Background: Parkinson’s disease (PD) patients often suffer from cardiac sympathetic denervation, a hallmark of which is orthostatic hypotension. Denervation supersensitivity to sympathomimetic drugs is also seen in such patients, and this phenomenon is important and can be sometimes dangerous. Case presentation: A 65-year-old male underwent gastrojejunostomy. The patient had severe PD and did not exhibit metaiodobenzylguanidine (MIBG) accumulation in his heart, which was indicative of cardiac sympathetic nerve denervation. When 8 mg of ephedrine was administered intravenously, an unexpectedly large increase in blood pressure was observed. The phenomenon recurred when 4 mg of ephedrine was administered again, and nicardipine was required to suppress the patient’s blood pressure. Conclusions: Denervation supersensitivity is not as well recognized as other complications seen in PD patients, but anesthesiologists should be aware of it because sympathomimetic drugs can have excessively strong effects in patients with the condition. Keywords: Cardiac sympathetic denervation, Denervation supersensitivity, Ephedrine, Metaiodobenzylguanidine, Parkinson’sdisease Background patients, and it has been demonstrated to be caused by car- Parkinson’s disease (PD) is a common and complex neuro- diac sympathetic nerve denervation, which results in sym- degenerative disorder. The pathological hallmark of PD is pathetic neurotransmitter noradrenaline deficiency in the loss of dopaminergic neurons within the substantia nigra heart and blood vessels . On the other hand, there have pars compacta. The resultant dopaminergic deficiency only been a few reports about excessive cardiovascular within the basal ganglia results in movement disorders, responses to sympathomimetic drugs in PD patients due to such as bradykinesia (i.e., slowness during the initiation of denervation supersensitivity [3, 4]. This phenomenon is voluntary movements with a progressive reduction in the very important and can be sometimes dangerous but seems speed and amplitude of repetitive actions), muscle rigidity, to be rarely recognized and poorly understood. resting tremors, and postural instability . In addition to Here, we present a case of suspected supersensitivity these motor features, cognitive impairment, psychiatric to ephedrine in a patient with PD. symptoms, and autonomic dysfunction are also recognized in PD patients . Of these, orthostatic hypotension, an Case presentation autonomic nerve disorder, is frequently seen in PD A 65-year-old male (160 cm, 65 kg) with gastric outlet obstruction due to a stomach ulcer scar was scheduled * Correspondence: firstname.lastname@example.org for gastrojejunostomy. His medical history included PD Department of Anesthesiology, Kindai University Faculty of Medicine, 377-2, Ohno-Higashi, Osakasayama, Osaka 589-8511, Japan and hypertension. He had suffered from PD since he was © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Shirai et al. JA Clinical Reports (2018) 4:44 Page 2 of 4 58 years old, and had then orthostatic hypotension, ratio, which was obtained 4 h after the injection of occasional tremors in both upper limbs, slow movement, I-MIBG, was 1.099 (normal range > 2.0); and the and muscle rigidity. Although supine hypertension (SH) washout rate (WOR) was 73.4% (normal range 9–20%). is recognized as a feature of cardiovascular autonomic Information on the distribution of neurons and function failure that often accompanies orthostatic hypotension of the re-uptake pathway is provided by the H/M ratio, in patients with PD, the SH was not documented in the while the WOR provides information on the sympathetic present case because the tilt test, which can detect SH drive . , was not performed. His PD symptom progression In the operating room, after the placement of standard was scored as stage 4 according to the Hoehn and Yahr monitors, a Touhy needle was inserted into the epidural scale , which consists of five stages of 1 (light) to 5 space at Th , and an epidural catheter was inserted 10–11 (severe). Stage 4 is defined as patients with severely dis- 5 cm into the epidural space. Then, 3 ml of 1% mepiva- abling disease, but still able to walk or stand unassisted. caine was injected through the catheter with no motor He was orally taking 20 mg of nicardipine for hyperten- block. General anesthesia was induced with 80 mg pro- sion, and 400 mg of levodopa, 10.8 mg of carbidopa, pofol and remifentanil, and the trachea was intubated 100 mg of entacapone, 25 mg of