflex inactivation. With a lack of buffering
of blood pressures. I don’t know whether that’s contributing to what’s going on but this would be a typical kind of labile
hypertension in that setting. – We felt that this had a
very strong hyper adrenergic flavor to the hypertension as well. – Any other comments from the audience. There are two, Dr. Bursztyn first. – I wonder how how blood pressure higher than 300 with limiters was measured in a clinic. What instrument? – That was a reported
from an outside physician but we don’t have actual
documentation of that that was passed on by
the patient I believe. Dr. Roach you might want to clarify. – I think the referring physician who measured this simply inferred that when the blood pressure cuff
sits at 300 it’s probably at or greater than that level. – So two clarifying
questions about the comment on barrio reflex failure. First, the pattern of evening hypertension which is one that I cannot
find in the literature. I know that people have observed, I have certainly observed
but it’s a very common pattern in the way this patient had. The second one has to do with the fact that she has hypo thyroidism, so I just want to confirm
that the hypo thyroidism was not due to a total
thyroidectomy with a full exploration of the neck
which would be probably one of the possible links. It was not. She didn’t have any
history of neck surgery or radiation,
which would be another key question when you’re
thinking about someone with barrio reflex failure have several patients with barrio reflex
failure from radiation to the neck as well for thyroid cancer but she did not have that history, did not have surgical
intervention of the thyroid. – Let’s move on. – Alright so we had a strong suspicion that medications could be contributing to the hyper adrenergic
state that this patient had this is a short list of considerations sympathicomimetic such as
ephedra, pseudoephedrine, cocaine, even yohimbine has been reported that you can still get
off the internet from supplement companies. Prescription drug
withdrawal and our suspicion was for Clonidine or alpha
two adrenergic agonists or drug withdrawal from alcohol and she had no, we
questioned her about that. Dr. Oates questioned her about that and she reported no history of exposure to any of these medicines or alcohol, we had a low suspicion for any of these. So one of our participants has already suggested that Tizanidine, questioned the timing of Tizanidine and she did take that
once daily in the evening and so we considered that to be one of the strongest considerations. So when we’re thinking about Clonidine like agents, I’ve put
the chemical structures up here so you can see the similarities. Moxonidine is available in the European physician’s have access to this but it’s not prescribed or
available in the U.S. We in the United States,
we have Guanfacine, Dexmedetomidine is used
principally in ICUs not as an out patient and Methyldopa is another alpha two
agonist that’s commonly used and Dr. Oates has a long history in describing the
initial use of Methyldopa for hypertension but she wasn’t taking any of these medications. But she was taking
Zanaflex which is referred to Tizanidine is the generic name, Zanaflex is frequently what patients will refer to it as,
is billed as a central muscle relaxant, it’s an alpha two agonist and so that’s been mentioned or questioned the timing about when she took this by one of our participants. So we felt that Tizanidine could be contributing in this case. Tizanidine, compared to Clonidine has been described as a
centrally acting muscle relaxant whereas Clonidine has been described as a centrally
acting any hypertensive but if you look at the
package insert itself for Tizanidine it’s
describe in the package insert as an alpha two agonist at receptor sites and
presumably reduces spasticity by increasing pre synaptic
inhibition at motor neurons and they quote that they
refer that it has no direct action on the skeletal muscles. So the principle muscle relaxant activity of Tizanidine appear to be central alpha
two agonist activities. It’s useful to review the pharmacology of Tizanidine compared to Clonidine. The principle difference between the two drugs is the half life of
two and a half hours for Tizanidine, compared to a half life reported to be 12 to 16
hours, these are taken directly from the package inserts form the manufacturers. They both have reasonable and similar bioavailability and both
undergo first pass metabolism in the liver and they also
differ in their metabolism in that Clonidine is both
hepatically and renally cleared but Tizanidine is principally
and almost entirely cleared by CYP1A2 mechanisms in the liver. So we considered that
Tizanidine rebound hypertension could be a cause of rebound
hypertension in this patient. This would be very analogous to Clonidine withdrawal hypertension and so I’ve put a time course of blood pressure and plasma norepinephrine levels from a classic paper describing Clonidine rebound hypertension. You can see that within
12 to 24 hours of the last Clonidine dose there’s
a peak in blood pressure and also a rise in plasma
