The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 3 943-946
Copyright © 2000 by The Endocrine Society
Severe Hypertension Induced by the Long-Acting Somatostatin Analogue Sandostatin LAR in a Patient with Diabetic Autonomic Neuropathy
Rodica Pop-Busui,
William Chey and
Martin J. Stevens
Department of Internal Medicine, Division of Endocrinology and
Metabolism (R.P.-B., M.J.S.), and Division of Gastroenterology (W.C.),
University of Michigan, Ann Arbor, Michigan 48109-0678
Address correspondence and requests for reprints to: Martin J. Stevens, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan Medical Center, 5570 MSRB II, Box 0678, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0678. E-mail: stevensm{at}umich.edu
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Abstract
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A 26-yr-old woman with type 1 diabetes and severe symptomatic autonomic
neuropathy was treated with the long-acting somatostatin analogue
Sandostatin LAR for intractable diarrhea. Her diarrhea had previously
been successfully managed with three daily injections of octreotide
without adverse consequences. She was given a single dose of
Sandostatin LAR and within 2 weeks reported the development of
increasingly frequent and severe headaches. Three weeks after the
injection, she was admitted to hospital with severe hypertension, which
eventually resolved with the administration of antihypertensive agents.
No other underlying cause of the hypertension was discovered.
Rechallenge of the patient with octreotide resulted in a transient
hypertensive episode, which lasted 3 h. Severe hypertension,
therefore, seems to be a possible adverse effect of treatment of
diabetic diarrhea with somatostatin analogues, which should be used
with great caution in subjects with severe autonomic dysfunction.
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Introduction
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REFRACTORY diarrhea complicating
diabetes can occur in up to 20% of patients with advanced diabetic
autonomic neuropathy (DAN) (1). It is characterized by severe nocturnal
exacerbations and may be secondary to abnormal intestinal motility,
sphincter malfunction, bacterial overgrowth, pancreatic exocrine
insufficiency, and/or bile salt malabsorption (1, 2). A causative
association has been identified between sympathetic denervation, rapid
distal small bowel transit, and diarrhea complicating diabetes (3). The
treatment of diabetic diarrhea is largely dependent on its etiology.
Conventional treatments comprise broad spectrum antibiotics, bile salt
binders such as cholestyramine, and loperamide, which may attenuate
aberrant motility. Increasingly, diabetic patients with persistent
refractory diarrhea are being treated with the somatostatin analogue
octreotide (4), which attenuates secretory diarrhea resulting from a
broad spectrum of pathologies, including diabetes (5, 6, 7). Octreotide
has also been reported to attenuate both postprandial and orthostatic
hypotension, complicating autonomic failure (8, 9, 10, 11) via a mechanism
that may involve a reduction of vasodilatory gut peptides.
Sandostatin LAR is a recently developed long-acting somatostatin
analogue. We report a 26-yr-old woman with type 1 diabetes and severe
intractable diabetic diarrhea secondary to autonomic neuropathy who
developed an episode of severe hypertension, necessitating hospital
admission in response to Sandostatin LAR therapy. Hypertension has not
been previously reported to be an adverse effect of Sandostatin LAR
treatment. Blood pressure should be closely monitored in DAN patients
treated with somatostatin analogues for diabetic diarrhea.
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Case Report
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We report the case of a 26-yr-old woman with a 16-yr history of
type 1 diabetes mellitus admitted to the University Medical Center with
a hypertensive urgency. She reported intermittent headaches for 2 weeks
prior to admission, which had become persistent for the last 2 days.
Eight days before her admission, home blood pressure monitoring
revealed blood pressures in excess of 150/110 mm Hg. She was scheduled
to be admitted to have elective plastic surgery, but was found to have
a blood pressure of 200/120 mm Hg, her surgery was canceled and she was
admitted instead for hypertension control. She complained of nausea and
vomiting, but denied neck pain or visual changes.
