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Head-up Tilt Table Testing
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Head-up Tilt Table Testing Wayne O. Adkisson and David G. Benditt
CHAPTER OUTLINE Historical Background
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Transient Loss of Consciousness and Syncope
630
Pathophysiology of Loss of Consciousness
630
Approach to the Diagnosis of Syncope
631
Physiological Impact of Upright Posture
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Reflex Faints
632
Head-up Tilt as a Useful Model of Spontaneous Vasovagal Syncope
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Pathophysiology of Orthostatic Hypotension
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Orthostatic Provocation for Assessing Susceptibility to Vasovagal Syncope and Orthostatic Hypotension 633 Protocols for Head-up Tilt Table Testing and Active Standing Test
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Video-Electroencephalogram Monitoring
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Laboratory Environment and Patient Preparation
635
Active Standing Versus Head-up Tilt Test
636
Reproducibility of Head-up Tilt Table Testing and Active Standing Test
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Risks and Complications
636
Head-up Tilt Testing and Treatment of Vasovagal Syncope 636 Overview of Uses for Head-up Tilt Table Testing
636
Conclusions 636
Historical Background Head-up tilt has been used for more than half a century by physiologists and physicians to study cardiovascular adaptation to changes in position, to model responses to hemorrhage, and to evaluate hemodynamic and neuroendocrine responses in congestive heart failure, autonomic dysfunction, and hypertension. During such studies, incidental observations noted that some test subjects experienced total or near-total transient loss of consciousness due to systemic hypotension induced by the head-up tilt procedure.1–5 Further, in some cases hypotension was associated with unexpected marked bradycardia, including prolonged asystolic periods that terminated spontaneously (Fig. 67.1). By way of example, Hammill and colleagues5 used 60-degree–head-up posture in an attempt to enhance the diagnostic precision of conventional diagnostic cardiac stimulation studies. In the course of this procedure, a typical vasovagal reaction occurred in 6 of 104 subjects. The investigators noted this result but undertook no formal assessment of the observation. It was the landmark study by Kenny and colleagues6 that ultimately led to the concept of using head-up tilt as a diagnostic tool for eliciting the susceptibility to reflex syncope, and in particular vasovagal syncope (VVS). Initially, prolonged periods of head-up tilt at angles of 40 to 60 degrees were used in an attempt to provoke 630
VVS in susceptible individuals. Subsequently, to improve sensitivity of the test, additional interventions were introduced including administration of pharmacological agents (discussed in more detail later) either alone or in conjunction with physical maneuvers such as carotid sinus massage. Several of these additional provocative measures did improve the head-up tilt test sensitivity and remain in use; however, as a rule, their addition has been at the cost of lower specificity. The difficulties in assessing sensitivity and specificity of head-up tilt table testing are discussed in more detail later. Since its introduction as a clinical diagnostic laboratory tool, the uses of the head-up tilt table testing have expanded. Whereas tilt table testing remains widely accepted for the evaluation of an individual’s susceptibility to VVS in selected cases, it has also found a place, albeit less well studied, in the evaluation of (1) orthostatic hypotension (OH), (2) postural orthostatic tachycardia syndrome (POTS), and (3) psychogenic pseudosyncope/pseudoseizures.7 In this chapter, we review the role of head-up tilt table testing in the evaluation of VVS and OH, discuss limitations of such testing, and review a methodology for its use.
Transient Loss of Consciousness and Syncope For the most part, patients referred for head-up tilt table testing have previously presented with one or more apparent transient loss of consciousness (TLOC) spells. However, in certain of these cases, the presentation may not have been true loss of consciousness; consequently, the basis for referral may be more broadly viewed as consultation for assessment of self-limited spontaneous collapse (Fig. 67.2). It is the consultant’s responsibility to ascertain whether there has been “true” TLOC. If TLOC is deemed to have occurred, then the differential diagnosis primarily includes syncope, epileptic seizures, intoxications, and possibly metabolic disturbances; tilt table testing may be helpful in selected cases for distinguishing among these disorders. On the other hand, if it is determined that TLOC did not occur, then the differential diagnosis principally includes psychogenic pseudosyncope/ pseudoseizures, mechanical falls, malingering, and cataplexy (see Fig. 67.2). Tilt table testing may be particularly helpful in identifying pseudosyncope/pseudoseizures. Specifically, the individuals afflicted with this disorder are highly suggestible, and the test may demonstrate normal heart rate and blood pressure despite the patient’s head slumping over and seemingly having a loss of consciousness event. Pseudosyncope/pseudoseizure should not be confused with malingering. In our experience, it is exceedingly rare that such patients are trying to mislead by “faking” these events. The episodes are quite real to the sufferer.
Pathophysiology of Loss of Consciousness Neuronal tissue has limited energy storage capabilities; consequently, maintenance of oxygenated blood flow to the brain is critical. In healthy young individuals, cerebral blood flow (CBF) ranges from 50 to 60 mL/100 g of brain tissue per minute. This represents approximately 12% to 15% of the resting cardiac output. Blood flow of that magnitude can easily supply the minimum oxygen (O2) requirement needed to maintain consciousness, which is typically 3.0 to 3.5 mL O2/100 g tissue per minute.8–10 However, the safety margin for oxygen delivery may be severely
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FIGURE 67.1 Electrocardiogram (ECG) of a patient during spontaneous episode of vasovagal syncope. The strips are continuous and show the typical sinus rate slowing prior to the event. In this example, sinus arrest did not occur (note P waves remain visible) but progressive AV block results in ventricular asystole. The slowing of the sinus rate helps distinguish a vasovagal event from sinoatrial block or sinus pauses related to sinus node dysfunction.
Self-limited spontaneous collapse
TLOC
Yes
• Syncope • Seizure • Concussion • Intoxication • Metabolic?
No
• Psychogenic: pseudosyncope pseudoseizure • Fall • Cataplexy • Malingering
FIGURE 67.2 Schematic diagram illustrating an approach to the patient with self-limited collapse. The first step in the assessment is to determine whether there has been transient loss of consciousness (TLOC). For syncope to have occurred, TLOC must have occurred. The use and limitations of head-up tilt table testing to help differentiate among various causes of syncope is discussed in the text.
impaired in the elderly; in persons with hypertension, diabetes mellitus, or heart failure; and in hypoxemic states (e.g., chronic pulmonary disease). In general, a loss of nutrient flow to the brain for 6 to 10 seconds is sufficient to cause a loss of consciousness.11 For the most part, CBF remains adequate over perfusion pressures ranging from 50 to 170 mm Hg12,13 due to cerebral autoregulation.14 However, abrupt perfusion changes may cause transient CBF inadequacy. In the face of rapid changes in perfusion pressure, cerebral autoregulation may be unable to prevent a drop in CBF, which, if of sufficient magnitude, will result in syncope.
Approach to the Diagnosis of Syncope Many conditions may cause the physiological disturbances that result in syncope (Table 67.1). Reflex syncope, OH, and cardiac arrhythmias are among the more frequent causes. Of the reflex syncope syndromes, VVS is the most common cause of syncope
across all age groups, and consequently virtually all medical practitioners will encounter VVS patients. In the case of VVS, the diagnosis can be established in most cases by the medical history without further testing.7,15 However, when the history surrounding the event is “atypical,” even an experienced history-taker may not be able to establish a firm diagnosis. In some cases it may not be possible to obtain an adequate history, especially in the elderly.16,17 Furthermore, witnesses may not have been present, or they may be unable to provide sufficiently reliable details needed to establish a specific diagnosis. In such cases, availability of diagnostic tests becomes important. Additionally, even when VVS is evident to an experienced clinician, patients who have been subject to several previous unsuccessful evaluations may remain skeptical, and the consultant may reasonably elect to recommend additional testing in an attempt to reproduce the patient’s symptoms under controlled and observed conditions. The head-up tilt table test is the most widely available diagnostic intervention for such cases.
Physiological Impact of Upright Posture Upright posture elicits an orthostatic stress as the effects of gravity result in a redistribution of circulating blood volume in the body.1,2,4,6–8 As upright posture is achieved; the effects of gravity result in shifting of 500 to 1000 mL of blood to the lower part of the body and in particular to the highly compliant splanchnic bed.8,18 This initial redistribution is rapid and occurs in the first 10 seconds. If upright posture is maintained, over the course of 10 minutes, an additional 700 mL of protein-free fluid is filtered into the interstitial space. The combined effect of these two shifts is a reduction of venous return and stroke volume. In humans, diminution of stroke volume upon the assumption of an upright position is compensated for by both an increase in heart rate and by the constriction of both resistance and capacitance blood vessels. An increase in heart rate alone is usually insufficient to maintain cardiac output and CBF. Systemic vasoconstriction is crucial for maintenance of adequate blood pressure. Loss of consciousness can only be prevented if the compensatory mechanisms maintain arterial pressure at a level at least equal to the minimum value needed to ensure adequate CBF. Short-term cardiovascular responses triggered by orthostatic stress are primarily mediated by the autonomic nervous system via arterial mechanoreceptors (baroreceptors responding to pressure, stretch, or both) located in the aortic arch and carotid
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TABLE 67.1 Classification of the causes of syncope CARDIOVASCULAR REFLEX SYNDROMES
ORTHOSTATIC HYPOTENSION
ARRHYTHMIA
STRUCTURAL
Vasovagal syncope Carotid sinus syncope Situational: • Cough • Postmicturition • Others
Secondary autonomic failure (common): • Drug induced • Diabetes • Amyloidosis • Alcohol Primary autonomic failure (rare): • Parkinson disease • Multiple system atrophy • Lewy body dementia • Pure autonomic failure ≈15%
Bradycardia • Sinus node disease • Conduction system disease Tachycardia • Supraventricular • Ventricular Ion channel disorders
Valvular stenosis Cardiomyopathy Ischemic • Nonischemic • Hypertrophic • Arrhythmogenic Pulmonary hypertension Pulmonary emboli Aortic dissection
≈10%
≈5%
≈60% of cases of syncope ≈10% unknown
A
B FIGURE 67.3 Beat-to-beat blood pressure recordings obtained during head-up tilt-table testing. (A) and (B) were obtained from the same patient during the passive phase of head-up tilt testing. (A) demonstrates the typical oscillations often seen prior to the onset of the vasovagal reflex. At the time (A) was recorded, the patient reported no symptoms. (B) was recorded 3 minutes after (A). The patient complained of her typical premonitory symptoms at the point marked by the red arrow. Hypotension progressed and loss of consciousness occurred as the table was being returned to the supine position (yellow arrow). The concomitant bradycardia is not striking, but the heart rate did drop by more than 10%. In the VASIS schema, this would be a type I (mixed) tilt table response.