zonisamide, and 36 mg with the aid of 60 mg rocuronium. Anesthesia was main- of rotigotine for PD. His preoperative blood pressure tained with an oxygen/air mixture and 4.5–5% desflur- and heart rate were in good control with around 130/80 ane. Eight milliliters of 1% mepivacaine was injected into and 60–80 beats per min, respectively. His preoperative the epidural space 10 min before the operation, and a electrocardiograph showed a normal sinus rhythm with continuous infusion of 188 ml of 0.2% ropivacaine and no ST-T changes, and echocardiography revealed no 0.6 mg fentanyl into the epidural space was started at a abnormalities. However, severely decreased I-metaio- rate of 4 ml/h. Eight milligrams of ephedrine was admin- dobenzylguanidine (MIBG) accumulation in the heart istered intravenously when the patient’s blood pressure was observed. The early heart-to-mediastinum (H/M) decreased, and an unexpectedly large increase in blood ratio, which was obtained 15 min after the injection of pressure was observed. This phenomenon recurred I-MIBG, was 1.305 (normal range > 2.0); the late H/M when 4 mg of ephedrine was administered again, but Fig. 1 The patient’s anesthesia chart. Small amounts of ephedrine (8 or 4 mg) reproducibly induced large increases in blood pressure, and treatment with nicardipine, a calcium channel blocker, was required to suppress the second blood pressure increase Shirai et al. JA Clinical Reports (2018) 4:44 Page 3 of 4 this time, nicardipine was required to suppress the administration of 8 mg of ephedrine induced an patient’s blood pressure (Fig. 1). Interestingly, his heart unusually marked increase in the patient’s blood pres- rate was not affected by ephedrine (Fig. 1). At this time, sure when it was first administered. A second dose of we considered that denervation supersensitivity to ephe- ephedrine (4 mg) also induced a marked increase in drine had been induced and stopped using catechol- blood pressure. It is true that ephedrine sometimes amines. After the completion of the operation, the markedly increases either heart rate or blood pressure, patient was extubated. His postoperative course was but in the present case, the degree of the blood pressure uneventful. increases induced by small amounts of ephedrine was unusual (to the extent that nicardipine was required). Discussion Thus, we consider that the most plausible explanation We reported a case in which ephedrine unexpectedly for the observed increases in blood pressure was the caused a marked increase in blood pressure in a patient patient’s cardiac denervation supersensitivity. As the with PD, whose cardiac sympathetic nerves were almost mechanisms of denervation supersensitivity are ascribed completely denervated. Cardiac sympathetic denervation to the absence of norepinephrine uptake and/or to can be diagnosed based on a reduction in or loss of increased density of β-adrenergic receptors in MIBG accumulation in the heart. MIBG is an analog of post-synaptic membranes , drugs which do not have noradrenaline, which is taken up by adrenergic neurons β-adrenergic stimulant effects, such as phenylephrine in a similar fashion to noradrenaline, but does not and vasopressin, would be better and safer. Interestingly, undergo intracellular metabolism or exhibit physio- the blood pressure elevations by ephedrine were gradual logical activity . The early H/M ratio reflects the and continued for a while in the present case, and with- integrity of presynaptic nerve terminals and their uptake out nicardipine administration after the second ephe- functions. The late H/M ratio provides information on drine administration, the blood pressure would have neuronal functions from uptake mechanisms to the continued to increase further (Fig. 1). We cannot clarify release of neurotransmitters from the storage vesicles the reason of this phenomenon, but it may have taken located at nerve terminals. The MIBG WOR is an index time to activate intracellular signal transduction system of the degree of sympathetic drive . In the present in the heart cells. In the report of Miyamoto et al., VT case, the patient had severely low H/M ratios both in also happened 2 h after the start of noradrenaline infu- the early phase and in the late phase and a markedly sion . More interestingly, the patient’s heart rate did high washout rate, all of which were indicative of cardiac not change markedly after the administration of ephe- sympathetic denervation. drine, even though ephedrine has β-adrenergic as well Orthostatic