case report treatment of refractory postural tachycardia...

$: Case Report Treatment of Refractory Postural Tachycardia ...downloads.hindawi.com/journals/crim/2015/545029.pdf · management of this condition, in the absence of established protocol$
Case ReportTreatment of Refractory Postural Tachycardia Syndrome withSubcutaneous Octreotide Delivered Using an Insulin Pump

Muhammad Khan1 Jing Ouyang1 Karen Perkins1 John Somauroo2 and Franklin Joseph1

1Department of Diabetes amp Endocrinology Countess of Chester Hospital NHS Foundation Trust Chester CH2 1UL UK2Department of Cardiology Countess of Chester Hospital NHS Foundation Trust Chester CH2 1UL UK

Correspondence should be addressed to Muhammad Khan md0u930bliverpoolacuk

Received 3 October 2014 Revised 27 March 2015 Accepted 30 March 2015

Academic Editor W Zidek

Copyright copy 2015 Muhammad Khan et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Postural Tachycardia Syndrome (PoTS) represents a disorder of the autonomic nervous system that results in symptoms oforthostatic intolerance Despite having a severe impact on the patientrsquos quality of life the current treatment options for PoTS arebased on limited evidence Subsequently this results in clinicians having to utilise a variety of treatment regimens in the hope ofsuccessfully providing symptomatic relief However the options available for PoTS are not without significant side effects that canworsen an already debilitating condition Our cases provide a further novel treatment option for clinicians to consider in PoTSrefractory to established treatments

1 Introduction

Postural Tachycardia Syndrome (PoTS) represents a subsetof dysautonomic conditions characterised by features oforthostatic intolerance and tachycardia but without thepresence of orthostatic hypotension [1] Formal guidelineson the management of PoTS are lacking yet the sparse lit-erature on this condition suggests several possible treatmentoptions One such pharmacological agent is the somatostatinanalogue octreotide Although not specifically licensed forthe treatment of PoTS the limited literature outlining itsefficacymakes it a useful adjunct for the symptomatic controlof PoTS However the use of octreotide can be expensivecan be associated with debilitating side effects and can causeinconvenience due to the required frequency of injectionsWe present two cases of PoTS inadequately controlled withexisting treatments that included octreotide Both patientseventually benefited from the subcutaneous octreotide deliv-ered using an insulin pump We believe this to be the firstreported instance of this means of administration

2 Case Report

21 Case Presentation

211 Case 1 A 24-year-old woman presented with suddenonset of recurrent light-headedness and severe orthostaticintolerance relieved with recumbence following a pyrexial ill-ness She complained of light-headedness nausea heat intol-erance breathlessness and fatigue but no palpitations Initialphysical examination reported no abnormalities except fora regular resting heart rate of 99 beats per minute (bpm)and soft systolic murmur Biochemical investigations chestX-ray and an electrocardiogram revealed no abnormalitiesHolter monitoring identified a sinus rhythm alternating withsinus tachycardia thus raising the possibility of an underlyingdiagnosis of PoTS Diagnostic tilt table testing (TTT) wasordered and confirmed the diagnosis of PoTS due to anincrease in the patientrsquos heart rate from 88 bpm at supineposition to 122 bpm within 10 minutes of standing in theabsence of orthostatic hypotension (supine blood pressure

Hindawi Publishing CorporationCase Reports in MedicineVolume 2015 Article ID 545029 4 pageshttpdxdoiorg1011552015545029

2 Case Reports in Medicine

13690mmHg blood pressure within 10 minutes of standing148103mmHg)

Initial management included an increase in both fluidintake to 3 litres per day and salt intake through slowsodium MR (600mg 10 per day) Medications includingfludrocortisone (300 120583g once daily) bisoprolol (25mg twicedaily) paroxetine (20mg once daily) midodrine (5mg threetimes daily) and ivabradine (75mg twice daily) were trialledboth serially and then in combination but each proved to beineffective Subcutaneous (SC) octreotide was trialled withthe dose increasing from 25 120583g twice daily to 50120583g at 90-minute intervals six times a day (300 120583g24 h) Despite symp-tomatic relief she reported excruciating abdominal crampsand episodes of diarrhoea occurring invariably followingeach injection The escalating orthostatic symptoms resultedin her being wheelchair dependent and the progressivedecline in her quality of life culminating in her being forcedto withdraw from her job and suffering an episode ofclinical depression The severity and frequency of side effectsprompted the notion of possibly administering SC octreotidevia an insulin pump

