University of Groningen Patterns of orthostatic hypotension and the evaluation of syncope van Wijnen, Veera Kariina

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Patterns of orthostatic hypotension and the evaluation of syncope

van Wijnen, Veera Kariina

DOI:

10.33612/diss.112725119

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van Wijnen, V. K. (2020). Patterns of orthostatic hypotension and the evaluation of syncope. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.112725119

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CHAPTER

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SUMMARY

The average adult stands up approximately 50-60 times per day. The human body has efficient neural cardiovascular control mechanism to compensate for the rapid downward gravitational shift of about 500 cc of blood. Nonetheless, orthostasis is a frequent trigger for hypotension with light-headedness and syncope in young and older adults. Cardiovascular responses evoked during active standing are therefore a simple means of assessing short-term neural cardiovascular control.

The first aim of this thesis was to detect and define the different orthostatic blood pressure recovery patterns in the first 180 seconds of standing i.e. initial orthostatic hypotension, delayed blood pressure recovery and sustained orthostatic hypotension. The second aim was to provide insight into the evaluation and management of syncope patients in the emergency department and syncope unit. The following paragraphs discuss the main findings of this thesis, implications of the results and future perspectives on patient care and research.

Part I: Orthostatic blood pressure recovery patterns

Chapter two is a comprehensive review discussing age-related changes in cardiovascular control

in healthy subjects. It is based on research from the past 30 years using noninvasive beat-to-beat blood pressure monitoring. It defines the spectrum of abnormal orthostatic blood pressure recovery patterns within the first 180 s of standing.

In order to define these definitions, normal age-related changes in young and older adults were studied. In healthy adults, regardless of age, blood pressure upon standing will on average recover to supine baseline values within 30 seconds of standing. However, failure of mechanisms that control arterial blood pressure throughout life can influence the capability of orthostatic blood pressure to recover, resulting in transient or sustained hypotension. Initial orthostatic hypotension, defined as a fall in systolic blood pressure of >40 mmHg within 15 seconds of standing and quick recovery within 30 seconds, is a common cause of (pre)syncope in young adults. The clinical meaning in older adults is still debated, because it has not been linked to outcomes such as falls and syncope. Delayed blood pressure recovery was defined as a decrease in systolic blood pressure of >20 mmHg at 30 seconds of standing, but with full recovery within 3 minutes of standing. It is increasingly recognized as risk factor for injurious and unexplained falls, and furthermore associated with cardiovascular morbidity and mortality. Sustained orthostatic hypotension was defined as a sustained decrease in systolic blood pressure of >20mmHg or diastolic blood pressure of >10 mmHg during 60 - 180 seconds of standing. The definitions formed on the basis of the studies in chapter two have been used throughout this thesis.

Chapter three is a review article providing a practical guide to active standing testing and

analysis using continuous non-invasive blood pressure monitoring. Following chapter two, this chapter aimed to improve comparability and clinical utility of the active lying-to-standing test

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with continuous blood pressure measurement. The differences between intermittent blood pressure measurement and non-invasive finger arterial pressure measurement were addressed. Intermittent measurement is easy to perform and interpret, but is only suitable in steady state conditions and automated devices take 30-45 seconds. If performed correctly, non-invasive continuous measurement during orthostasis is a powerful tool in assessing individuals at risk of falls, syncope and autonomic disorders.

Chapter four is a retrospective study of young adults (≤30 years) who visited the syncope unit

in a tertiary referral center. From 371 young adults 26 (7%) patients were diagnosed with initial orthostatic hypotension as the primary cause for episodes of (pre)syncope. This study aimed to assess the frequency of an abnormally large fall in systolic blood pressure upon standing in patients with a typical clinical diagnosis of initial orthostatic hypotension i.e. they all had a typical history of frequent complaints of severe light-headedness and on occasion syncope in the first 15 s after active standing up.

The main finding was that in 42% of these young patients the clinical diagnosis could not be confirmed with a positive measurement result, i.e. initial orthostatic hypotension during continuous blood pressure measurement. Thus, the diagnosis of initial orthostatic hypotension as the cause of (pre)syncope is based on a typical history and after the exclusion of sustained orthostatic hypotension. The absence of a large fall in systolic blood pressure during the clinical evaluation in these patients is likely explained by factors like time of the day and the short period in supine position before standing up (5-10 minutes). It is known that sleep, supine posture and physical activity have a direct impact on orthostatic intolerance.

This study also showed that buttock clenching is the ideal method to combat this large fall in blood pressure. Buttock clenching is easy to perform in young adults and with disappearance of symptoms the diagnosis is confirmed. Lastly, arising from squatting is a known trigger for initial orthostatic hypotension and this provocation can be used to diagnose and educate patients with complaints of initial orthostatic hypotension.