sinuses. Mechanoreceptors in the heart wall (both atria and ventricles) as well as in the lungs may contribute as well. Reflex activation of central sympathetic outflow to the systemic vasculature may be augmented by local reflex mechanisms, such as the venoarteriolar reflex. More global mechanisms such as the muscle skeletal pump (active even without overt movement) and the respiratory pump also contribute. All of these mechanisms may play a useful adjunctive role in maintaining cardiac output and arterial pressure, primarily by augmenting venous return. Failure of compensatory mechanisms during orthostatic stress, assuming no preexisting volume overload, results in impaired venous return and leads to diminished stroke volume, systemic arterial pressure, and CBF. If CBF reduction is of sufficient magnitude, loss of consciousness results. In this setting, loss of consciousness may be principally due to inadequate maintenance of blood pressure in the face of gravitational stress (i.e., “orthostatic hypotension” or “orthostatic syncope”) but may additionally be contributed to by an inappropriate reflex response resulting in vasodilation (i.e., vasodepressor response) and severe or relative bradycardia.7,8,19
Reflex Faints Reflex syncope is the preferred term encompassing all conditions in which reflexes modify heart rate (cardioinhibition) and vascular
tone (vasodepression) so as to predispose to systemic hypotension of sufficient severity to cause inadequate cerebral perfusion. Thus reflex syncope incorporates VVS, carotid sinus syndrome, and the situational faints (see later). Other umbrella terms for reflex syncope that have been used, but are less desirable, include neutrally mediated (reflex) syncope and neurocardiogenic syncope. VVS is the most common reflex syncope, but despite much study, its pathophysiology remains incompletely understood. In any case, systemic hypotension is principally due to vasodilation, mediated by a marked reduction in both the sympathetic vasoconstrictor outflow to skeletal muscle and a substantial increase in venous capacitance, especially in the splanchnic bed. Finally, a parasympathetically mediated bradycardia may also contribute, but usually has a lesser role than vasodilation for producing systemic hypotension.
Head-up Tilt as a Useful Model of Spontaneous Vasovagal Syncope Several observations suggest that symptomatic hypotension–bradycardia associated with a positive result on head-up tilt table testing is comparable to spontaneous VVS. First, both induced and spontaneous VVS episodes are associated with similar premonitory symptoms (nausea, diaphoresis) and signs (pallor, loss of postural tone). Second, the temporal sequence of blood pressure and heart rate changes during tilt-induced syncope parallels that
HEAD-UP TILT TABLE TESTING
BOX 67.1 Utility of head-up tilt testing 1. A ssess susceptibility to vasovagal syncope and/or orthostatic hypotension in a controlled and safe environment. 2. Determine whether induced symptoms correspond to spontaneous clinical symptoms. 3. Educate patients regarding warning symptoms so they may take preventive measures. 4. Potentially identify syncope mimics (e.g., psychogenic pseudosyncope). 5. Support the diagnosis in suspected postural orthostatic tachycardia syndrome. 6. Enhance patient confidence that the diagnosis (i.e., vasovagal syncope, orthostatic hypotension, or postural orthostatic tachycardia syndrome) is correct.
seen in spontaneous events (Fig. 67.3). Finally, plasma catecholamines before and during both spontaneous and tilt-induced syncope exhibit similar patterns. Specifically, there is a premonitory (before hypotension is evident) increase in circulating catecholamines with epinephrine to a greater extent than norepinephrine in both spontaneous as well as tilt-induced VVS.20,21
Pathophysiology of Orthostatic Hypotension A 2011 consensus statement provided a working definition of OH and its several common variants22; specifically, OH was defined as a drop in systolic blood pressure of ≥20 mm Hg or a drop in diastolic blood pressure of ≥10 mm Hg that usually occurs within 3 minutes of active standing or passive tilt to a minimum of 60 degrees. In hypertensive patients, a fall of at least 30 mm Hg systolic was deemed more appropriate. Moving from a supine to upright posture rarely induces syncope in healthy patients. However, a fleeting sensation of “graying out,” “dizziness,” or “unsteadiness” immediately (usually in the first 15 seconds) upon assuming an upright position is common (so-called “immediate” or “initial” OH), so much so that most individuals do not find it a cause for concern. Symptomatic immediate OH usually requires a blood pressure drop of approximately 40 mm Hg, albeit very brief such that cerebrovascular autoregulation does not have adequate time to respond.22 “Delayed” or “classical” OH is that which occurs after a period of standing or passive tilt, typically of 3 minutes (an arbitrary cut-off) or somewhat more in duration.22 Finally and less often, the blood pressure decline occurs very slowly, and the symptoms may not develop for more than 5 minutes after the posture change; this scenario may be termed “progressive” OH and is particularly difficult to recognize as the relationship to recent postural change is at best tenuous. The greater the delay in the onset of symptomatic hypotension, the more likely that the individual has moved away from a chair, bed, or other means of support, and as such has greater propensity for injury.
Orthostatic Provocation for Assessing Susceptibility to Vasovagal Syncope and Orthostatic Hypotension Several publications address the utility and indications for headup tilt testing (Box 67.1).7,23 The next European Society of Cardiology (ESC) guideline update is expected in 2017. In addition, the Heart Rhythm Society recently commented on the staffing requirements for performing head-up tilt table testing.24 Finally, an American College of Cardiology/American Heart Association Syncope guideline, which will include recommendations related to the use of head-up tilt table testing, is to be published in 2016. Increasingly, laboratories that undertake head-up tilt table testing are encouraged to include an active standing test component.7 Active standing, unlike the passive head-up tilt, activates
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TABLE 67.2 Indication for head-up tilt table testing CLASS
LEVEL OF EVIDENCES
I
B
I
C
IIa
C
IIb
C
III
B
III
C
CLINICAL SETTING Single episode of unexplained syncope in high-risk setting or occupational implications Recurrent in absence of structural heart disease Syncope in setting of heart disease when cardiac causes have been excluded If there is clinical value in demonstrating susceptibility to reflex syncope to the patient To discriminate reflex syncope from orthostatic hypotension To discriminate syncope with jerking movements from epilepsy Evaluation of recurrent unexplained falls Evaluation of frequent syncope and the possibility of psychiatric illness Not recommended to assess efficacy of therapy Isoproterenol tilt testing should not be done in patients with ischemic heart diseases
Modified from Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J. 2009;21:2631-2671.
skeletal muscle pumps. The ESC guidelines7 recommend active standing as the test of choice for suspected OH. During such testing, we recommend use of noninvasive beat-to-beat blood pressure monitoring. We also prefer a 5- to 10-minute active standing test duration as opposed to the 3-minute test recommended in the ESC guidelines.7 Indications for head-up tilt table testing are summarized in Table 67.2.7 There is general agreement that tilt table testing should be used primarily for confirming a suspected diagnosis. This latter point is important since false-positive tests do occur (especially in young patients); consequently, in the absence of a strong correlation between tilt table–induced and spontaneous symptoms, a positive test should not be assumed to be diagnostic. The gold standard for VVS diagnosis is the clinical history (including witness observations). A negative tilt study in a patient with a classic history of VVS does not exclude the diagnosis, and a positive study will not alter therapy. However, as noted earlier, head-up tilt table testing is sometimes offered in this circumstance to convince a skeptical patient that the diagnosis is correct (see Box 67.1). Finally, neither head-up tilt table testing nor active standing is considered to be useful in diagnosing or excluding other forms of reflex syncope such as carotid sinus syndrome or situational faints. On the other hand, upright posture may be advantageous to better elicit the hemodynamic consequences of diagnostic interventions such as carotid sinus massage in patients with suspected carotid sinus syndrome.7 Our view of appropriate current clinical uses of head-up tilt table testing is summarized in Table 67.3.
Protocols for Head-up Tilt Table Testing and Active Standing Test The first step in the tilt test procedure is a period of rest (typically 10 to 15 minutes) after the instrumentation and monitoring equipment have been attached. Thereafter the patient is passively tilted to a 60- to 70-degree head-up position. The patient is supported by a foot-plate and gently applied body straps to prevent falling. The duration of the tilt varies by laboratory but is typically
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TABLE 67.3 Sensitivity, specificity, and diagnostic odds ratio of head-up tilt test protocols (estimates with 95% confidence intervals)
Overall passive protocols Overall isoproterenol protocols Overall nitroglycerine protocols
SENSITIVITY (%)
SPECIFICITY (%)
DIAGNOSTIC ODDS RATIO
37 (29–46) 61 (52–69) 66 (60–72)
96 (92–98) 86 (79–91) 89 (84–92)
10.14 (6.70–15.34) 8.33 (6.38–10.86) 14.40 (11.50–18.05)
Modified from Forleo C, Guida P, Iacoviello M, et al. Head-up tilt testing for diagnosing vasovagal syncope: a meta-analysis. Int J Cardiol. 2013;168:27-35.