212 Case 2 A 14-year-old girl presented to her gen-eral practitioner with a year long history of intermittentheadaches associated with palpitations light headednessnausea dizziness and ldquogoing palerdquo upon standing froma supine position Additionally she reported experiencingldquotunnel visionrdquo which preceded brief episodes of loss ofconsciousness Initial examination noted pallor regular rest-ing heart rate of 80 bpm blood pressure of 12064mmHgon sitting and 12268mmHg on standing and a relativetachycardia that resolved on standing All other examinationswere normal Laboratory investigations echocardiogramand MRI to rule out intracranial pathology were normal24-hour ambulatory electrocardiogram showed recurringintermittent sinus tachycardia that coincided with the patientexperiencing symptoms Due to the progressive worsen-ing in the severity of her symptoms the patient forciblyremoved herself from extracurricular activities in schoolleaving her expressing low self-esteem and worthlessnessdue to the feelings of ldquovulnerabilityrdquo upon standing Withher symptoms having such a negative impact on her lifephysically socially and psychologically she became reclusiveand isolated and was diagnosed with depression by theadolescent psychiatrists Following review by a cardiologistthe following year the possibility of PoTS was consideredDiagnostic TTTwas conducted which identified an elevationin her heart rate from 80 whilst supine to 140 bpm within 10minutes of standing in the absence of orthostatic hypotension(supine blood pressure 11473mmHg blood pressure within10 minutes of standing 12482mmHg) thus confirming adiagnosis of PoTS

Therapies such as an increase in fluids to 3 litres per dayslow sodium MR (up to 600mg eight per day) fludrocorti-sone (up to 200 120583g once daily) and midodrine (maximum5mg three times daily escalation ofmidodrine to 10mg threetimes daily resulted in peripheral vasospasm and intermittentloss of sensation in both hands and feet) were sequentially

trialled either as monotherapy or in combination with noresolution of symptoms As the frequency of symptomsincreased further the patient felt ldquoinhibitedrdquo by her symp-toms started to take excessive periods off school and feltldquoimmense dreadrdquo at the prospect of returning to schoolWithno effective symptomatic control the patient was trialled on25 120583g of SC octreotide three times daily that was titrated to50 120583g six times daily (300 120583g24 h) coverage for this methodwas obtained via an ldquoindividual patient funding requestrdquo tothe local medicines management group Although providinga degree of symptomatic control which allowedher tomanageeffectively at university her quality of life was significantlyhindered by the nausea and diarrhoea associated with eachinjection Furthermore she also reported bladder dysfunc-tion acne hair loss dysmenorrhoea and intermittent vaginalbleeding following the initiation of octreotide As a result ofthe adverse side effects from the intermittent injections sheunderwent a trial of octreotide administered via an insulinpump

22 Treatment

221 Case 1 Following an initial period of education on howto use the insulin pump by a specialist diabeticendocrinenurse the patient received 10 120583g of octreotide per hour fora total of 12 hours (120 120583g24 h) over a course of two weeksthrough the Animas 2020 insulin pump coverage for thismethod was obtained in an identical manner as for patient1 She replaced her reservoir (20mL cartridge) on alternatedays and the cannula and infusion set (inset II infusion set6mm cannula 60 cm (2310158401015840) tubing) were replaced every thirdday

222 Case 2 After education on use of an insulin pump by aspecialist diabeticendocrine nurse the patient received 11120583gof octreotide per hour for a total of 12 hours (132 120583g24 h)over a three-month period via the aforementioned insulinpump Due to personal preference the patient replaced bothher infusion (inset II infusion set 6mm cannula 60 cm (2310158401015840)tubing) and cannula set on a daily basis

23 Outcome

231 Case 1 Following the two-week period the patientreported a remarkable transformation in both physical andsocial functioning She was no longer wheelchair dependentand was able to maintain an upright posture with no sideeffects Additionally she reported a significant improvementin her quality of life and given the vast improvement in hersymptoms she could return to work and conduct basic taskswithout suffering from disabling orthostatic symptoms Todate the patient reports no adverse effects resulting fromeither her underlying PoTS or use of the insulin pumpand remains well controlled on a treatment regimen of SCoctreotide 120 120583g24 h via an insulin pump

232 Case 2 At her 3-month review the patient was com-pletely transformed and elated She reported a significant

Case Reports in Medicine 3

improvement in her functionality with none of the sideeffects she had experienced with the intermittent injectionsThe dysmenorrhea and acne resolved with the use of athird-generation oral contraceptive pill and her hair losshad improved her intermittent vaginal bleeding being wasattributed to the use of intermittent octreotide Presently thepatient remains asymptomatic on a combination of 11 120583g perhour for an average of 14 waking hours a day of octreotidevia an insulin pump in combination with 5mg of midodrinethree times daily 200 120583g of fludrocortisone once daily and600mg of slow sodium six per day The patient reports nodifficulties in using the insulin pump

