Ambulatory Norepinephrine Treatment of Severe Autonomic Orthostatic

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Journal of the American College of Cardiology Vol. 37, No. 1, 2001 © 2001 by the American College of Cardiology ISSN 0735-1097/01/$20.00 Published by Elsevier Science Inc. PII S0735-1097(00)01062-7 Autonomic Dysfunction Ambulatory Norepinephrine Treatment of Severe Autonomic Orthostatic Hypotension Olaf Oldenburg, MD,* Anna Mitchell, MD,† Jens Nu¨rnberger, MD,† Susanne Koeppen, MD,‡ Raimund Erbel, MD, FACC, FESC,* Thomas Philipp, MD,† Andreas Kribben, MD† Essen, Germany

OBJECTIVES This study was designed to establish a patient-controlled, ambulatory norepinephrine treatment of refractory orthostatic hypotension due to primary autonomic failure. BACKGROUND Autonomic dysfunction leads to disabling postural hypotension. Particularly in primary autonomic dysfunction, repeated syncope and immobilization can be the result. Medical treatment of orthostatic hypotension often fails in advanced cases. METHODS Ambulatory, patient-controlled norepinephrine therapy was initiated in six patients with orthostatic hypotension due to primary autonomic failure that had been refractory to conventional treatment. Before this therapy, three patients were bedridden; one was immobilized in a wheelchair. All had recurrent syncope and tolerated upright tilt-table testing for less than 15 min despite extensive medical treatment. For ambulatory treatment, a port-a-cath system was implanted and, using a CADD ambulatory infusion pump, norepinephrine was infused in individually adjusted dosages. RESULTS Norepinephrine infusion therapy enabled all patients to sit, stay and walk around for more than 45 min. One patient died after a ﬁve-year treatment period, another after nine months because of nonhemorrhagic brain stem infarctions, both in the absence of norepinephrine treatment. The remaining four patients are still mobile after a period of 19, 10, 9 and 7 months, respectively. None of them has suffered complications due to arterial hypo- or hypertension, and there has been no infection of the infusion system. CONCLUSIONS In these selected patients with refractory orthostatic hypotension due to primary autonomic dysfunction, ambulatory norepinephrine infusion therapy has proved to be a promising new therapeutic option. Further long-term studies including more patients are necessary to assess additional indications, reliability and safety of this new method. (J Am Coll Cardiol 2001;37: 219–23) © 2001 by the American College of Cardiology

Patients with severe orthostatic hypotension due to auto- ambulatory norepinephrine-infusion system was used to nomic dysfunction have a severely impaired quality of life. treat orthostatic hypotension in selected patients with Shy- Besides other neurological problems, orthostatic hypoten- Drager or Bradbury-Eggleston syndrome. sion is one of the leading symptoms and, if advanced, is often refractory to conventional medical treatment. Because METHODS of the postural hypotension, recurrent presyncope or syncope, patients are often immobilized. Most adolescent Patients and conventional medical treatment. In six pa- patients with primary autonomic orthostatic hypotension tients with autonomic failure and orthostatic hypotension have either Shy-Drager syndrome (multiple system atrophy) refractory to conventional therapy, ambulatory patient- or Bradbury-Eggleston syndrome (idiopathic orthostatic controlled norepinephrine-infusion therapy was studied hypotension, pure autonomic failure) (1). (Table 1). The diagnoses of autonomic failure and ortho- Despite the limited reliability of plasma catecholamine static hypotension were based on the characteristic medical measurements in the supine and upright positions to estab- history, physical and extensive neurological examination, lish the autonomic origin of orthostatic hypotension (2), autonomic testing and repeated upright tilt-table tests administration of exogenous norepinephrine can maintain (4–8). Over a period of at least three months, all patients an adequate blood pressure (BP) level and can help to avoid received nonpharmacological and pharmacological therapy orthostatic hypotension (3). Thus, the aim of this study was of increasing intensity. Basic therapy consisted of increased to establish a new long-term and ambulatory treatment of ﬂuid and salt intake, elastic stockings, balneotherapy and otherwise refractory cases of orthostatic hypotension. An professional tilt training (5,9,10). Pharmacological treatment started with augmenting dosages of ﬂudrocortisone,