Her past medical history was significant for unstable
diabetes (last HbA1C, 8.7%) complicated by severe DAN (Table 1
), background retinopathy, and
diabetic nephropathy with an average urinary microalbumin of 100 mg/24
h. The clinical manifestations of her autonomic dysfunction comprised
persistent orthostatic hypotension with falls in systolic blood
pressure ranging from 30–80 mm Hg. Monitoring of her blood pressure
both at home and at three monthly intervals in the outpatient clinic
revealed systolic blood pressures typically ranging from 90–110 mm Hg,
with no systolic values recorded above 130 mm Hg. Her daily hypotensive
episodes had required intermittent therapy with the 
-1-agonist
midodine, which increased her blood pressure by 5–10 mm Hg. Her other
complications included refractory diabetic diarrhea, gastroparesis with
subsequent permanent J tube placement, esophageal dysmotility and
esophageal stricture requiring dilatation, neurogenic bladder requiring
self-catheterization, a unilateral Charcot joint, and painful diabetic
peripheral neuropathy. Her gastrointestinal dysmotility resulted in
erratic blood glucose control with episode of unpredictable severe
hypoglycemia requiring third party intervention. Her current insulin
treatment regimen comprised insulin pump therapy. There was no previous
history of hypertension. Her medications included prokinetic agents but
no antihypensive medications.
Neuropathy and gastrointestinal assessment
The results of standardized cardiovascular autonomic function
testing revealed severe parasympathetic and sympathetic autonomic
neuropathy (Table 1
). Gastric-emptying studies confirmed the presence
of a severe gastroparesis. Her diarrhea had been present for 9 yr and
was characterized by the passage of 10–15 loose stools/day and
nocturnal exacerbations with incontinence. Extensive repetitive
evaluation of her diarrhea had not revealed an etiology other than
dysmotility and periodic bacterial overgrowth secondary to DAN. After
the failure of multiple antidiarrhea drug therapy regimens, including
repetitive courses of antibiotics, bile salt binders, and dysmotility
agents, sc octreotide therapy was initiated at a dose of 75 µg every
evening. This significantly decreased the number of episodes of
diarrhea for 6–9 h after the injection. Octreotide was gradually
titrated up to 75 µg tid with the number of diarrhea episodes
decreasing to 6–8 per day. By self report, 1 week after the initiation
of the octreotide treatment, headaches developed beginning shortly
after octreotide injection and persisting for 1–2 h. These were
associated with systolic blood pressure values ranging from 130–140 mm
Hg.
For convenience, she was switched to the long-acting
somatostatin analogue Sandostatin LAR. This was given as a single im
injection of 20 mg. Within 2 weeks she reported the development of
increasingly frequent and severe headaches, and 3 weeks after the
injection of Sandostatin LAR she was admitted to hospital with
hypertensive urgency.
Laboratory evaluation
Biochemical assessment of plasma electrolytes, toxicology screen,
urinary catecholamines, renin/aldosterone, magnetic resonance
angiogram, head computed tomography scan, abdominal and chest X-rays,
and electrocardiogram were unremarkable and did not reveal a cause for
the hypertension. The hypertension was managed acutely with labetolol
and then with inderal, which was continued for an additional 2 weeks
before being discontinued secondary to recurrence of her orthostatic
hypotension. Her diarrhea was exacerbated when the octreotide was
discontinued.
The time-dependent changes in her blood pressure in
relation to the analogue Sandostatin LAR therapy are shown in Fig. 1. The peak of the blood pressure
associated with her severe hypertension episode occurred approximately
3 weeks after the injection of analogue Sandostatin LAR. During this
episode, postural hypotension was still observed since systolic blood
pressures fell up to 40 mm Hg while standing, even when the supine
systolic blood pressure was greater than 170 mm Hg.
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Figure 1. Time-dependent changes in blood pressure in
relation to Somatostatin LAR (SLAR) therapy. SLAR was given as a single
im injection of 20 mg on March 10, 1999. Three weeks after the
injection, the patient was admitted with hypertensive urgency.
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Reviewing the patient’s records of home blood pressure
monitoring, we noted a significant rise in the systolic blood pressure,
which would occur approximately 15 min after each injection of
octreotide and would peak after 2 h and then decline to baseline
after 3–4 h.
The changes in her systolic blood pressure before and after 75
µg sc octreotide, recorded in the outpatient clinic, are shown in
Fig. 2. After octreotide injection, blood
pressure began to increase by 45 min and was maximally increased (by
80%) 180 min after the injection.
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Discussion
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Here, we report a young patient with type 1 diabetes and
severe autonomic dysfunction who develops severe hypertension after
somatostatin analogue therapy for diabetic diarrhea. A transient
hypertensive episode was documented, which persisted for 3 h
following therapy with octreotide. Administration of the long-acting
somatostatin analogue Sandostatin LAR was associated with a severe
hypertension, which persisted for several weeks. Hypertension,
therefore, seems to be a potential adverse effect of treatment of
diabetic diarrhea with somatostatin analogues. This therapy should be
used with great caution in subjects with severe autonomic
dysfunction.