20 to 45 minutes. If needed, pharmacological provocation may be used in conjunction with a head-up tilt. Various pharmacological agents have been used, but the most common are nitroglycerin and isoproterenol (discussed later). Both increase the sensitivity of the test but at the cost of lower specificity. As noted earlier, there is no test or laboratory procedure that provides a gold standard for the diagnosis of VVS. VVS is a clinical diagnosis that is primarily based on the medical history including eyewitness observations. The authors consider a head-up tilt study to be positive if the vasovagal reflex is induced and reproduces the patient’s clinical symptomatology. Induction of VVS that does not reproduce the patient’s clinical symptoms is problematic. In a patient with little or no doubt regarding the clinical diagnosis of VVS, a tilt test is not usually warranted unless it is being used to educate the patient (see Box 67.1). In this case, a negative study does not exclude the diagnosis and should be considered to be a false negative. A few laboratories favor a very short tilt test protocol that includes pharmacological provocation from the start. Concerns about adverse drug reactions and the potential for diminished specificity and sensitivity have limited the acceptance of these approaches. Further, a recent report described a shortened tilt protocol that provoked syncope through a painful stimulus.25 We do not advocate this approach as the deliberate infliction of pain poses, in our opinion, ethical concerns.
Passive Drug-Free Tilt Testing The 1986 report by Kenny and associates6 used a 60-degree head-up tilt for up to 60 minutes. The test triggered symptomatic hypotension and bradycardia consistent with a vasovagal reaction in 10/15 patients with syncope of unknown etiology and in only 1/10 control subjects without a history of syncope. Subsequent studies refined the tilt test methodology. By way of example, Fitzpatrick and colleagues26 investigated the use of a bicycle saddle or seat attached to the tilt table but found that it resulted in an excessive number of positive studies, presumably due to the obstruction of venous return. The saddle tilt configuration has been abandoned. These investigators also demonstrated that the use of tilt angles less than 60 degrees resulted in inadequate test sensitivity. Finally, with respect to conventional 60- or 70-degree tilt angles, these same authors26 also concluded that given the average time to the onset of syncope (24 ± 10 minutes), a headup tilt duration of 45 minutes was sufficient. Accordingly, they proposed a protocol utilizing a 60-degre inclination for 45 minutes and observed positive responses for patients with syncope of unknown origin in 75% with a specificity of 93%. The findings of Fitzpatrick and colleagues26 were instrumental in defining a practical head-up tilt test protocol. Later, based primarily on reports by Almquist et al.,27 Natale et al.,28 and Waxman et al.,29 the angle of the table was set, in most laboratories, to the 60- to 70-degree angle used today. The 45-minute duration persisted for many years, but the more widespread acceptance of pharmacological provocation (initially isoproterenol in North America but with increasing change to nitroglycerin) allowed for the adoption of shorter tilt duration (the so-called Italian protocol), typically 20 minutes.
Passive Tilt Testing With Pharmacological Provocation The use of isoproterenol as a provocative agent for tilt table tests in the diagnosis of VVS was introduced in 1989 by both Waxman et al.29 and Almquist et al.27 Almquist et al. used a short protocol in which if the initial 10 minutes of passive tilt were not diagnostic, the patient was returned to the supine position and given isoproterenol at a dose of 1 mg/min. After a new steady-state heart rate was achieved, the patient again underwent a head-up tilt. This process was repeated to a maximum dose of 5 mg/min. Using this protocol, 9/11 patients with syncope of unknown origin and negative electrophysiology studies developed hypotension and bradycardia, while only 2/18 control subjects did. In its use as a provocative agent in tilt table testing, isoproterenol has not been without controversy. In particular, Kapoor and Brant30 raised concerns over the potentially low specificity (45% to 65%) of isoproterenol provocation. Later, Morillo and colleagues31 proposed a low-dose isoproterenol protocol, in which after 15 minutes of tilt, incremental doses of isoproterenol (up to 3 mg/min) were administered while the patient remained in a head-up position; they reported a 61% rate of positive responses and a specificity of 93%. Although isoproterenol is still employed as a provocative agent, its use has waned for several reasons. First, mixing and delivering isoproterenol is time consuming. Second, patients frequently complain of drug-induced anxiety and palpitations. Third, there is the concern of causing ischemia in patients with coronary artery disease. Finally, in the United States at least, the cost of isoproterenol has increased dramatically; this is not due to a shortage of the drug but rather to change in ownership.32 If for no other reason than to minimize undue expense, the authors suggest that nitroglycerine (see later) be the preferred provocative agent. In 1994, Raviele and colleagues33 introduced the use of intravenous nitroglycerin infusion as an alternative to isoproterenol provocation during head-up tilt table testing. Using their nitroglycerin infusion protocol, 21/40 patients (53%) with syncope of unknown origin had a positive head-up tilt test, with a specificity of 92%. Ten of the 40 patients developed progressive hypotension without bradycardia. The latter outcome was not considered a positive result but rather was attributed to the hypotensive effect of the medication and was classified as an “exaggerated” response. Later, Raviele and coworkers34 demonstrated that sublingual nitroglycerin was a highly effective alternative to intravenous infusion. After 45 minutes of baseline head-up tilt, a 0.3-mg dose of sublingual nitroglycerine was given. With this protocol, the authors reported an overall positive tilt rate of 51% (25% during the baseline tilt and 26% after nitroglycerin provocation). The specificity was 94%. An “exaggerated” response to nitroglycerin was seen in 14% of patients with syncope of unknown origin and in 15% of control patients. Recently, Forleo and colleagues35 performed a metaanalysis of 55 studies published prior to March 2012 (see Table 67.3). They included English-only publications involving patients with unexplained syncope and asymptomatic control patients without a history of syncope. Excluding duplicate publications, studies that enrolled fewer than 10 patients, and protocols using tilt
HEAD-UP TILT TABLE TESTING
angulation of less than 60 degrees or greater than 80 degrees, the resulting selected studies comprised 4361 patients with syncope (mean age, 41 ± 17 years) and 1791 control patients (mean age, 39 ± 17 years). The tilt angle was 60 degrees in 30 studies (2937 patients and 1005 controls), 70 degrees in 15 (991 patients and 485 controls), and 80 degrees in 10 (433 patients and 301 controls). The average overall duration of the tilt was 46 ± 16 minutes (range, 10 to 110 minutes); passive phase, 33 ± 12 minutes, and a provoked stage of 23 ± 12 minutes. In 30 studies, the provocative agent was nitroglycerine; in 22 other studies, it was isoproterenol. The analysis revealed a significant inverse relationship between sensitivity and specificity. The summary receiver-operating curve demonstrated a good overall ability to differentiate between symptomatic patients and asymptomatic controls with an area under the curve of 0.84 (95% confidence interval [CI], 0.81 to 0.87). Not unexpectedly, pharmacological protocols enhanced sensitivity and lowered specificity. Tilt protocols that included nitroglycerin provocation had the highest diagnostic odds ratio (14.40; 95% CI, 11.50 to 18.05) and the greatest sensitivity (66%; 95% CI, 60% to 72%). Current guidelines7 recommend a minimum head-up tilt test duration of 20 minutes and a maximum of 45 minutes for the passive component. Forleo and coauthors35 noted that there was a lack of general agreement regarding the optimal duration of the tilt study. Further, they conceded that their analysis did not “clarify completely” the effect of tilt duration on diagnostic accuracy. They observed that longer passive tilt duration was associated with a higher rate of positivity. Also, an inverse relationship was noted between subject age and sensitivity, while age was associated with an enhanced specificity for the active phase of tilt. The authors speculate that a longer duration of passive tilt might be appropriate for younger patients, while a shorter duration of passive tilt might be beneficial in older patients.
Adenosine and Adenosine Triphosphate It has been postulated that endogenous adenosine release may play a role in some forms of syncope,36,37 and both adenosine and its precursor adenosine triphosphate (ATP) have been reported to unmask susceptibility to reflex paroxysmal atrioventricular (AV) block.36–39 It may be that ATP identifies patients at risk for reflex paroxysmal sinus arrest or AV block and thereby identifies patients likely to benefit from pacemakers.40 However, the US Food and Drug Administration has not approved ATP for injection. That, along with the uncertainty regarding substituting adenosine for ATP, has undermined their use for tilt testing in the United States.
Shifting Patient Patterns in the Tilt Table Testing Laboratory Insmuch as head-up tilt table testing is not usually warranted in patients with a classic history of VVS (see Box 67.1 for exceptions), we have noted a shift in the type of patient being referred for laboratory evaluation. While the evaluation of TLOC of unknown causes remains important, the trend has been toward the use of tilt studies to assess OH and its subtypes to discriminate between so-called convulsive syncope (VVS associated with jerking movements) versus a true seizure disorder (in these cases with addition of video-electroencephalogram [EEG] monitoring during tilt), POTS, and in patients with possible psychogenic pseudosyncope/pseudoseizures. The shift in patient referral patterns has led to the frequent inclusion of ancillary tests not associated with traditional headup tilt table testing. Along with the aforementioned addition of video-EEG monitoring, many of our patients now undergo a basic panel of autonomic tests prior to the head-up tilt table testing. The addition of this autonomic testing has proven useful in
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the evaluation of OH, especially in the elderly or patients with conditions such as diabetes mellitus associated with an increased risk of secondary autonomic dysfunction. A review of such testing is available for interested readers.41 Autonomic testing is performed prior to head-up tilt, beginning with the patient in a seated position. Noninvasive beat-tobeat blood pressure measurement is used throughout along with continuous ECG monitoring and occasionally with electrical bioimpedance splanchnic blood flow assessment. The Valsalva maneuver is performed in all patients undergoing autonomic testing in our laboratory. Patients over 40 years of age also undergo carotid sinus massage while seated upright. Many patients also undergo assessment of hemodynamic response to volitional cough.41
Video-Electroencephalogram Monitoring In the 2009 ESC syncope practice guidelines,7 the use of head-up tilt table testing for discriminating convulsive syncope from epilepsy was given a IIb indication (Level of Evidence C). Inasmuch as distinguishing epilepsy from syncope and vice-versa causes considerable diagnostic difficulty,42 head-up tilt table testing may be helpful43 especially with the addition of EEG monitoring during the tilt test.44 Our laboratory has experienced a marked increase in referrals from the neurology service for head-up tilt table testing with EEG monitoring. We provide the tilt table study and its interpretation while the neurologists interpret the video-EEG recording.