Chapter five describes a prospective cohort study in 116 suspected (pre)syncope patients in the

emergency department. In this study continuous non-invasive BP monitoring during the active lying-to-standing test was used to determine the frequency of abnormal orthostatic BP recovery patterns. In this population nearly half of the (pre)syncope patients had an abnormal orthostatic blood pressure pattern. This suggests that continuous non-invasive blood pressure measurement can potentially identify more specific and concerning causes of (pre)syncope, especially because a final diagnosis was missing in a number of these patients. It is known that initial orthostatic hypotension and sustained orthostatic hypotension are under recognized causes of syncope by emergency physicians. A better understanding of these orthostatic syndromes is important in differentiating between causes of syncope upon standing.

SUMMARY AND FUTURE PERSPECTIVES

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Chapter six is a prospective cohort study describing the hemodynamic changes underlying the

orthostatic blood pressure patterns following chapter 5. This was the first study to investigate the hemodynamic changes in a real life situation (i.e. the emergency department) and the first to investigate the underlying causes of delayed blood pressure recovery. The main finding was that an impaired increase in systemic vascular resistance was the main determinant of a delayed blood pressure recovery. This suggests that both the use of vasodilators and impaired sympathetic vasoconstrictor function should be considered as a cause of delayed blood pressure recovery.

This chapter also covered the changes underlying normal blood pressure recovery, initial orthostatic hypotension and sustained orthostatic hypotension. In patients with sustained orthostatic hypotension a wide range of changes in blood pressure, heart rate, cardiac output and systemic vascular resistance were seen. This indicates that multiple mechanisms can cause hypotension (e.g. solely or a combination of hypovolemia, autonomic dysfunction, medication).

The hemodynamic changes underlying initial orthostatic hypotension were conspicuously similar to the findings in chapter four. In general, the fall in blood pressure upon standing is a mismatch between an increase in cardiac output (due to a central shift in blood volume increasing cardiac filling) and decrease in systemic vascular resistance (due to rapid vasodilatation in contracting leg muscles).

Chapter seven is an invited editorial discussing the findings of an observational study in 3174

community-dwelling adults aged 50 years and over in Ireland. In this study the longitudinal association between symptomatic orthostatic hypotension at 30 s of standing and the occurrence of incident late-life depression in the TILDA cohort is reported.

The conclusion of the editorial was that the association found between symptomatic delayed blood pressure recovery and incident late life depression is a complex and probably multifactorial relationship. The association found may be related to the strain of repetitive episodes of arterial hypotension resulting in cerebral hypoperfusion in patients with (symptomatic) delayed blood pressure recovery on standing. These findings suggest that physicians should ask their patients whether they experience light-headedness upon standing. If so, intensive antihypertensive treatment should be individualized to mitigate their possible negative impact on initial orthostatic blood pressure control and related morbidity.

Chapter eight is an editorial letter in which a patient case is discussed about the distinction

between delayed orthostatic hypotension (orthostatic hypotension past 3 minutes of standing) and vasovagal reflex syncope during head-up tilt. Because reflex syncope and delayed orthostatic hypotension are both characterized with a phase of hemodynamic instability, it is not easy to differentiate. In this chapter it is argued that delayed orthostatic hypotension in older adults can be interpreted as either a vasovagal reflex preceded by a prolonged phase of hemodynamic instability (presyncope) or as a form of mild autonomic dysfunction. Inducing syncope will distinguish between both forms, since vasovagal reflex syncope will show a characteristic steep fall in blood pressure and without exception a terminal decrease in heart rate.

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PART II: Syncope - evaluation and management

Chapter nine and chapter ten are based on a prospective cohort study in 101 suspected (pre)

syncope patients referred to the emergency department and subsequently seen at the syncope unit for further evaluation and management. Follow-up was one year.

Chapter nine describes the diagnostic accuracy of the initial evaluation at the emergency

department in pre (syncope) patients. The diagnostic accuracy of the evaluation by initial treating physicians was compared with the evaluation of the research physician following the Syncope Guideline of the European Society of Cardiology (ESC). This clinical audit showed that usual clinical care resulted in a diagnostic accuracy of 65% (95% CI 56–74%), while standardised evaluation by the ESC syncope guideline resulted in a diagnostic accuracy of 80% (95% CI 71–87%; p=0.009). Diagnostic accuracy was determined by dedicated follow-up and a syncope expert committee. The evaluation by the initial treating physician was characterized by many additional investigations and consultations of other specialists. Furthermore, in most cases the ESC syncope guidelines were not complied with, e.g. orthostatic blood pressure was measured in only 40% of the patients. Results suggest that all additional investigations and consultations do not result in a higher diagnostic accuracy than standardised evaluation according to ESC guidelines, and that history taking is the most important diagnostic test in suspected syncope patients