From the *Division of Internal Medicine, Department of Cardiology, University directly and indirectly acting sympathomimetics (mido- Hospital, Essen, Germany; †Division of Internal Medicine, Department of Nephrol- drine, norfenefrine, yohimbine, amezinium) and erythro- ogy and Hypertension, University Hospital, Essen, Germany; and the ‡Clinic of poietin (11–15). Neurology, University Hospital, Essen, Germany. Manuscript received May 3, 2000; revised manuscript received August 1, 2000, Norepinephrine treatment. The intensive nonpharmaco- accepted September 14, 2000. logical and pharmacological therapy did not improve ortho- 220 Oldenburg et al. JACC Vol. 37, No. 1, 2001 Norepinephrine Treatment of Orthostatic Hypotension January 2001:219–23 6 5 75 10 45 Abbreviations and Acronyms 10 Ͻ Ͻ Ͼ ϭ Ͻ BP blood pressure 50–100 Bedridden HUTϭ hea-up tilt table test Female MAPϭ mean arterial blood pressure 5 72 10 45 10 static hypotension and the associated symptoms in these 10 Ͻ Ͼ Ͻ Ͻ 20–50 patients (Table 1); three of them were still bedridden, and wheelchair one patient with Shy-Drager syndrome was still conﬁned to Male his wheelchair. Therefore, we tested the effects of intravenous infusion of norepinephrine. We administered norepinephrine in increasing individual dosages (5 to 20 ng/kg 4 5 57 45 10 10 250 body weight/min) using a temporary intravenous indwelling Ͻ Ͼ Ͻ Ͻ catheter and an infusion pump (Original Perfusor Braun, B. Ͼ Braun Melsungen, Melsungen, Germany). Blood pressure Male was continuously monitored (Dinamap). The administration of norepinephrine was started in the supine position. After systolic BP had risen about 20 to 30 mm Hg, the 3 5 5 5 62 45 Ͻ Ͻ patients were allowed to sit up. Then the patients were Ͻ Ͼ mobilized, and norepinephrine dosages were adjusted sev- 50–100 Bedridden Bedridden Conﬁned to eral times during standing and stopped before sitting or Female lying down. A bolus application on demand was necessary to maintain adequate BP while changing from supine to sitting or from sitting to an upright position. Additionally, it was necessary to work out two different dosages, one for sitting 2 5 73 25 25 45 10

and a higher one for standing position in some patients. Ͻ Ͻ Ͻ Ͼ Success of the temporary norepinephrine infusion was the Ͻ requirement for the implantation of a permanent Unlimited intravenous-infusion system. Female Permanent norepinephrine infusion. After elucidation about potential hazards of a continuous and self-controlled norepinephrine therapy (e.g., infections, embolization, hypertension and stroke), written informed consent was ob- 1 71 25 50 45 15 tained. A port-a-cath (SIMS Deltec Inc., St. Paul, Minne- 10 Ͻ Ͻ Ͼ Ͻ sota) system was implanted, and every patient was taught to Ͻ handle an ambulatory infusion pump (CADD, SIMS Male Deltec Inc., St. Paul, Minnesota). In cooperation with the Bradbury-Eggleston Bradbury-Eggleston Shy-Drager Shy-Drager Shy-Drager Shy-Drager patients and their relatives and during continuous noninva- sive BP monitoring, individual dosages for sitting, standing and walking were established. Individual programming of the infusion pump was necessary to ﬁnd an optimal treatment regimen. In general, mobilization and ambulation of the patients with Bradbury-Eggleston syndrome was much easier than it was for the patients with accompanying Parkinson symptoms (Shy-Drager syndrome). Before entering an upright or sitting position, the patient Patient Age (yrs) Gender Norepinephrine treatment Unlimited Conventional treatment Norepinephrine treatment Conventional treatment Without therapy had to switch on the system to start the continuous Syndrome administration of norepinephrine. Additional bolus on demand were given to ﬁll the port-a-cath system and to change from a supine to a sitting or upright position. The pump was switched off or adjusted to a lower infusion rate