Laboratory Environment and Patient Preparation The laboratory should be quiet, dimly lit, at a comfortable temperature, and as nonthreatening as possible. We ask our patients to fast for 2 to 3 hours prior to testing. Longer periods of fasting may result in dehydration, with the potential to affect testing. Since OH is a consideration in most TLOC patients undergoing study, we direct them to take their antihypertensives, including diuretics, the morning of testing. Medications previously prescribed for the treatment of VVS are held for five half-lives before testing. If patients have been fasting for more than 4 hours, normal saline is given intravenously (250 to 500 mL depending on the duration of fasting status) prior to the tilt. Venous cannulation is done at least 20 minutes prior to testing. If ancillary autonomic testing is to be done, it is completed 15 to 20 minutes prior to initiating the tilt table testing. We forewarn patients that, although we will be monitoring them, we will not be talking with them, and if they experience symptoms they should inform the staff.
Recordings Three or more simultaneous ECG leads should be recorded continuously, along with beat-to-beat blood pressure monitoring. Arterial access should only rarely be required. If arterial access is needed, at least 20 minutes of quiet rest is required before tilt testing. The use of blood pressure cuffs, whether automated or manual, is discouraged. The process of taking a measurement cannot help but stimulate the patient; such systems can be painful and do provide the beat-to-beat monitoring required.
Tilt Table Design The table should be capable of smoothly achieving an angle of 60 to 70 degrees within 10 to 15 seconds. Likewise, the table should be capable of quickly being returned to the horizontal position should clinical circumstances require (e.g., syncope, excessive hypotension). A footboard is needed and the patient should be secured gently so as to prevent falling.
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Tilt Angle and Duration
Risks and Complications
Tilt angles of 60 or 70 degrees should be used. Lesser degrees of tilt have been shown to have poor sensitivity. Tilt angles of 80 degrees or higher suffer from a lack of specificity. In terms of duration, current recommendations7 call for not less than 20 minutes and not greater than 45 minutes. In our laboratory the passive phase of the tilt is 20 minutes. At that time, if the patient has been asymptomatic, 0.4 mg of nitroglycerin is given sublingually. In children, a passive drug-free head-up tilt tends to be favored. In such cases (e.g., in the absence of pharmacological provocation), it may be necessary to extend tilt test duration to 45 or even 60 minutes.
The risks associated with head-up tilt table testing are minimal. A return to the supine position is typically all that is needed to avoid adverse events. As noted above, patients should be gently restrained to avoid falling. With respect to the active standing test, the risk of falling is the primary concern. The technical and nursing staff performing the active standing test should be aware of the “falls risk” possibility and should be authorized to return the patient to a supine or seated position promptly if a fall seems imminent. A chair at hand is usually adequate. Although none have yet been observed at our institution, there have been reports of ventricular arrhythmias with the use of isoproterenol. The decline in the use of isoproterenol as a provocative agent has reduced that risk even further. To our knowledge, there have been no reports of ventricular arrhythmias with use of nitroglycerine for provocation. Prolonged asystole has been reported during tilt testing, but long asystolic spells longer than 20 seconds are rare. Nevertheless, recognition of asystole is an important issue for the support staff. They need to be educated that asystole is selflimited and resolves with returning the patient to a supine position and that there is almost never any need for atropine, cardiopulmonary resuscitation, or transcutaneous pacing. It is prudent to warn staff new to tilt table testing that asystolic episodes can be very dramatic, with myotonic jerks and patients who appear to be in extremis. In almost all cases, overreacting to these events is likely to do more harm than good. Finally, we make it a point to warn patients that after a syncopal episode they may continue to feel unwell (fatigue, headache) for several hours. Although, medically, they could return to work or school, we advise against planning significant activity following the tilt study.
Personnel The Heart Rhythm Society has published staffing recommendations.24 In general, tilt table testing requires staffing similar to an exercise stress testing laboratory. The physician does not need to be in immediate attendance but does need to be in close proximity. The relationship of any induced symptoms to the patient’s spontaneous symptoms should be documented.
Active Standing Versus Head-up Tilt Test The active standing test complements head-up tilt table testing and can be undertaken in the laboratory at the same time, or separately in the clinic. In particular, the “initial” and “classic” forms of OH may be diagnosed by active standing (see definitions provided earlier). Beat-to-beat blood pressure recording is desirable during active standing as it is with tilt table testing, and testing may therefore be more suitable for the laboratory setting. The active standing test has the advantage of corresponding more closely to real-life situations than does tilt table testing. It is simple to perform in the clinic or the laboratory and does not require expensive equipment. However, a medical attendant should remain close to the patient to prevent a fall that could lead to injury. Clearly, active standing may not be possible in some circumstances, such as debilitated patients, patients with severe autonomic dysfunction, patients with muscular dystrophy, and so on.
Reproducibility of Head-up Tilt Table Testing and Active Standing Test A major issue with assessing reproducibility of a test utilizing orthostatic stress is how to control for variation in volume status prior to testing. Nevertheless, tilt-test reproducibility has been investigated using multiple tilts on the same day, a few days apart, and a few weeks apart. The experience in our laboratory suggests that the reproducibility of tilt-induced VVS is acceptable for use as a diagnostic test.45 The positivity or negativity of two sequential tests done 30 minutes apart was concordant in 87% of cases. In particular, a negative test has high reproducibility. In one study, none of the patients who were tilt-negative on the initial test developed syncope on repeat testing.45 The reproducibility of tilt testing with longer interest intervals is similar. Reproducibility with a 3- to 7-day separation was 90% in 21 patients (including isoproterenol provocation), although the level of provocation needed was different in 24%. At intervals of 1 to 6 weeks between testing (including isoproterenol provocation), there was 85% reproducibility in 46 patients who were initially tilt negative and 90% reproducibility in those who were initially tilt positive.46 Head-up tilt table testing using nitroglycerin for provocation also shows acceptable reproducibility.47,48 There has not been rigorous examination of the reproducibility of the active standing test.
Head-up Tilt Testing and Treatment of Vasovagal Syncope As noted in Table 67.3, the 2009 ESC guidelines7 do not view head-up tilt table testing as useful for the testing efficacy of therapy for VVS. This use of head-up tilt table testing for defining treatment was given a Class III indication. On the other hand, of interest is the recent observation that a negative tilt study appears to identify a subgroup of syncope patients, who, if found to have significant bradycardia or asystole as part of their clinical syncope picture (usually documented by long-term ambulatory ECG monitoring), are likely to benefit from permanent pacing.49 If this observation is confirmed, it would suggest a role for head-up tilt table testing for “pacemaker therapy stratification,” even if the VVS diagnosis was clear on clinical grounds.
Overview of Uses for Head-up Tilt Table Testing Established indications for head-up tilt table testing were noted earlier7 and in Table 67.3. Additionally, head-up tilt table testing has been used (albeit with less supportive evidence) in (1) chronic fatigue syndrome, (2) POTS, (3) recurrent vertigo, (4) recurrent transient ischemic attacks, and (5) conduction system disease that, at electrophysiological testing, does not appear severe enough to explain syncope. With the possible exception of POTS, we do not advocate these other applications, and the existing practice guidelines do not provide support for such use.
Conclusions Head-up tilt table testing, either drug-free or if necessary with pharmacological provocation (most often nitroglycerine) has
HEAD-UP TILT TABLE TESTING
proven to be a useful, readily available, and safe modality for identifying susceptibility to VVS and confirming suspected OH. However, tilt testing has not been shown to be a reliable means of testing the efficacy of therapeutic interventions. Additionally, head-up tilt table testing is not known to be helpful in evaluating other forms of reflex syncope, with the possible exception of clarifying the hemodynamic impact of carotid sinus stimulation in patients with suspected carotid sinus syndrome. Head-up tilt table testing has been the subject of numerous studies, resulting in the development of widely accepted protocols. These protocols offer a level of reproducibility, sensitivity, specificity, and predictive value on par with other widely used cardiovascular tests, such as exercise testing.
637
Finally, head-up tilt table testing is finding new roles in the evaluation in distinguishing between epilepsy and syncope, detecting psychogenic pseudosyncope/pseudoseizures, and in the assessment of patients initially considered having epilepsy but in whom confirmation of the diagnosis has been elusive. In all of these cases, the tilt test is best combined with ancillary testing, particularly the video-EEG.
Acknowledgment Dr Benditt is supported in part by a grant in support of heartbrain research from the Dr. Earl E. Bakken family.