Chapter ten is a prospective cohort study in 72 (pre)syncope patients initially seen in the emergency

department and referred to the syncope unit for follow-up. The aim was to study which patients would benefit from referral to the syncope unit using patient-reported outcome measures. The main findings of this study are that younger patients and patients with recurrent syncope showed improvement in quality of life and a decrease in recurrences, indicating that referral to a syncope unit is potentially beneficial. According the ESC syncope guidelines patients with intermediate risk, such as patients with orthostatic hypotension, should be referred to the syncope unit. However, no improvement in patient-related symptoms was found in this category of patients.

FUTURE PERSPECTIVES

Orthostatic blood pressure measurement

This thesis aimed to improve recognition of potentially harmful causes of (pre)syncope upon standing in young and older adults. Initial orthostatic hypotension is primarily recognized as a cause of (pre)syncope in younger adults, while a delayed blood pressure recovery on standing has been recognized as a cause of (injurious and unexplained) falls and is associated with morbidity and mortality in older adults. Future research should aim to unravel which determinant of the blood pressure changes during the first 60s upon standing are most relevant regarding symptoms and negative outcomes.

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There are several aspects to delayed blood pressure recovery that warrant future research. Firstly the association between a symptomatic fall in blood pressure and cerebral hypoperfusion. Recent studies suggest that the recovery of systolic blood pressure within the first 30 seconds of standing is a more determining factor in the development of symptoms than nadir or delta (1-3). In the analysis of initial orthostatic hypotension and delayed recovery the nadir blood pressure, delta blood pressure, the time to nadir (4) and the time to recovery of blood pressure should be taken into account. Secondly, to study whether orthostatic symptoms in these patients are linked to cerebral hypoperfusion with insufficient oxygen supply, near-infrared spectroscopy and transcranial Doppler ultrasonography should be involved in the study design (5,6).

Of note, measurement of noninvasive finger arterial pressure is reliable to track orthostatic changes in blood pressure, but does not display the correct absolute values (7). It is also known that symptoms related to orthostatic hypotension occur when systolic blood pressure falls to values below 80 mmHg (8). Simultaneous measurement of cerebral perfusion, oxygen supply and the occurrence of symptoms during orthostatic blood pressure measurement with a noninvasive finger arterial pressure measurement device will presumably increase reliability.

The symptoms and the implications of a delayed blood pressure recovery pattern over time can be investigated in a large prospective study in older adults at the syncope unit and falls clinic. In the syncope unit the hypothesis that delayed blood pressure recovery is a form of mild autonomic dysfunction can be investigated using cardiovascular autonomic function tests. In addition, repeated orthostatic blood pressure measurements during follow-up can be used to study the effect of stopping potentially harmful drugs. In patients with suspected mild autonomic dysfunction, progression to sustained orthostatic hypotension should be studied. During follow-up the association with injurious and unexplained falls, (pre) syncope and subsequent morbidity and mortality including cognitive impairment should be outcome measures.

Finally, the findings of future studies are important in the light of discussions on the treatment of hypertension in older adults. Further research is needed to determine whether strict antihypertensive medication in late life (i.e. introducing normotension or relative hypotension in a chronically hypertensive individual) can lead to ischemia and therefore cognitive dysfunction or late life depression (2,9-11).

Management of syncope patients in the emergency setting

The evaluation of (pre)syncope patients in the emergency department is more challenging than other settings, because the reason for referral is often a suspected serious cause of syncope (12). Furthermore, physicians work under time pressure and history taking is sometimes difficult shortly after the episode has taken place. Despite the higher chance of a serious cause of syncope in the emergency department compared to general practice, benign causes of syncope such as reflex mediated syncope are still by far the most common cause of syncope. This also accounts for the older population (13).

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This thesis aimed to emphasize the importance of thorough history taking in the emergency setting. A detailed history, however, takes time, i.e. slow medicine, which seems counterintuitive in the hectic emergency setting. Emergency physicians are trained to quickly recognize patients at high risk of adverse events and management is directed at risk stratification (14). A standardized approach, emphasizing on history taking and physical examination, has not become part of daily practice, despite the evidence that it improves diagnostic rate and decreases associated health care costs.