norepinephrine levels so this would be similar to what we might be seeing in our patient. So going back to this is
again the blood pressure trend but this time I’ve highlighted the timing of when she would be taking Tizanidine. She took 12 milligrams at bedtime and I’ll point out that usually Tizanidine because of its short half life is prescribed either
three or four times a day but we note that our patient
took this only at bed time. The reason she did this
was due to drowsiness that occurred when she takes
Tizanidine during the day and that’s a frequent description of Tizanidine use by patients and they frequently self select the
timing to be at bedtime only. The usual dose is also four milligrams where she waws taking 12 milligrams at bed time which is quite
a high dose for one dose. So our clinical suspicion was this was Tizanidine induced daily
rebound hypertension and when thinking about potential ways to treat this the suggested way to remove Tizanidine from the regimen is to taper it slowly
by two milligrams a day or to take it regularly
three or four times a day rather than once a day. It’s helpful also to replace Tizanidine in these cases with
another alpha two agonist so Clonidine, Methyldopa, or Guanfacine. In the United States would be options to give this patient and less preferred would be possibly to use combined alpha and beta blockade. So here’s the resolution of this case. The patient attempted to taper Tizanidine as an outpatient by reducing slowly the doses but she continued to have severely high
blood pressure at night associated with symptoms and so she was brought into the hospital. She continued to have high blood pressure and low morning blood
pressures in the hospital. She was treated with IV
fluids for the hypotension and additional anti
hypertensives were added. Clonidine was added while
she was tapered off of Tizanidine in the hospital. So you can see this is
the period that was shown previously and up to the point that she was hospitalized, blood pressure
during the hospitalization and after certainly became less labile and tended to be more controlled. Shown below is the lability
of the blood pressure so the peak minus the
trough blood pressure within a day so she had
swings of 100 millimeters of mercury from the peak to
the trough blood pressure. And you can say with the
removal of Tizanidine, addition of Clonidine
and taper off of this she had much less labile blood pressure after this drug was withdrawn. So to review some more on Tizanidine, it’s similar to Clonidine, it suppresses the sympathetic nervous system and another fact is that
can mimic autonomic failure or autonomic group, Dr. Biaggioni and others have seen I
believe similar autonomic failure cases from Tizanidine from patients that don’t know
that it can also cause this. I’ve mentioned before that patients self select to dose only at bed time and this is primarily
due to sedative effects. It can be abused by some patients due to the sedative and also has had reported to have hallucinatory effects. One other factor that’s important
is the drug interaction. So this may influence the
side effects from the drug and potentially the rebound hypertension. And I mentioned that CYP1A2 inhibitors it’s principally metabolized via CYP1A2 and so this makes it susceptible to CYP1A2 inhibitor interactions. This has actually been
well described by a group I believe in the Netherlands,
Granforz and colleagues have done several nice
papers demonstrating the effect of potent CYP1A2 inhibitors, Fluvoxamine, and Ciprofloxacin. So Ciprofloxacin much more commonly used but Fluvoxamine has a dramatic affect on drug exposure, there’s
a 33 fold increase in drug exposure with Fluvoxamine. I’ve spoken with people in
the clinical pharmacology division and have referred
to this as possibly the largest drug interaction
they’ve ever seen. Ciprofloxacin has about a tenfold increase in drug exposure and you
can see that compared to the drug concentration curves the actual therapeutic drug exposure is dwarfed by what happens
during these drug exposures during CYP1A2 inhibition. And this actually has clinical ramifications on blood pressure. The blood pressure responds quite well to the drug concentration and also the sedative effects. So blood pressure during co administration of Fluvoxamine or with Ciprofloxacin produces much greater
blood pressure reduction when co administered with Tizanidine. And these are the best
described and the most potent drug interactions
but there’s a long list of other drugs that can
interact with this medication that patients may also be taking. So very commonly used
drugs like Amiodarone Even over the counter medications that may not be reported like
Cimetidine and Famotidine and other Quinolones may interact with Tizanidine but their interactions are less well described so we don’t know the effect for each of these. Also, estrogen or oral contraceptive pills also have an interaction
that’s been reported. Our group is led by Mike
Stein and Cecilia Chung have looked at whether this impacts blood pressure in the hospital in patients that are taking Tizanidine as outpatient, come into the hospital and then are co administered
these CYP1A2 inhibitors. And they did find by looking