REFERENCES 1. Allen SC, Taylor CL, Hall VE. A study of orthostatic insufficiency by the tiltboard method. Am J Physiol. 1945;143:11–18. 2. McMicheal J, Sharpey Shafer EP. Cardiac output in man by a direct Fick method: effect of posture, venous pressure change, atropine and adrenaline. Brit Heart J. 1944;6:33–40. 3. Sharpey Shafer EP. Syncope. Brit Med J. 1956;1:506–509. 4. Davies R, Slater JDH, Forsling ML, Payne N. The response of arginine vasopressin and plasma renin to postural change in normal man, with observations on syncope. Clin Sci. 1976;51:267–274. 5. Hammill SC, Holmes DR, Wood DL, et al. Electrographic testing in the upright position: improved evaluation of patients with rhythm disturbances using a tilt table. J Am Coll Cardiol. 1984;4:65–71. 6. Kenny RA, Ingram A, Bayliss J, Sutton R. Head-up tilt: a useful test for investigating unexplained syncope. Lancet. 1986;1:1352–1355. 7. Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J. 2009;21:2631–2671. 8. Rowell LB. Human Circulation. Regulation During Physical Stress. New York: Oxford University Press; 1986. 9. Folino FA. Cerebral autoregulation and syncope. Prog Cardiovasc Dis. 2007;50:49–80. 10. Schondorf R, Benoit J, Stein R. Cerebral autoregulation in orthostatic intolerance. Ann N Y Acad Sci. 2001;940:514–526. 11. Rossen R, Kabat H, Anderson JP. Acute arrest of cerebral circulation in man. Arch Neurol Psychiatry. 1943;50:510–528. 12. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. Stroke. 1989;20:45–52. 13. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev. 1990;2:161–192. 14. Guo H, Tierney N, Schaller F, Raven PB, Smith SA, Shi X. Cerebral autoregulation is preserved during orthostatic stress superimposed with systemic hypotension. J Appl Physiol. 2006;100:1785–1792. 15. van Dijk JG, Thijs RD, Benditt DG, Wieling W. A guide to disorders causing transient loss of consciousness: focus on syncope. Nature Rev Neurosci. 2009;5:438–448. 16. Shaw FE, Kenny RA. The overlap between syncope and falls in the elderly. Postgrad Med J. 1997;73:635–639. 17. McIntosh SJ, Lawson J, Kenny RA. Clinical characteristics of vasodepressor, cardioinhibitory, and mixed carotid sinus syndrome in the elderly. Am J Med. 1993;95:203–208. 18. Stewart JM. Postural tachycardia syndrome and reflex syncope: similarities and differences. J Pediatr. 2009;154: 481–485. 19. Mathias CJ. Role of autonomic evaluation in the diagnosis and management of syncope. Clin Auton Res. 2004;14(suppl 1):45–54. 20. Benditt DG, Lurie KG, Adler SW, et al. Pathophysiology of vasovagal syncope. In: Blanc JJ, Benditt DG, Sutton R, eds. Neurally Mediated Syncope: Pathophysiology,
Investigation, and Treatment. Armonk, NY: Futura Publishing; 1996:1–24. 21. Ermis C, Samniah N, Lurie KG, Sakaguchi S, Benditt DG. Adrenal/renal contribution to circulating norepinephrine in posturally induced neurally mediated reflex syncope. Am J Cardiol. 2003;91:746–750. 22. Freeman R, Wieling W, Axelord FB, et al. Consensus statement of the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton Neurosci. 2011;161:46–48. 23. Benditt DG, Ferguson DW, Grubb BP, et al. Tilt table testing for assessing syncope. J Am Coll Cardiol. 1996;28:263–275. 24. Haines DE, Beheiry S, Akar JG, et al. Heart Rythm Society expert consensus statement on electrophysiology laboratory standards: process, protocols, equipment, personnel, and safety. Heart Rhythm. 2014;11:e9–e51. 25. Adamec I, Mismas A, Zaper D, Junakovic A, Hajnsek S, Habek M. Short pain-provoked head-up tilt test for the confirmation of vasovagal syncope. Neurol Sci. 2013;34:869–873. 26. Fitzpatrick AP, Theodorakis G, Vardas P, Sutton R. Methodology of head-up tilt testing in patients with unexplained syncope. J Am Coll Cardiol. 1991;17: 125–130. 27. Almquist A, Goldenberg IF, et al. Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med. 1989;320:346–351. 28. Natale A, Akhtar M, Jazayeri M, et al. Provocation of hypotension during head-up tilt testing in subjects with no history of syncope or presyncope. Circulation. 1995;92:54–58. 29. Waxman MB, Yao L, Cameron DA, Wald RW, Roseman J. Isoproterenol induction of vasodepressor-type reaction in vasodepressor-prone persons. Am J Cardiol. 1989;63:58–65. 30. Kapoor WN, Brant N. Evaluation of syncope by upright tilt testing with isoproterenol. A nonspecific test. Ann Intern Med. 1992;116:358–363. 31. Morillo CA, Klein GJ, Zandri S, Yee R. Diagnostic accuracy of a low-dose isoproterenol head-up tilt protocol. Am Heart J. 1995;129:901–906. 32. Heart Rhythm Society, “Special Notice Regarding Pricing of Isoproterenol/Isuprel.” Press release; April 8, 2015. 33. Raviele A, Gasparini G, Di Pede F, et al. Nitroglycerin infusion during upright tilt: a new test for the diagnosis of vasovagal syncope. Am Heart J. 1994;127:103–111. 34. Raviele A, Menozzi C, Brignole M, et al. Value of head-up tilt testing potentiated with sublingual nitroglycerin to assess the origin of unexplained syncope. Am J Cardiol. 1995;76:267–272. 35. Forleo C, Guida P, Iacoviello M, et al. Head-up tilt testing for diagnosing vasovagal syncope: a meta-analysis. Int J Cardiol. 2013;168:27–35.
36. Sinkovec M, Grad A, Rakovec P. Role of endogenous adenosine in vasovagal syncope. Clin Auton Res. 2001;11:155–161. 37. Shen WK, Hammill SC, Munger TM, et al. Adenosine: potential modulator for vasovagal syncope. J Am Coll Cardiol. 1996;28:146–154. 38. Brignole M; Gaggioli G; Menozzi C; et al. Adenosineinduced atrioventricular block in patients with unexplained syncope: the diagnostic value of ATP testing. Circulation. 96:3921–3927. 39. Flammang D, Erickson M, McCarville S, Church T, Hamani D, Donal E. Contribution of head-up tilt testing and ATP testing in assessing the mechanisms of vasovagal syndrome: preliminary results and potential therapeutic implications. Circulation. 1999;99:2427–2433. 40. Flammang D, Church TR, De Roy L, et al. ATP Multicenter Study. Treatment of unexplained syncope: a multicenter, randomized trial of cardiac pacing guided by adenosine 5’-triphosphate testing. Circulation. 2012;125:31–63. 41. Adkisson WO, Benditt DG. Syncope due to autonomic dysfunction: diagnosis and management. Med Clin North Am. 2015;99:691–710. 42. Adkisson WO, Benditt DG. Treatment of ‘refractory’ epilepsy: syncope incognito unmasked by implantable ambulatory electrocardiographical recordings. Europace. 2012;14:1540–1542. 43. Rangel I, Freitas J, Correia AS, et al. The usefulness of the head-up tilt test in patients with suspected epilepsy. Seizure. 2014;23:367–370. 44. van Dijk JG, Thijs RD, van Zwet E, et al. The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes. Brain. 2014;137:576–585. 45. Chen MY, Goldenberg IF, Milstein S, et al. Cardiac electrophysiologic and hemodynamic correlates of neurally mediated syncope. Am J Cardiol. 1989;63:66–72. 46. Sheldon R, Splawinski J, Killam S. Reproducibility of isoproterenol tilt-table tests in patients with syncope. Am J Cardiol. 1992;69:1300–1305. 47. Del Rosso A, Bartoletti A, Bartoli P, et al. Methodology of head-up tilt testing potentiated with sublingual nitroglycerin in unexplained syncope. Am J Cardiol. 2000;85:1007–1011. 48. Foglia-Manzillo G, Giada F, Beretta S, Corrado G, Santarone M, Raviele A. Reproducibility of head-up tilt testing potentiated with sublingual nitroglycerin in patients with unexplained syncope. Am J Cardiol. 1999;84:284–288. 49. Brignole M, Donateo P, Tomaino M, et al. International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3). Circ Arrhythm Electrophysiol. 2014;7:10–16.
67
Head-up Tilt Table Testing Wayne O. Adkisson and David G. Benditt
CHAPTER OUTLINE Historical Background
630
Transient Loss of Consciousness and Syncope
630
Pathophysiology of Loss of Consciousness
630
Approach to the Diagnosis of Syncope
631
Physiological Impact of Upright Posture
631
Reflex Faints
632
Head-up Tilt as a Useful Model of Spontaneous Vasovagal Syncope
632
Pathophysiology of Orthostatic Hypotension
633
Orthostatic Provocation for Assessing Susceptibility to Vasovagal Syncope and Orthostatic Hypotension 633 Protocols for Head-up Tilt Table Testing and Active Standing Test
633
Video-Electroencephalogram Monitoring
635
Laboratory Environment and Patient Preparation
635
Active Standing Versus Head-up Tilt Test
636
Reproducibility of Head-up Tilt Table Testing and Active Standing Test
636
Risks and Complications
636
Head-up Tilt Testing and Treatment of Vasovagal Syncope 636 Overview of Uses for Head-up Tilt Table Testing
636
Conclusions 636
Historical Background Head-up tilt has been used for more than half a century by physiologists and physicians to study cardiovascular adaptation to changes in position, to model responses to hemorrhage, and to evaluate hemodynamic and neuroendocrine responses in congestive heart failure, autonomic dysfunction, and hypertension. During such studies, incidental observations noted that some test subjects experienced total or near-total transient loss of consciousness due to systemic hypotension induced by the head-up tilt procedure.1–5 Further, in some cases hypotension was associated with unexpected marked bradycardia, including prolonged asystolic periods that terminated spontaneously (Fig. 67.1). By way of example, Hammill and colleagues5 used 60-degree–head-up posture in an attempt to enhance the diagnostic precision of conventional diagnostic cardiac stimulation studies. In the course of this procedure, a typical vasovagal reaction occurred in 6 of 104 subjects. The investigators noted this result but undertook no formal assessment of the observation. It was the landmark study by Kenny and colleagues6 that ultimately led to the concept of using head-up tilt as a diagnostic tool for eliciting the susceptibility to reflex syncope, and in particular vasovagal syncope (VVS). Initially, prolonged periods of head-up tilt at angles of 40 to 60 degrees were used in an attempt to provoke 630
VVS in susceptible individuals. Subsequently, to improve sensitivity of the test, additional interventions were introduced including administration of pharmacological agents (discussed in more detail later) either alone or in conjunction with physical maneuvers such as carotid sinus massage. Several of these additional provocative measures did improve the head-up tilt test sensitivity and remain in use; however, as a rule, their addition has been at the cost of lower specificity. The difficulties in assessing sensitivity and specificity of head-up tilt table testing are discussed in more detail later. Since its introduction as a clinical diagnostic laboratory tool, the uses of the head-up tilt table testing have expanded. Whereas tilt table testing remains widely accepted for the evaluation of an individual’s susceptibility to VVS in selected cases, it has also found a place, albeit less well studied, in the evaluation of (1) orthostatic hypotension (OH), (2) postural orthostatic tachycardia syndrome (POTS), and (3) psychogenic pseudosyncope/pseudoseizures.7 In this chapter, we review the role of head-up tilt table testing in the evaluation of VVS and OH, discuss limitations of such testing, and review a methodology for its use.