This also includes orthostatic blood pressure measurement. Orthostatic vital signs are not routinely tested in the emergency department, despite recommendation by the ESC and American Heart Association syncope guidelines (14,15). In fact, emergency physicians have questioned the value and importance of orthostatic blood pressure measurement (16). They argue that there is no evidence of discriminatory value, that universal performance of orthostatic vital signs on syncope patients in the emergency department are a waste of time that may mislead diagnosticians, and fails to inform the decision in regard to which patients benefit from further diagnostic testing or inpatient services. Even though this thesis aimed to explain why detection of the underlying cause is important in the emergency department, including syndromes of orthostatic intolerance, current practice and research show that focus is mainly on risk stratification. This thesis concludes that referral to the syncope unit is indicated in patients initially seen in the emergency department, with recurrent low risk syncope, or with intermediate or high risk characteristics. This to then determine the final diagnosis in order the explain the mechanism of the episode to the worried patient (i.e. more than it is not the heart or epilepsy) and determine appropriate follow-up management (14).

Future research in the emergency setting should focus on safety of referral to syncope units or referral back to the general practitioner (17). This should be a randomized controlled trial, multicenter, in patients with recurrent (pre) syncope referred to the emergency department. Patients should be randomized between follow-up at the syncope unit and referral to the general practitioner. Primary outcome measures should be diagnostic accuracy, syncope recurrence rate, quality of life and mortality. Patient-related outcome measures are increasingly recognized as important parameters and should therefore be an important part of the study design. Nevertheless, quality of life as an outcome measure is difficult to interpret because many factors can be of influence the quality of life and changes in the scores are often minimal. Therefore future studies should use both disease-specific and general quality of life questionnaires (18). Secondary outcomes would be injury or re-admission due to (pre)syncope (or unexplained falls). In older frail patients, referral to the syncope unit should also be accompanied by a referral for comprehensive geriatric assessment.

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REFERENCES

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(2) Briggs R, Carey D, Kennelly SP, Kenny RA. Longitudinal Association Between Orthostatic Hypotension at 30 Seconds Post-Standing and Late-Life Depression. Hypertension 2018 May;71 (5):946-954.

(3) van Wijnen VK, Harms MPM, Wieling W. Orthostatic Hypotension in the First Minute After Standing Up: What Is the Clinical Relevance and Do Symptoms Matter? Hypertension 2018 May;71 (5):816-818.

(4) Mol A, Reijnierse EM, Trappenburg MC, van Wezel RJA, Maier AB, Meskers CGM. Rapid Systolic Blood Pressure Changes After Standing Up Associate With Impaired Physical Performance in Geriatric Outpatients. J Am Heart Assoc 2018 Nov 6;7 (21):e010060.

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(7) Imholz BP, Wieling W, van Montfrans GA, Wesseling KH. Fifteen years experience with finger arterial pressure monitoring: assessment of the technology. Cardiovasc Res 1998 Jun;38 (3):605-616.

(8) Wieling W, Thijs RD, van Dijk N, Wilde AA, Benditt DG, van Dijk JG. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain 2009 Oct;132 (Pt 10):2630-2642.

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(10) Wright CB. Should Hypertension Be Treated in Late Life to Preserve Cognitive Function? Pro Side of the Argument. Hypertension 2018 May;71 (5):781-786.

(11) Findlay MD, Dawson J, Dickie DA, Forbes KP, McGlynn D, Quinn T, et al. Investigating the Relationship between Cerebral Blood Flow and Cognitive Function in Hemodialysis Patients. J Am Soc Nephrol 2019 Jan;30 (1):147-158.

(12) Cook OG, Mukarram MA, Rahman OM, Kim SM, Arcot K, Thavorn K, et al. Reasons for Hospitalization Among Emergency Department Patients With Syncope. Acad Emerg Med 2016 Nov;23 (11):1210-1217.

(13) Colman N, Nahm K, Ganzeboom KS, Shen WK, Reitsma J, Linzer M, et al. Epidemiology of reflex syncope. Clin Auton Res 2004 Oct;14 Suppl 1:9-17.

(14) Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli A, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018 Mar 19.

(15) Writing Committee Members, Shen WK, Sheldon RS, Benditt DG, Cohen MI, Forman DE, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: A report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2017 Aug;14 (8):e155-e217.

(16) Bloom AS, Devlin JJ. Discriminatory Value of Orthostatic Vital Signs in the Emergency Department Evaluation of Syncope. Ann Emerg Med 2017 Sep;70 (3):438-439.

(17) Sun BC, Costantino G, Barbic F, Bossi I, Casazza G, Dipaola F, et al. Priorities for emergency department syncope research. Ann Emerg Med 2014 Dec;64 (6):649-55.e2.

(18) Linzer M, Gold DT, Pontinen M, Divine GW, Felder A, Brooks WB. Recurrent syncope as a chronic disease: preliminary validation of a disease-specific measure of functional impairment. J Gen Intern Med 1994 Apr;9 (4):181-186.

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