immediately before sitting or lying down to avoid episodes Clinical Characteristics of Patients Treated With Norepinephrine of severe hypertension in supine or sitting positions. Follow-up. After discharge from the hospital, follow-up head-up (min) Table 1. Tilt tolerance describes theto maximal impaired tolerated condition, time of physical a strength 60° and head-up coordination tilt-table problems test due before to the parkinsonism. onset of presyncope or syncope. The limited walking distance during norepinephrine treatment in patients with Shy-Drager syndrome is due Walking distance (m) Without therapy visits at least every three months were arranged in our Tilt tolerance 60° JACC Vol. 37, No. 1, 2001 Oldenburg et al. 221 January 2001:219–23 Norepinephrine Treatment of Orthostatic Hypotension outpatient clinic. During these visits, the history and a full physical examination were obtained, and repeated BP measurements, including 24-h ambulatory measurements, were taken to determine whether the infusion dosage was still optimally adjusted. Special attention was taken to maintain the integrity of the infusion system and to watch for signs of infection. The family physician, a surgeon or an anesthesi- ologist in cooperation with a local pharmacy replaced drug cassettes, port-needles and infusion systems. Parameters of successful treatment. Success of the ther- Figure 1. apy was assessed as degree of mobilization, including deter- Changes of MAP during a 60° head-up tilt-table test (HUT) in a patient with Shy-Drager syndrome (Patient 4). Syncope occurred after mination of unimpaired walking distance, 60° upright tilt- 10 min during conventional nonpharmacological and pharmacological table tests and 24-h ambulatory BP monitoring. treatment (lower line), whereas a symptom-free 45 min test was possible Ethics. Written informed consent was obtained. The local with the patient-controlled, ambulatory norepinephrine treatment (upper line). Heart rate remained stationary in both cases. MAP ϭ mean arterial ethics committee approved the study protocol, and all blood pressure. investigations were conducted according to Good Clinical Practice guidelines. conventional treatment, whereas short episodes of hypertension occurred during a delayed turn off while sitting or RESULTS lying down or if inappropriate bolus applications were given. Long-term follow-up. Ambulatory norepinephrine ther- Symptoms and syncope. Symptoms of orthostatic hypo- apy was successful initially in all six patients in the program. tension, like dizziness, blurred vision, dyspnea and nausea, The longest therapy period was five years in a female patient were noticeably improved in all patients and limited to with Shy-Drager syndrome (Patient 6). This patient died at errors in operating the infusion pump. These consisted of age 75 years because of a nonhemorrhagic brain stem starting the infusion late on the one hand or unnecessary infarction that occurred one morning while she tried to get bolus applications with consecutive short hypertensive epi- up without starting the infusion pump. sodes on the other hand. No syncope occurred during A second non-hemorrhagic stroke was responsible for the appropriate norepinephrine infusion. death of a 72-year-old patient with Shy-Drager syndrome Walking distance. During continuous norepinephrine in- (Patient 5). In this case, ambulatory infusion therapy was fusion, all patients were mobilized and enabled to walk stopped six months earlier. Increasing compliance and around unaided. None of the patients was bedridden or coordination problems had led the family physician to stop confined to a wheelchair anymore. The walking distance in the norepinephrine treatment. Although conventional ther- patients with Bradbury-Eggleston syndrome was unlimited, apy had been reintroduced, the patient was confined to his whereas it was finite in patients with Shy-Drager syndrome. wheelchair again. Nevertheless, the latter increased their distance about 4 to The other four patients are still being treated successfully 25-fold compared with conventional medical treatment. and have been mobile for a period of 19, 10, 9 and 7 Tilt-table testing. Tilt-table results during patient- months, respectively. Infections or embolization have not controlled norepinephrine infusion improved markedly occurred in any case; hospitalization has been necessary in compared with the initial testing or combined nonpharma- only one patient (Patient 1) at one-year follow-up. cological and pharmacological (conventional) treatment (Table 1). As an example of successful norepinephrine DISCUSSION therapy, Figure 1 shows the tilt-table results of a patient with Shy-Drager syndrome (Patient 4). During conven- Autonomic orthostatic hypotension is a rare but severely tional treatment, orthostatic hypotension with syncope oc- disabling condition. Impaired autonomic reflexes with in- curred after 10 min at a mean arterial BP of 50 mm Hg, adequate rise of plasma catecholamine levels and an almost whereas norepinephrine infusion enabled the patient to fixed heart rate lead to a decrease in BP because of the tolerate 45 min of tilt-table testing without symptoms. In deficient vasoconstrictor tone and the lack of increase in both cases, heart rate did not change notably. heart rate (16,17). The upright position is associated with Ambulatory BP measurements. Intermittent and contin- symptoms like blurred vision, light-headedness, dizziness, uous 24-h BP measurements showed markedly reduced head and neck discomfort, presyncope or even syncope. episodes of orthostatic hypotension during norepinephrine Conventional treatment. The conventional approach in infusion therapy. Figure 2 shows the example of a patient treating patients with autonomic orthostatic hypotension with Shy-Drager syndrome (Patient 4) in whom recurrent consists of a combination of nonpharmacological and phar- episodes of orthostatic hypotension were successfully macological regimens of increasing intensity (5,9– treated with the new therapy. In general, supine hyper- 12,14,15,18,19). Regardless of optimal nonpharmacological tensive episodes were markedly decreased compared with or pharmacological treatment, the autonomic insufficiency 222 Oldenburg et al. JACC Vol. 37, No. 1, 2001 Norepinephrine Treatment of Orthostatic Hypotension January 2001:219–23