through the electronic medical record that there is an
increased in incidence of either severe hypotension,
low blood pressure or a blood pressure drop in these patients and they compared the
blood pressure response to a controlled medication
such as Cyclobenzaprine which is another muscle
relaxant that’s not associated with alpha two affects and they found that the risk was significantly higher with Tizanidine co administered
with CYP1A2 inhibitors. So this is a real world effect that can be detected in a noisy
electronic medical record. So the next question is
who prescribes Tizanidine so most likely this is given by primary care physicians because they’re the largest number of prescribers, they prescribe the largest
number of prescriptions in the Untied States but there may be physicians or specialties that prescribe it more often than primary care physicians and when you look at the CMS data, we found that there could be a reason that we’re seeing this or we’re reporting this is because it’s more often prescribed here in the southeast and it’s increasing
over time so you can see this is presented as a percent
of all state prescriptions. The darker color would be a
higher percent of prescriptions. So it’s slightly more often
prescribed in the Southeast and you can see from
2013 to 14 even ’15 ’16 there’s an increase so that we see this more often in the southeast. And that may be why patients
are referred to our clinic. And maybe we recognize it
more often than other areas. We’ve see this in other patients, we’ve presented and selected this case just to be illustrative but we and my partners have seen multiple cases of similar presentations. So who is prescribing
Tizanidine in the United States? If you look at Tizanidine prescription as a percentage of
specialty prescriptions, patients that are, physicians that are involved in pain management, chronic pain management
prescribe Tizanidine more often as a percentage of prescription than other providers so the top specialties here of pain management are anaesthesiology, neuro surgery which often they’re involved in
management of chronic pain and in fact our patient had received this prescription from a neuro surgeon. So in summary, Tizanidine may be the cause of rebound hypertension in patients and we believe strongly that it was in our case, the principle reason in this case is that it was given at bedtime due
to the sedative effects and taken in larger amounts, larger dose than should be taken. And the presentation is
often with hyper adrenergic symptoms, CYP1A2 inhibitor
drug interactions may precipitate sever hypotension which may mimic autonomic failure as well which I did not present today but there are other presentations of that or reports of that. And Tizanidine is often prescribed by pain specialists as well as
primary care physicians. And we’re seeing this more often probably due the alternative, to using it as an alternative to opioids. And so we believe that in
the years going forward we’re gonna see this more often. Due to the opioid epidemic
in the United States. So rebound hypotension are likely to be seen more commonly. Alright and I believe we’ve got Dr. Oates wanted to present one
more case just after this which is very short, two slides. – So you might ask, are there other alpha 2 agonists out there waiting to surprise us in our kind of a practice. So this is a patient who was 86 years old, she had renovascular hypertension that had been stinted, blood pressure was very well controlled on a triple drug regimen but with small doses of the drugs and then there was a phone call, patient’s husband called she had been at church sitting down for a while and then when she tried to stand up she almost fainted, had to lie on the floor and her blood
pressure at that time was 72 over 57 and she was profoundly sedated for the rest of that day. The patient has borderline glaucoma and that morning after
seeing her ophthalmologist took for the first time took a morning dose of the ocular Brimonidine drops. And Brimonidine is an alpha two agonist and you can see what the result was, supposedly selectively delivering a drug to the eye but it runs
down the lacrimal duct and becomes orally absorbed and a patient who’s already on anti hypertensive drugs then the result that you see isn’t one that you expect,
it’s sever hypotension. It’s probably worth pointing out that for both this drug and Tizanidine the clinical trials allowed FDA approval were done in individuals who were carefully selected not to be on any hypertensive drugs and in those individuals maybe much less likely to see problems with hypotension. Thank you very much. (applause) – Thank you very much,
we have a few minutes for audience comments please. – Just while you’re
coming to the microphone, we’ve already discussed how
extreme these blood pressure fluctuations were in
this particular patient, do you have any explanation for that behind the very high dose she was taking? – The high dose combined
with the once daily administration I think is
the strongest predictor. I think it’s a similar
story that I’ve seen in a number of patients, I think I’ve seen this at least five