3 Discussion

Postural Tachycardia Syndrome (PoTS) is a heterogeneousgroup of disorders clinically defined in adults as a sustainedrise in heart rate ofge30 beats perminute (bpm) or an increasein heart rate to ge120 bpm within 10 minutes of movementfrom a supine to upright position or head-up tilt [1 2]However differing diagnostic criteria exist for paediatricpatients aged 14 or above whereby PoTS is defined as a rise inheart rate ge40 bpmwithin 5 minutes of standing from supineposition or head-up tilt [3] Despite a number of cases andcase series in the literature there is presently no concreteepidemiological data regarding the exact prevalence of PoTSHowever PoTS is noted to primarily affect women (ratio of5 1) who are predominantly young but the age range canextend between 15 and 50 years [4ndash6]

With such sparse information regarding the intricaciesof this condition PoTS reflects a syndrome that is com-monly unfamiliar to the vast majority of physicians therebyresulting in the condition being significantly underdiagnosedwithin the medical community It is this lack of awareness ofPoTS that unfortunately exposes patients with this conditionto the various orthostatic symptoms described in our casesMoreover patients are left exposed to suffering from the lossin both physical and psychological functioning arising fromPoTS due to the lengthy period of time between presentationand diagnosis

Although the diagnosis of PoTS can be confirmedrelatively easily with the use of tilt table testing (TTT)management of this condition in the absence of establishedprotocol or guidelines can be challenging However thereis evidence for a handful of both pharmacological andnonpharmacological adjuncts that can achieve symptomaticcontrol of PoTS [1 6] These agents are not without adverseeffects which in some scenarios such as those described inour cases can further impede the existing impaired qualityof life [6] In cases of PoTS refractory to established agentsoctreotide is often utilised as the final therapeutic choice afterother alternatives have been exhausted [7]

Octreotide is a somatostatin analogue which binds withhigh affinity to somatostatin receptor subtypes 2 and 5 [8]The principal mechanism of action for this agent in thetreatment of PoTS is to stimulate vasoconstriction in splanch-nic vasculature thus increasing venous return [6] Presentlythere are currently two methods of delivery by which

octreotide can be administered to the patient Short-acting(ie immediate release) octreotide is injected subcutaneouslyin the hip thigh or abdomen between 2 and 6 times per dayIn contrast long-acting octreotide analogue injections aredelivered intramuscularly into the gluteal muscle once every4 weeks [9]

Although the evidence base for use of octreotide inPoTS is substantially limited the few trials conducted haveidentified it as a useful treatment option [7 10 11] Howeveroctreotide has side effects dependent on the method ofadministration Intermittent subcutaneous injections resultin nausea abdominal pain and diarrhoea all of whichoccurred in the cases described Furthermore long-termadministration has been associated with development ofimpaired glucose tolerance biliary stasis and rarely overthyperglycaemia [8 9] In addition to this use of presentformulations of octreotide exposes patients to the physicaldiscomfort and possible psychological stigma associated withrepeated injection use Another limitation to the use ofoctreotide is its financial implication The annual costs canrange from m1350 to m13100 depending on the formulationand dosage used [9]

Our cases highlight a novel method of delivery toovercome the side effects of the intermittent subcutaneousinjections as well as the cost of the analogue preparationsFor our case series we had internally calculated the 5-yearlycost of delivering octreotide via an insulin pump to beapproximately m5200 (estimates used m4000 every 5 years forthe insulin pump m1400 per year for consumables and m3000per year for octreotide (100 120583gmL ampoules 4 ampoulesevery 3 days) total cost over 5 years of m26000 total cost peryear of m5200) which is substantially less than the estimatedm24000 per year for long-acting release of octreotide at40mg every 3 weeks Furthermore as the total daily dosagerequired was lower compared to the dosage received viaintermittent SC octreotide and octreotide was only beingdelivered during waking ambulant hours the patientsrsquo risk oflong-term exposure is at least theoretically reduced Finallywith fewer injections being required with this method itreduces the burden of physical discomfort and the stigmaassociated with injecting