Transient Loss of Consciousness and Syncope For the most part, patients referred for head-up tilt table testing have previously presented with one or more apparent transient loss of consciousness (TLOC) spells. However, in certain of these cases, the presentation may not have been true loss of consciousness; consequently, the basis for referral may be more broadly viewed as consultation for assessment of self-limited spontaneous collapse (Fig. 67.2). It is the consultant’s responsibility to ascertain whether there has been “true” TLOC. If TLOC is deemed to have occurred, then the differential diagnosis primarily includes syncope, epileptic seizures, intoxications, and possibly metabolic disturbances; tilt table testing may be helpful in selected cases for distinguishing among these disorders. On the other hand, if it is determined that TLOC did not occur, then the differential diagnosis principally includes psychogenic pseudosyncope/ pseudoseizures, mechanical falls, malingering, and cataplexy (see Fig. 67.2). Tilt table testing may be particularly helpful in identifying pseudosyncope/pseudoseizures. Specifically, the individuals afflicted with this disorder are highly suggestible, and the test may demonstrate normal heart rate and blood pressure despite the patient’s head slumping over and seemingly having a loss of consciousness event. Pseudosyncope/pseudoseizure should not be confused with malingering. In our experience, it is exceedingly rare that such patients are trying to mislead by “faking” these events. The episodes are quite real to the sufferer.
Pathophysiology of Loss of Consciousness Neuronal tissue has limited energy storage capabilities; consequently, maintenance of oxygenated blood flow to the brain is critical. In healthy young individuals, cerebral blood flow (CBF) ranges from 50 to 60 mL/100 g of brain tissue per minute. This represents approximately 12% to 15% of the resting cardiac output. Blood flow of that magnitude can easily supply the minimum oxygen (O2) requirement needed to maintain consciousness, which is typically 3.0 to 3.5 mL O2/100 g tissue per minute.8–10 However, the safety margin for oxygen delivery may be severely
HEAD-UP TILT TABLE TESTING
631
67
FIGURE 67.1 Electrocardiogram (ECG) of a patient during spontaneous episode of vasovagal syncope. The strips are continuous and show the typical sinus rate slowing prior to the event. In this example, sinus arrest did not occur (note P waves remain visible) but progressive AV block results in ventricular asystole. The slowing of the sinus rate helps distinguish a vasovagal event from sinoatrial block or sinus pauses related to sinus node dysfunction.
Self-limited spontaneous collapse
TLOC
Yes
• Syncope • Seizure • Concussion • Intoxication • Metabolic?
No
• Psychogenic: pseudosyncope pseudoseizure • Fall • Cataplexy • Malingering
FIGURE 67.2 Schematic diagram illustrating an approach to the patient with self-limited collapse. The first step in the assessment is to determine whether there has been transient loss of consciousness (TLOC). For syncope to have occurred, TLOC must have occurred. The use and limitations of head-up tilt table testing to help differentiate among various causes of syncope is discussed in the text.
impaired in the elderly; in persons with hypertension, diabetes mellitus, or heart failure; and in hypoxemic states (e.g., chronic pulmonary disease). In general, a loss of nutrient flow to the brain for 6 to 10 seconds is sufficient to cause a loss of consciousness.11 For the most part, CBF remains adequate over perfusion pressures ranging from 50 to 170 mm Hg12,13 due to cerebral autoregulation.14 However, abrupt perfusion changes may cause transient CBF inadequacy. In the face of rapid changes in perfusion pressure, cerebral autoregulation may be unable to prevent a drop in CBF, which, if of sufficient magnitude, will result in syncope.
Approach to the Diagnosis of Syncope Many conditions may cause the physiological disturbances that result in syncope (Table 67.1). Reflex syncope, OH, and cardiac arrhythmias are among the more frequent causes. Of the reflex syncope syndromes, VVS is the most common cause of syncope
across all age groups, and consequently virtually all medical practitioners will encounter VVS patients. In the case of VVS, the diagnosis can be established in most cases by the medical history without further testing.7,15 However, when the history surrounding the event is “atypical,” even an experienced history-taker may not be able to establish a firm diagnosis. In some cases it may not be possible to obtain an adequate history, especially in the elderly.16,17 Furthermore, witnesses may not have been present, or they may be unable to provide sufficiently reliable details needed to establish a specific diagnosis. In such cases, availability of diagnostic tests becomes important. Additionally, even when VVS is evident to an experienced clinician, patients who have been subject to several previous unsuccessful evaluations may remain skeptical, and the consultant may reasonably elect to recommend additional testing in an attempt to reproduce the patient’s symptoms under controlled and observed conditions. The head-up tilt table test is the most widely available diagnostic intervention for such cases.
Physiological Impact of Upright Posture Upright posture elicits an orthostatic stress as the effects of gravity result in a redistribution of circulating blood volume in the body.1,2,4,6–8 As upright posture is achieved; the effects of gravity result in shifting of 500 to 1000 mL of blood to the lower part of the body and in particular to the highly compliant splanchnic bed.8,18 This initial redistribution is rapid and occurs in the first 10 seconds. If upright posture is maintained, over the course of 10 minutes, an additional 700 mL of protein-free fluid is filtered into the interstitial space. The combined effect of these two shifts is a reduction of venous return and stroke volume. In humans, diminution of stroke volume upon the assumption of an upright position is compensated for by both an increase in heart rate and by the constriction of both resistance and capacitance blood vessels. An increase in heart rate alone is usually insufficient to maintain cardiac output and CBF. Systemic vasoconstriction is crucial for maintenance of adequate blood pressure. Loss of consciousness can only be prevented if the compensatory mechanisms maintain arterial pressure at a level at least equal to the minimum value needed to ensure adequate CBF. Short-term cardiovascular responses triggered by orthostatic stress are primarily mediated by the autonomic nervous system via arterial mechanoreceptors (baroreceptors responding to pressure, stretch, or both) located in the aortic arch and carotid
632
CARDIAC ELECTROPHYSIOLOGY
TABLE 67.1 Classification of the causes of syncope CARDIOVASCULAR REFLEX SYNDROMES
ORTHOSTATIC HYPOTENSION
ARRHYTHMIA
STRUCTURAL
Vasovagal syncope Carotid sinus syncope Situational: • Cough • Postmicturition • Others
Secondary autonomic failure (common): • Drug induced • Diabetes • Amyloidosis • Alcohol Primary autonomic failure (rare): • Parkinson disease • Multiple system atrophy • Lewy body dementia • Pure autonomic failure ≈15%
Bradycardia • Sinus node disease • Conduction system disease Tachycardia • Supraventricular • Ventricular Ion channel disorders
Valvular stenosis Cardiomyopathy Ischemic • Nonischemic • Hypertrophic • Arrhythmogenic Pulmonary hypertension Pulmonary emboli Aortic dissection
≈10%
≈5%
≈60% of cases of syncope ≈10% unknown
A
B FIGURE 67.3 Beat-to-beat blood pressure recordings obtained during head-up tilt-table testing. (A) and (B) were obtained from the same patient during the passive phase of head-up tilt testing. (A) demonstrates the typical oscillations often seen prior to the onset of the vasovagal reflex. At the time (A) was recorded, the patient reported no symptoms. (B) was recorded 3 minutes after (A). The patient complained of her typical premonitory symptoms at the point marked by the red arrow. Hypotension progressed and loss of consciousness occurred as the table was being returned to the supine position (yellow arrow). The concomitant bradycardia is not striking, but the heart rate did drop by more than 10%. In the VASIS schema, this would be a type I (mixed) tilt table response.
sinuses. Mechanoreceptors in the heart wall (both atria and ventricles) as well as in the lungs may contribute as well. Reflex activation of central sympathetic outflow to the systemic vasculature may be augmented by local reflex mechanisms, such as the venoarteriolar reflex. More global mechanisms such as the muscle skeletal pump (active even without overt movement) and the respiratory pump also contribute. All of these mechanisms may play a useful adjunctive role in maintaining cardiac output and arterial pressure, primarily by augmenting venous return. Failure of compensatory mechanisms during orthostatic stress, assuming no preexisting volume overload, results in impaired venous return and leads to diminished stroke volume, systemic arterial pressure, and CBF. If CBF reduction is of sufficient magnitude, loss of consciousness results. In this setting, loss of consciousness may be principally due to inadequate maintenance of blood pressure in the face of gravitational stress (i.e., “orthostatic hypotension” or “orthostatic syncope”) but may additionally be contributed to by an inappropriate reflex response resulting in vasodilation (i.e., vasodepressor response) and severe or relative bradycardia.7,8,19
Reflex Faints Reflex syncope is the preferred term encompassing all conditions in which reflexes modify heart rate (cardioinhibition) and vascular
tone (vasodepression) so as to predispose to systemic hypotension of sufficient severity to cause inadequate cerebral perfusion. Thus reflex syncope incorporates VVS, carotid sinus syndrome, and the situational faints (see later). Other umbrella terms for reflex syncope that have been used, but are less desirable, include neutrally mediated (reflex) syncope and neurocardiogenic syncope. VVS is the most common reflex syncope, but despite much study, its pathophysiology remains incompletely understood. In any case, systemic hypotension is principally due to vasodilation, mediated by a marked reduction in both the sympathetic vasoconstrictor outflow to skeletal muscle and a substantial increase in venous capacitance, especially in the splanchnic bed. Finally, a parasympathetically mediated bradycardia may also contribute, but usually has a lesser role than vasodilation for producing systemic hypotension.