Figure 2. Ambulatory blood pressure measurements (MAP) during medical treatment (dashed line) and patient-controlled norepinephrine treatment (solid line) in a patient with Shy-Drager syndrome (Patient 4). The initial drop in MAP at 8:30 h during norepinephrine treatment was due to a delayed start of the infusion pump; the high pressure at 14:50 h was due to an inadvertent additional bolus application. The blood pressure drops at night, especially during conventional treatment, are due to recurrent postural changes during micturition because of urinary incontinence. MAP ϭ mean arterial blood pressure. can lead to immobilization and confinement to bed in toms (Bradbury-Eggleston syndrome) than it was for pa- advanced cases. Another disadvantage of the conventional tients with Shy-Drager syndrome. Even this therapeutic medical treatment is the development or the worsening of approach will not prevent serious complications of the hypertension in patients who remain in the supine position underlying disease in all instances. But although difficulties (20). arose in some cases, an improved quality of life was Norepinephrine infusion. Polinsky et al. (3) first used a conveyed to patients with both syndromes. temporary norepinephrine infusion to overcome orthostatic Conclusions. In selected patients with severe and refrac- hypotension during tilt-table testing in two patients with tory orthostatic hypotension due to autonomic failure, Shy-Drager syndrome. The aim of the current study was to ambulatory and patient-controlled norepinephrine treat- establish an ambulatory and long-term treatment of ortho- ment seems to be a promising long-term therapy in com- static hypotension in cases of severe autonomic failure. We pliant patients. However, further studies enrolling larger tested the effects of a patient-controlled, ambulatory nor- patient numbers are necessary to establish the role of epinephrine infusion therapy on BP in supine, sitting and ambulatory norepinephrine infusion in the treatment of upright positions. In all patients, norepinephrine infusion autonomic orthostatic hypotension and to assess additional prevented symptomatic orthostatic hypotension; mobiliza- indications, reliability and safety of this new method. tion was possible in all cases, and some patients were able to walk for the first time in months. Reprint requests and correspondence: Dr. Olaf Oldenburg, Infusion system. The port-a-cath system is a widely used Division of Internal Medicine, Department of Cardiology, Uni- system for intermittent application of different chemother- versity Hospital Essen, Hufelandstrasse #55, D-45122 Essen, apeutic agents, mostly in patients with cancer or AIDS. In Germany. E-mail: [email protected]. patients with an impaired immune system, the overall complication rate is 13% to 19%; infections occur in 2% to 5% and occlusions in 3% to 6.5% of all cases (21,22). We REFERENCES have not observed complications related to the implantable venous catheter system. 1. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Consensus statement on the Advantages and limitations. The major advantages of the definition of orthostatic hypotension, pure autonomic failure and new therapeutic tool were the ability to mobilize patients multiple system atrophy. Neurology 1996;46:1470. previously confined to bed and to avoid syncope. The 2. Meredith IT, Eisenhofer G, Lambert GW, Jennings GL, Thompson J, Esler MD. Plasma norepinephrine responses to head-up tilt are efficacy has been well-documented in symptom-free misleading in autonomic failure. Hypertension 1992;19:628–33. head-up tilt-table tests and in increased walking distance. 3. Polinsky RJ, Samaras GM, Kopin IJ. Sympathetic neural prosthesis for Treatment on demand meant that pre-existing hypertension managing orthostatic hypotension. Lancet 1983;1:901–4. 4. Mathias CJ. Orthostatic hypotension: causes, mechanisms and influ- present in the supine position was not aggravated. The encing factors. Neurology 1995;45:S6–11. requirement of compliant patients, who can handle the 5. Grubb BP, Karas B. Clinical disorders of the autonomic nervous system, is a possible limitation of this new therapeutic system associated with orthostatic intolerance: an overview of classifi- cation, clinical evaluation and management. Pacing Clin Electro- approach. Mobilization proved to be much easier in patients physiol 1999;22:798–810. without accompanying Parkinson-like neurological symp- 6. Goldstein DS, Holmes C, Cannon RO, III, Eisenhofer G, Kopin IJ. JACC Vol. 37, No. 1, 2001 Oldenburg et al. 223 January 2001:219–23 Norepinephrine Treatment of Orthostatic Hypotension

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