Although insulin pumps are primarily used for themanagement of diabetes their use has also been documentedin other conditions such as Addisonrsquos disease [12] Withregard to their use in PoTS there is anecdotal evidence tosupport this despite no literature presently documenting suchclaims In our documented cases both patients withdrewoctreotide from a vial that was then inserted into the insulincartridges for the corresponding insulin pump Additionallyeach patient received an hourly timed dose via the insulinpump during waking hours approximately 12 hours for eachpatient which was increased to 15 120583g during periods ofphysiological stress for example whilst exercising

In cases refractory to established treatments both physi-cians and patients can be overwhelmed by the prospect of noeffective management option being available Here we reportwhat we believe to be the first series of two such refractorycases of PoTS where symptom relief was obtained by thenovel delivery of octreotide via an Animas insulin pump


This technique provides physicians with another therapeuticoption in the armamentarium against PoTS that cliniciansmay consider utilising in the management of this condition

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B P Grubb Y Kanjwal and D J Kosinski ldquoThe posturaltachycardia syndrome a concise guide to diagnosis and man-agementrdquo Journal of Cardiovascular Electrophysiology vol 17no 1 pp 108ndash112 2006

[2] R Freeman W Wieling F B Axelrod et al ldquoConsensusstatement on the definition of orthostatic hypotension neurallymediated syncope and the postural tachycardia syndromerdquoAutonomic Neuroscience Basic amp Clinical vol 161 no 1-2 pp46ndash48 2011

[3] W Singer D M Sletten T L Opfer-Gehrking C K Brands PR Fischer and P A Low ldquoPostural tachycardia in children andadolescents what is abnormalrdquo Journal of Pediatrics vol 160no 2 pp 222ndash226 2012

[4] H Abed P Ball and L-X Wang ldquoDiagnosis and managementof postural orthostatic tachycardia syndrome a brief reviewrdquoJournal of Geriatric Cardiology vol 9 no 1 pp 61ndash67 2012

[5] Y Kanjwal D Kosinski and B P Grubb ldquoThe posturalorthostatic tachycardia syndrome definitions diagnosis andmanagementrdquo Pacing and Clinical Electrophysiology vol 26 no8 pp 1747ndash1757 2003

[6] S Carew M O Connor J Cooke et al ldquoA review of posturalorthostatic tachycardia syndromerdquo Europace vol 11 no 1 pp18ndash25 2009

[7] A E French C Shepherd A Horne et al ldquo160 High doseoctreotide a novel therapy for the treatment of drug refractorypostural orthostatic tachycardia syndrome in patients with jointhypermobility syndromerdquoHeart vol 97 supplement 1 ppA89ndashA90 2011

[8] S W J Lamberts A-J Van der Lely W W De Herder and LJ Hofland ldquoOctreotiderdquoThe New England Journal of Medicinevol 334 no 4 pp 246ndash254 1996

[9] British National Formularly httpwwwmedicinescompletecommcbnfcurrentPHP5808-octreotide-non-proprietaryhtm

[10] R D Hoeldtke K D Bryner M E Hoeldtke and G HobbsldquoTreatment of postural tachycardia syndrome a comparison ofoctreotide andmidodrinerdquoClinical Autonomic Research vol 16no 6 pp 390ndash395 2006

[11] R D Hoeldtke K D Bryner M E Hoeldtke and G HobbsldquoTreatment of autonomic neuropathy postural tachycardia andorthostatic syncope with octreotide LARrdquo Clinical AutonomicResearch vol 17 no 6 pp 334ndash340 2007

[12] K Loslashvas and E S Husebye ldquoContinuous subcutaneous hydro-cortisone infusion in Addisonrsquos diseaserdquo European Journal ofEndocrinology vol 157 no 1 pp 109ndash112 2007

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13690mmHg blood pressure within 10 minutes of standing148103mmHg)

Initial management included an increase in both fluidintake to 3 litres per day and salt intake through slowsodium MR (600mg 10 per day) Medications includingfludrocortisone (300 120583g once daily) bisoprolol (25mg twicedaily) paroxetine (20mg once daily) midodrine (5mg threetimes daily) and ivabradine (75mg twice daily) were trialledboth serially and then in combination but each proved to beineffective Subcutaneous (SC) octreotide was trialled withthe dose increasing from 25 120583g twice daily to 50120583g at 90-minute intervals six times a day (300 120583g24 h) Despite symp-tomatic relief she reported excruciating abdominal crampsand episodes of diarrhoea occurring invariably followingeach injection The escalating orthostatic symptoms resultedin her being wheelchair dependent and the progressivedecline in her quality of life culminating in her being forcedto withdraw from her job and suffering an episode ofclinical depression The severity and frequency of side effectsprompted the notion of possibly administering SC octreotidevia an insulin pump