Head-up Tilt as a Useful Model of Spontaneous Vasovagal Syncope Several observations suggest that symptomatic hypotension–bradycardia associated with a positive result on head-up tilt table testing is comparable to spontaneous VVS. First, both induced and spontaneous VVS episodes are associated with similar premonitory symptoms (nausea, diaphoresis) and signs (pallor, loss of postural tone). Second, the temporal sequence of blood pressure and heart rate changes during tilt-induced syncope parallels that
HEAD-UP TILT TABLE TESTING
BOX 67.1 Utility of head-up tilt testing 1. A ssess susceptibility to vasovagal syncope and/or orthostatic hypotension in a controlled and safe environment. 2. Determine whether induced symptoms correspond to spontaneous clinical symptoms. 3. Educate patients regarding warning symptoms so they may take preventive measures. 4. Potentially identify syncope mimics (e.g., psychogenic pseudosyncope). 5. Support the diagnosis in suspected postural orthostatic tachycardia syndrome. 6. Enhance patient confidence that the diagnosis (i.e., vasovagal syncope, orthostatic hypotension, or postural orthostatic tachycardia syndrome) is correct.
seen in spontaneous events (Fig. 67.3). Finally, plasma catecholamines before and during both spontaneous and tilt-induced syncope exhibit similar patterns. Specifically, there is a premonitory (before hypotension is evident) increase in circulating catecholamines with epinephrine to a greater extent than norepinephrine in both spontaneous as well as tilt-induced VVS.20,21
Pathophysiology of Orthostatic Hypotension A 2011 consensus statement provided a working definition of OH and its several common variants22; specifically, OH was defined as a drop in systolic blood pressure of ≥20 mm Hg or a drop in diastolic blood pressure of ≥10 mm Hg that usually occurs within 3 minutes of active standing or passive tilt to a minimum of 60 degrees. In hypertensive patients, a fall of at least 30 mm Hg systolic was deemed more appropriate. Moving from a supine to upright posture rarely induces syncope in healthy patients. However, a fleeting sensation of “graying out,” “dizziness,” or “unsteadiness” immediately (usually in the first 15 seconds) upon assuming an upright position is common (so-called “immediate” or “initial” OH), so much so that most individuals do not find it a cause for concern. Symptomatic immediate OH usually requires a blood pressure drop of approximately 40 mm Hg, albeit very brief such that cerebrovascular autoregulation does not have adequate time to respond.22 “Delayed” or “classical” OH is that which occurs after a period of standing or passive tilt, typically of 3 minutes (an arbitrary cut-off) or somewhat more in duration.22 Finally and less often, the blood pressure decline occurs very slowly, and the symptoms may not develop for more than 5 minutes after the posture change; this scenario may be termed “progressive” OH and is particularly difficult to recognize as the relationship to recent postural change is at best tenuous. The greater the delay in the onset of symptomatic hypotension, the more likely that the individual has moved away from a chair, bed, or other means of support, and as such has greater propensity for injury.
Orthostatic Provocation for Assessing Susceptibility to Vasovagal Syncope and Orthostatic Hypotension Several publications address the utility and indications for headup tilt testing (Box 67.1).7,23 The next European Society of Cardiology (ESC) guideline update is expected in 2017. In addition, the Heart Rhythm Society recently commented on the staffing requirements for performing head-up tilt table testing.24 Finally, an American College of Cardiology/American Heart Association Syncope guideline, which will include recommendations related to the use of head-up tilt table testing, is to be published in 2016. Increasingly, laboratories that undertake head-up tilt table testing are encouraged to include an active standing test component.7 Active standing, unlike the passive head-up tilt, activates
633
TABLE 67.2 Indication for head-up tilt table testing CLASS
LEVEL OF EVIDENCES
I
B
I
C
IIa
C
IIb
C
III
B
III
C
CLINICAL SETTING Single episode of unexplained syncope in high-risk setting or occupational implications Recurrent in absence of structural heart disease Syncope in setting of heart disease when cardiac causes have been excluded If there is clinical value in demonstrating susceptibility to reflex syncope to the patient To discriminate reflex syncope from orthostatic hypotension To discriminate syncope with jerking movements from epilepsy Evaluation of recurrent unexplained falls Evaluation of frequent syncope and the possibility of psychiatric illness Not recommended to assess efficacy of therapy Isoproterenol tilt testing should not be done in patients with ischemic heart diseases
Modified from Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J. 2009;21:2631-2671.
skeletal muscle pumps. The ESC guidelines7 recommend active standing as the test of choice for suspected OH. During such testing, we recommend use of noninvasive beat-to-beat blood pressure monitoring. We also prefer a 5- to 10-minute active standing test duration as opposed to the 3-minute test recommended in the ESC guidelines.7 Indications for head-up tilt table testing are summarized in Table 67.2.7 There is general agreement that tilt table testing should be used primarily for confirming a suspected diagnosis. This latter point is important since false-positive tests do occur (especially in young patients); consequently, in the absence of a strong correlation between tilt table–induced and spontaneous symptoms, a positive test should not be assumed to be diagnostic. The gold standard for VVS diagnosis is the clinical history (including witness observations). A negative tilt study in a patient with a classic history of VVS does not exclude the diagnosis, and a positive study will not alter therapy. However, as noted earlier, head-up tilt table testing is sometimes offered in this circumstance to convince a skeptical patient that the diagnosis is correct (see Box 67.1). Finally, neither head-up tilt table testing nor active standing is considered to be useful in diagnosing or excluding other forms of reflex syncope such as carotid sinus syndrome or situational faints. On the other hand, upright posture may be advantageous to better elicit the hemodynamic consequences of diagnostic interventions such as carotid sinus massage in patients with suspected carotid sinus syndrome.7 Our view of appropriate current clinical uses of head-up tilt table testing is summarized in Table 67.3.
Protocols for Head-up Tilt Table Testing and Active Standing Test The first step in the tilt test procedure is a period of rest (typically 10 to 15 minutes) after the instrumentation and monitoring equipment have been attached. Thereafter the patient is passively tilted to a 60- to 70-degree head-up position. The patient is supported by a foot-plate and gently applied body straps to prevent falling. The duration of the tilt varies by laboratory but is typically
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TABLE 67.3 Sensitivity, specificity, and diagnostic odds ratio of head-up tilt test protocols (estimates with 95% confidence intervals)
Overall passive protocols Overall isoproterenol protocols Overall nitroglycerine protocols
SENSITIVITY (%)
SPECIFICITY (%)
DIAGNOSTIC ODDS RATIO
37 (29–46) 61 (52–69) 66 (60–72)
96 (92–98) 86 (79–91) 89 (84–92)
10.14 (6.70–15.34) 8.33 (6.38–10.86) 14.40 (11.50–18.05)
Modified from Forleo C, Guida P, Iacoviello M, et al. Head-up tilt testing for diagnosing vasovagal syncope: a meta-analysis. Int J Cardiol. 2013;168:27-35.
20 to 45 minutes. If needed, pharmacological provocation may be used in conjunction with a head-up tilt. Various pharmacological agents have been used, but the most common are nitroglycerin and isoproterenol (discussed later). Both increase the sensitivity of the test but at the cost of lower specificity. As noted earlier, there is no test or laboratory procedure that provides a gold standard for the diagnosis of VVS. VVS is a clinical diagnosis that is primarily based on the medical history including eyewitness observations. The authors consider a head-up tilt study to be positive if the vasovagal reflex is induced and reproduces the patient’s clinical symptomatology. Induction of VVS that does not reproduce the patient’s clinical symptoms is problematic. In a patient with little or no doubt regarding the clinical diagnosis of VVS, a tilt test is not usually warranted unless it is being used to educate the patient (see Box 67.1). In this case, a negative study does not exclude the diagnosis and should be considered to be a false negative. A few laboratories favor a very short tilt test protocol that includes pharmacological provocation from the start. Concerns about adverse drug reactions and the potential for diminished specificity and sensitivity have limited the acceptance of these approaches. Further, a recent report described a shortened tilt protocol that provoked syncope through a painful stimulus.25 We do not advocate this approach as the deliberate infliction of pain poses, in our opinion, ethical concerns.
Passive Drug-Free Tilt Testing The 1986 report by Kenny and associates6 used a 60-degree head-up tilt for up to 60 minutes. The test triggered symptomatic hypotension and bradycardia consistent with a vasovagal reaction in 10/15 patients with syncope of unknown etiology and in only 1/10 control subjects without a history of syncope. Subsequent studies refined the tilt test methodology. By way of example, Fitzpatrick and colleagues26 investigated the use of a bicycle saddle or seat attached to the tilt table but found that it resulted in an excessive number of positive studies, presumably due to the obstruction of venous return. The saddle tilt configuration has been abandoned. These investigators also demonstrated that the use of tilt angles less than 60 degrees resulted in inadequate test sensitivity. Finally, with respect to conventional 60- or 70-degree tilt angles, these same authors26 also concluded that given the average time to the onset of syncope (24 ± 10 minutes), a headup tilt duration of 45 minutes was sufficient. Accordingly, they proposed a protocol utilizing a 60-degre inclination for 45 minutes and observed positive responses for patients with syncope of unknown origin in 75% with a specificity of 93%. The findings of Fitzpatrick and colleagues26 were instrumental in defining a practical head-up tilt test protocol. Later, based primarily on reports by Almquist et al.,27 Natale et al.,28 and Waxman et al.,29 the angle of the table was set, in most laboratories, to the 60- to 70-degree angle used today. The 45-minute duration persisted for many years, but the more widespread acceptance of pharmacological provocation (initially isoproterenol in North America but with increasing change to nitroglycerin) allowed for the adoption of shorter tilt duration (the so-called Italian protocol), typically 20 minutes.