Diabetic diarrhea is a common disabling complication of diabetic
patients with severe DAN. The mechanisms involved in its pathogenesis
are complex and often multifactorial. Neurological damage to the
enteric nervous system is thought to play a central role (3) with loss
of enterocyte -adrenergic receptor stimulation contributing to
impairment of motility and water absorption. The resultant high-volume
watery diarrhea is often refractory to therapy and disabling for
patients. Octreotide and its newly introduced long-acting analogue
Sandostatin LAR have been found to have beneficial effects in the
management of refractory secretory diarrhea resulting from a diverse
spectrum of pathologies, including diabetes (4, 7, 12, 13, 14).
Somatostatin analogues effectively control diarrhea and flushing in
patients with neuroendocrine tumors, diarrhea associated with short
bowel syndrome, ileostomy, and amyloidosis (4, 6).
Somatostatin analogue therapy may decrease diarrhea via
inhibiting the release of many gut and pancreatic peptides, including
vasoactive intestinal polypeptide, peptide histidine-methionine, 5-HT,
PGE2 (4, 5), through cAMP-dependent and -independent mechanisms. In
general, Sandostatin LAR is reported to be well tolerated with the
principal side effects of pain at injection site and abdominal
discomfort or bloating (13) being mild and self-limiting. A slightly
increased rate of biliary lithiasis has also been reported (13, 14).
Previous case reports have suggested that octreotide is beneficial for
the management of diarrhea in diabetic patients with autonomic
dysfunction (12, 15), but associated changes in blood pressure were not
reported. A randomized controlled clinical study in diabetic patients
with diarrhea has not yet been reported.
The subject of our report has severe disabling autonomic
dysfunction, which has affected many different organ systems.
Typically, she was disabled with orthostatic hypotension with systolic
blood pressure values usually being less than 100 mm Hg, which
intermittently required therapy with the -1-adrenoreceptor agonist
midodine. The time-dependent association of the transient episodes of
hypertension with octreotide therapy and the sustained increase in
blood pressure beginning 2–3 weeks after Sandostatin LAR therapy
implicate a causative association. Other causes of the hypertension
were systematically excluded, and although this individual did have
evidence of diabetic nephropathy, this did not seem to be responsible
for the hypertension because renal function remained stable throughout
the hypertensive episodes. To the best of our knowledge, there are no
previous reports of hypertensive actions of either somatostatin or its
analogues.
Subjects with autonomic failure and afferent baroreceptor
deficits from any etiology are supersensitive to vasodilator agents
(8, 9, 10), such as pancreatic and gut peptides. These vasoactive peptides
may play an enhanced role in the regulation of blood pressure in
subjects with autonomic failure through modulation of the large
splanchnic vascular bed. Administration of octreotide to these
individuals has been reported to induce a rapid pressor response, which
was not observed in normal subjects (9, 10). In some neurological
conditions, insulin may also play an important role in the regulation
of blood pressure, since it has been shown that exogenous insulin
administration lowers blood pressure in tetraplegic patients with
cervical spinal cord transection and in patients with autonomic failure
(11). In patients with autonomic failure, octreotide has been reported
to prevent alcohol-induced hypotension (16) and exert a rapid, but
brief, pressor effect. Octreotide has also been used in the management
of autonomic failure for relieving both postprandial and postural
hypotension (9, 10, 17). The pressor effects of the somatostatin
analogues could result from an imbalance of vasomodulatory agents, with
a resultant increase of vasoconstricting tone reflecting a decrease of
vasodilatory gut peptides and a relative preservation of
norepinephrine-mediated vasoconstriction. Octreotide may also have
direct effects of the vasculature since it decreases splanchnic blood
flow in human (18) and experimental studies (19) and constricts
isolated human mesenteric veins (20), perhaps through a direct effect
on the vascular smooth muscle. Therefore, in patients with
diabetes-induced autonomic dysfunction, failure of afferent
baroreceptor reflexes acting in concert with altered renal
responsiveness may predispose to aberrant blood pressure regulation in
response to somatostatin analogue therapy.
In summary, Sandostatin LAR therapy was associated with an
episode of severe hypertension in a patient with severe DAN.
Long-acting somatostatin analogues should be used with great caution in
patients with diabetic diarrhea, and fluctuations in blood pressure
should be closely monitored.
Received September 17, 1999.
Revised November 2, 1999.
Accepted November 10, 1999.
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Top
Abstract
Introduction
) and diastolic BP (
) were recorded at 30, 45,
60, 90, 120, and 180 min. Supine values are shown by continuous
lines, standing values by broken lines.