212 Case 2 A 14-year-old girl presented to her gen-eral practitioner with a year long history of intermittentheadaches associated with palpitations light headednessnausea dizziness and ldquogoing palerdquo upon standing froma supine position Additionally she reported experiencingldquotunnel visionrdquo which preceded brief episodes of loss ofconsciousness Initial examination noted pallor regular rest-ing heart rate of 80 bpm blood pressure of 12064mmHgon sitting and 12268mmHg on standing and a relativetachycardia that resolved on standing All other examinationswere normal Laboratory investigations echocardiogramand MRI to rule out intracranial pathology were normal24-hour ambulatory electrocardiogram showed recurringintermittent sinus tachycardia that coincided with the patientexperiencing symptoms Due to the progressive worsen-ing in the severity of her symptoms the patient forciblyremoved herself from extracurricular activities in schoolleaving her expressing low self-esteem and worthlessnessdue to the feelings of ldquovulnerabilityrdquo upon standing Withher symptoms having such a negative impact on her lifephysically socially and psychologically she became reclusiveand isolated and was diagnosed with depression by theadolescent psychiatrists Following review by a cardiologistthe following year the possibility of PoTS was consideredDiagnostic TTTwas conducted which identified an elevationin her heart rate from 80 whilst supine to 140 bpm within 10minutes of standing in the absence of orthostatic hypotension(supine blood pressure 11473mmHg blood pressure within10 minutes of standing 12482mmHg) thus confirming adiagnosis of PoTS

Therapies such as an increase in fluids to 3 litres per dayslow sodium MR (up to 600mg eight per day) fludrocorti-sone (up to 200 120583g once daily) and midodrine (maximum5mg three times daily escalation ofmidodrine to 10mg threetimes daily resulted in peripheral vasospasm and intermittentloss of sensation in both hands and feet) were sequentially

trialled either as monotherapy or in combination with noresolution of symptoms As the frequency of symptomsincreased further the patient felt ldquoinhibitedrdquo by her symp-toms started to take excessive periods off school and feltldquoimmense dreadrdquo at the prospect of returning to schoolWithno effective symptomatic control the patient was trialled on25 120583g of SC octreotide three times daily that was titrated to50 120583g six times daily (300 120583g24 h) coverage for this methodwas obtained via an ldquoindividual patient funding requestrdquo tothe local medicines management group Although providinga degree of symptomatic control which allowedher tomanageeffectively at university her quality of life was significantlyhindered by the nausea and diarrhoea associated with eachinjection Furthermore she also reported bladder dysfunc-tion acne hair loss dysmenorrhoea and intermittent vaginalbleeding following the initiation of octreotide As a result ofthe adverse side effects from the intermittent injections sheunderwent a trial of octreotide administered via an insulinpump

22 Treatment

221 Case 1 Following an initial period of education on howto use the insulin pump by a specialist diabeticendocrinenurse the patient received 10 120583g of octreotide per hour fora total of 12 hours (120 120583g24 h) over a course of two weeksthrough the Animas 2020 insulin pump coverage for thismethod was obtained in an identical manner as for patient1 She replaced her reservoir (20mL cartridge) on alternatedays and the cannula and infusion set (inset II infusion set6mm cannula 60 cm (2310158401015840) tubing) were replaced every thirdday

222 Case 2 After education on use of an insulin pump by aspecialist diabeticendocrine nurse the patient received 11120583gof octreotide per hour for a total of 12 hours (132 120583g24 h)over a three-month period via the aforementioned insulinpump Due to personal preference the patient replaced bothher infusion (inset II infusion set 6mm cannula 60 cm (2310158401015840)tubing) and cannula set on a daily basis

23 Outcome

231 Case 1 Following the two-week period the patientreported a remarkable transformation in both physical andsocial functioning She was no longer wheelchair dependentand was able to maintain an upright posture with no sideeffects Additionally she reported a significant improvementin her quality of life and given the vast improvement in hersymptoms she could return to work and conduct basic taskswithout suffering from disabling orthostatic symptoms Todate the patient reports no adverse effects resulting fromeither her underlying PoTS or use of the insulin pumpand remains well controlled on a treatment regimen of SCoctreotide 120 120583g24 h via an insulin pump

232 Case 2 At her 3-month review the patient was com-pletely transformed and elated She reported a significant



3 Discussion














References


















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















3 Discussion














References


















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















References


















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















case report treatment of refractory postural tachycardia...

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