hypotension, which can be caused by car- as α-adrenergic effects, probably because any heart diac sympathetic denervation, is easy to detect and, con- rate increase was suppressed by a reflex secondary to sequently, is well recognized in patients with PD. the rise in blood pressure. Similarly, Nakamura et al. However, denervation supersensitivity does not appear reported that dobutamine did not result in greater to be as well recognized as orthostatic hypotension, heart rate increases in PD patients than in controls, probably because it can only be detected when sym- in spite of the fact that it caused a marked elevation pathomimetic drugs are administered. In addition, it is of blood pressure . easy to overlook this phenomenon because there are so many causes of blood pressure elevations and/or heart Conclusions rate increases. Miyamoto et al. reported a case of ven- We encountered a case in which ephedrine induced an tricular tachycardia (VT) in a PD patient, which unusually large increase in blood pressure in a patient occurred after noradrenaline was administered at a rate with PD, whose cardiac sympathetic nerves were almost of 0.0 8–0.25 μg/kg/min to treat hypotension due to sep- completely denervated. We need to know that PD patients tic shock . The VT subsided when vasopressin was often suffer from cardiac sympathetic nerve denervation administered instead of noradrenaline. Furthermore, and cardiac denervation supersensitivity to sympatho- Nakamura et al. demonstrated that administering dobu- mimetic drugs. tamine at a rate of 4 μg/kg/min increased both systolic pressure and cardiac contractility more in PD patients Abbreviations than in controls, and this hyperdynamic response was MIBG: Metaiodobenzylguanidine; PD: Parkinson’s disease; VT: Ventricular significantly correlated with reduced H/M ratios . In tachycardia the current case, the patient suffered from orthostatic hypotension preoperatively and exhibited severely Availability of data and materials reduced cardiac MIBG accumulation, but his denerv- Data sharing is not applicable to this article as no datasets were generated ation supersensitivity was not recognized. However, the or analyzed during the current study. Shirai et al. JA Clinical Reports (2018) 4:44 Page 4 of 4 Authors’ contributions TS collected the data and wrote the manuscript. AK collected the data and helped TS with the preparation of the manuscript. KU, TU, MF, and TI performed the patient’s anesthetic management and helped TS with the preparation of the manuscript. SN helped TS write the manuscript and corrected English. All authors read and approved the final manuscript. Ethics approval and consent to participate Not applicable. Consent for publication The written informed consent for publication was obtained from the patient. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Received: 20 April 2018 Accepted: 27 May 2018 References 1. Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386:896–912. 2. Glodstein DS, Holmes C, Li S-T, Bruce S, Metman LV, Cannon RO III. Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med. 2000;133: 338–47. 3. Senard JM, Valet P, Durrieu G, Berlan M, Tran MA, Montastruc JL, et al. Adrenergic supersensitivity in parkinsonisms with orthostatic hypotension. Eur J Clin Investig. 1990;20:613–9. 4. Miyamoto K, Tanaka K, Tanaka T, Ide R, Hagiwara Y, Fukuda K, et al. Cardiac sympathetic denervation supersensitivity in Parkinson’s disease. J Jpn Soc Intensive Care Med (in Japanese). 2015;22:38–41. 5. Fanciulli A, Gӧbel G, Ndayisaba JP, Granta R, Duerr S, Strano S, et al. Supine hypertension in Parkinson’s disease and multiple system atrophy. Clin Auton Res. 2016;26:97–105. 6. Hoehn M, Yahr M. Parkinsonism: onset, progression and mortality. Neurology. 1967;17:427–42. 7. Agostini D, Nakajima K, Verherne HJ. Innervation of heart: imaging findings using [ I]-MIBC scintigraphy in different pathologies. In: Marzullo P, Mariani G, editors. From basic cardiac imaging to image fusion. Milan: Springer; 2013. p. 51–70. 8. Nakamura T, Hirayama M, Ito H, Takamori M, Hamada K, Takeuchi S, et al. Dobutamine stress test unmasks cardiac sympathetic denervation in Parkinson’s disease. J Neurol Sci. 2007;263:133–8. 9. Vatner DE, Lavallee M, Amano J, Finizola A, Homcy CJ, Vatner SF. Mechanisms of supersensitivity to sympathetic amines in the chronically denervated heart of the conscious dog. Circ Res. 1985;57:55–64.
JA Clinical Reports – Springer Journals
Published: Jun 6, 2018
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