or six times a year and new consults in a hypertension clinic and my partners see this as well and they all give a similar story. They’re sedating, they take it at night and have labile blood pressure. – Okay we have huge queue at
the microphone please start. – Sandra Taler Mayo
clinic, so I’m troubled by the management of this patient once you figured out that she should be tapered off the Zanadex. The question is how can you taper when you take a big dose at night. Why not just take her off because she’s going into withdrawal daily, put her on a dose of Clonidine and then taper the Clonidine over time. I feel like the problem was prolonged until she was put in the hospital. – You might be right in this case and I think this was the first case that was recognized
to be due to this. I frequently do exactly
what you’re saying, I’ll replace Tizanidine
with an alpha agonist, and I don’t recall having other patients needing hospitalization. – She was hospitalized
because of the suspect pheochromocytoma, and she was immediately put on Clonidine and then
taken off of the Tizanidine. – John Mathis was a very instructive case and I think as you
point out illustrates the potential problem with these agents, these kinds of agents and whereas in the guideline we were
very careful to point out the problem with Clonidine withdrawal, and to not to use
Clonidine prior to surgery because you might
precipitate a hypertensive crisis during the surgery. We did not pay attention to these kinds of muscle relaxant drugs, it seems to me that there should be if not a black box warning at least a very prominent warning on this, I don’t think it’s appreciated in the primary care community or even in the
hypertension community so thank you for presenting this. – Charles Tifft, Boston,
I wonder if there’s something else going on
with the first patient. In fact she’s had, we don’t know really how long she’s had diabetes and that sort of thing and whether she might have some component of autonomic disfunction to begin with that would set her up for much more violent problem with this drug withdrawal. And whether she’s had any kind of autonomic studies afterwards. – She had not had any further autonomic studies but her blood pressure after she came off of these drugs were– – Mic. – Her blood pressure after she came off these drugs were did not demonstrate orthostatic hypotension. – Okay and the last or penultimate point. – Sure, Atul Chugh, Indianapolis from St. Francis Heart Center. Last month I was asked to consult on a patient in the ICU, a 38 year old female with hypotension requiring pressers for a second degree mobitz tube block, the patient was presumably thought to have these issues secondary to
some sort of substance. Turns out that she was
surreptitiously using Tizanidine by hiding them in her bra. I guess the question is have you seen as the blood pressure goes, what have you seen with heart rate in these patients and have you seen any sort of rebound tachycardia or any issues
of tachyrhythmia as well? – I haven’t personally seen tachyrhythmia but the heart rate corresponds
with the blood pressure that’s well described
in the drug interaction studies which are reported here and it’s in our autonomic failure group they’ve personally reported to me they also see it looks just like autonomic failure with norepinephrine deficiency. I don’t know about mobitz tube block or Bradyarrhythmias or Tachyarrhythmias but you can certainly get
hyper adrenergic rebound associated with all the arrhythmias that are similarly associated with that. – Okay so last question for those of us who don’t practice in United States, I have not come across this
drug in United Kingdom. Is it prescribed elsewhere
or is it a U.S. special, do you know, if not we need to find out before we publish the paper I think because the journal reaches
international audience. – That’s a great question, I do know that it’s not available in the EU but I don’t know about how many other countries this might be available in so the audience might be able to help educate us. – Gary, Australia? – No I don’t know, I was
happened by some doubt who you showed from Holland which suggests it was big
news to us as well but– – Well they’re at least aware of it. – Okay last comment please. – Two things, first of all
it is available in Canada although I’ve not seen that
effect from it so thank you. The other question or comment we talked a lot about autonomics,
all the blood pressures were they sitting, was there ever supine, was there ever an
orthostatic blood pressure done to look at that? – These were seated home blood pressures recorded with the home
blood pressure monitor by the husband and
wife, she was documented to have orthostatic hypertension as well in the clinic and in the hospital but those were not routinely done, I don’t believe at home, Dr. Oates might he knows the case. – Not at home. – ‘Cause when we think
of the pm blood pressure, if we think about it from an ABPM we think about it as a supine but
this would’ve been a sitting so would’ve been a bit
different from that perspective. – Okay, I think the time has come to thank this team, this was a great presentation, thank you very much (applause)

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