Passive Tilt Testing With Pharmacological Provocation The use of isoproterenol as a provocative agent for tilt table tests in the diagnosis of VVS was introduced in 1989 by both Waxman et al.29 and Almquist et al.27 Almquist et al. used a short protocol in which if the initial 10 minutes of passive tilt were not diagnostic, the patient was returned to the supine position and given isoproterenol at a dose of 1 mg/min. After a new steady-state heart rate was achieved, the patient again underwent a head-up tilt. This process was repeated to a maximum dose of 5 mg/min. Using this protocol, 9/11 patients with syncope of unknown origin and negative electrophysiology studies developed hypotension and bradycardia, while only 2/18 control subjects did. In its use as a provocative agent in tilt table testing, isoproterenol has not been without controversy. In particular, Kapoor and Brant30 raised concerns over the potentially low specificity (45% to 65%) of isoproterenol provocation. Later, Morillo and colleagues31 proposed a low-dose isoproterenol protocol, in which after 15 minutes of tilt, incremental doses of isoproterenol (up to 3 mg/min) were administered while the patient remained in a head-up position; they reported a 61% rate of positive responses and a specificity of 93%. Although isoproterenol is still employed as a provocative agent, its use has waned for several reasons. First, mixing and delivering isoproterenol is time consuming. Second, patients frequently complain of drug-induced anxiety and palpitations. Third, there is the concern of causing ischemia in patients with coronary artery disease. Finally, in the United States at least, the cost of isoproterenol has increased dramatically; this is not due to a shortage of the drug but rather to change in ownership.32 If for no other reason than to minimize undue expense, the authors suggest that nitroglycerine (see later) be the preferred provocative agent. In 1994, Raviele and colleagues33 introduced the use of intravenous nitroglycerin infusion as an alternative to isoproterenol provocation during head-up tilt table testing. Using their nitroglycerin infusion protocol, 21/40 patients (53%) with syncope of unknown origin had a positive head-up tilt test, with a specificity of 92%. Ten of the 40 patients developed progressive hypotension without bradycardia. The latter outcome was not considered a positive result but rather was attributed to the hypotensive effect of the medication and was classified as an “exaggerated” response. Later, Raviele and coworkers34 demonstrated that sublingual nitroglycerin was a highly effective alternative to intravenous infusion. After 45 minutes of baseline head-up tilt, a 0.3-mg dose of sublingual nitroglycerine was given. With this protocol, the authors reported an overall positive tilt rate of 51% (25% during the baseline tilt and 26% after nitroglycerin provocation). The specificity was 94%. An “exaggerated” response to nitroglycerin was seen in 14% of patients with syncope of unknown origin and in 15% of control patients. Recently, Forleo and colleagues35 performed a metaanalysis of 55 studies published prior to March 2012 (see Table 67.3). They included English-only publications involving patients with unexplained syncope and asymptomatic control patients without a history of syncope. Excluding duplicate publications, studies that enrolled fewer than 10 patients, and protocols using tilt
HEAD-UP TILT TABLE TESTING
angulation of less than 60 degrees or greater than 80 degrees, the resulting selected studies comprised 4361 patients with syncope (mean age, 41 ± 17 years) and 1791 control patients (mean age, 39 ± 17 years). The tilt angle was 60 degrees in 30 studies (2937 patients and 1005 controls), 70 degrees in 15 (991 patients and 485 controls), and 80 degrees in 10 (433 patients and 301 controls). The average overall duration of the tilt was 46 ± 16 minutes (range, 10 to 110 minutes); passive phase, 33 ± 12 minutes, and a provoked stage of 23 ± 12 minutes. In 30 studies, the provocative agent was nitroglycerine; in 22 other studies, it was isoproterenol. The analysis revealed a significant inverse relationship between sensitivity and specificity. The summary receiver-operating curve demonstrated a good overall ability to differentiate between symptomatic patients and asymptomatic controls with an area under the curve of 0.84 (95% confidence interval [CI], 0.81 to 0.87). Not unexpectedly, pharmacological protocols enhanced sensitivity and lowered specificity. Tilt protocols that included nitroglycerin provocation had the highest diagnostic odds ratio (14.40; 95% CI, 11.50 to 18.05) and the greatest sensitivity (66%; 95% CI, 60% to 72%). Current guidelines7 recommend a minimum head-up tilt test duration of 20 minutes and a maximum of 45 minutes for the passive component. Forleo and coauthors35 noted that there was a lack of general agreement regarding the optimal duration of the tilt study. Further, they conceded that their analysis did not “clarify completely” the effect of tilt duration on diagnostic accuracy. They observed that longer passive tilt duration was associated with a higher rate of positivity. Also, an inverse relationship was noted between subject age and sensitivity, while age was associated with an enhanced specificity for the active phase of tilt. The authors speculate that a longer duration of passive tilt might be appropriate for younger patients, while a shorter duration of passive tilt might be beneficial in older patients.
Adenosine and Adenosine Triphosphate It has been postulated that endogenous adenosine release may play a role in some forms of syncope,36,37 and both adenosine and its precursor adenosine triphosphate (ATP) have been reported to unmask susceptibility to reflex paroxysmal atrioventricular (AV) block.36–39 It may be that ATP identifies patients at risk for reflex paroxysmal sinus arrest or AV block and thereby identifies patients likely to benefit from pacemakers.40 However, the US Food and Drug Administration has not approved ATP for injection. That, along with the uncertainty regarding substituting adenosine for ATP, has undermined their use for tilt testing in the United States.
Shifting Patient Patterns in the Tilt Table Testing Laboratory Insmuch as head-up tilt table testing is not usually warranted in patients with a classic history of VVS (see Box 67.1 for exceptions), we have noted a shift in the type of patient being referred for laboratory evaluation. While the evaluation of TLOC of unknown causes remains important, the trend has been toward the use of tilt studies to assess OH and its subtypes to discriminate between so-called convulsive syncope (VVS associated with jerking movements) versus a true seizure disorder (in these cases with addition of video-electroencephalogram [EEG] monitoring during tilt), POTS, and in patients with possible psychogenic pseudosyncope/pseudoseizures. The shift in patient referral patterns has led to the frequent inclusion of ancillary tests not associated with traditional headup tilt table testing. Along with the aforementioned addition of video-EEG monitoring, many of our patients now undergo a basic panel of autonomic tests prior to the head-up tilt table testing. The addition of this autonomic testing has proven useful in
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the evaluation of OH, especially in the elderly or patients with conditions such as diabetes mellitus associated with an increased risk of secondary autonomic dysfunction. A review of such testing is available for interested readers.41 Autonomic testing is performed prior to head-up tilt, beginning with the patient in a seated position. Noninvasive beat-tobeat blood pressure measurement is used throughout along with continuous ECG monitoring and occasionally with electrical bioimpedance splanchnic blood flow assessment. The Valsalva maneuver is performed in all patients undergoing autonomic testing in our laboratory. Patients over 40 years of age also undergo carotid sinus massage while seated upright. Many patients also undergo assessment of hemodynamic response to volitional cough.41
Video-Electroencephalogram Monitoring In the 2009 ESC syncope practice guidelines,7 the use of head-up tilt table testing for discriminating convulsive syncope from epilepsy was given a IIb indication (Level of Evidence C). Inasmuch as distinguishing epilepsy from syncope and vice-versa causes considerable diagnostic difficulty,42 head-up tilt table testing may be helpful43 especially with the addition of EEG monitoring during the tilt test.44 Our laboratory has experienced a marked increase in referrals from the neurology service for head-up tilt table testing with EEG monitoring. We provide the tilt table study and its interpretation while the neurologists interpret the video-EEG recording.
Laboratory Environment and Patient Preparation The laboratory should be quiet, dimly lit, at a comfortable temperature, and as nonthreatening as possible. We ask our patients to fast for 2 to 3 hours prior to testing. Longer periods of fasting may result in dehydration, with the potential to affect testing. Since OH is a consideration in most TLOC patients undergoing study, we direct them to take their antihypertensives, including diuretics, the morning of testing. Medications previously prescribed for the treatment of VVS are held for five half-lives before testing. If patients have been fasting for more than 4 hours, normal saline is given intravenously (250 to 500 mL depending on the duration of fasting status) prior to the tilt. Venous cannulation is done at least 20 minutes prior to testing. If ancillary autonomic testing is to be done, it is completed 15 to 20 minutes prior to initiating the tilt table testing. We forewarn patients that, although we will be monitoring them, we will not be talking with them, and if they experience symptoms they should inform the staff.
Recordings Three or more simultaneous ECG leads should be recorded continuously, along with beat-to-beat blood pressure monitoring. Arterial access should only rarely be required. If arterial access is needed, at least 20 minutes of quiet rest is required before tilt testing. The use of blood pressure cuffs, whether automated or manual, is discouraged. The process of taking a measurement cannot help but stimulate the patient; such systems can be painful and do provide the beat-to-beat monitoring required.
Tilt Table Design The table should be capable of smoothly achieving an angle of 60 to 70 degrees within 10 to 15 seconds. Likewise, the table should be capable of quickly being returned to the horizontal position should clinical circumstances require (e.g., syncope, excessive hypotension). A footboard is needed and the patient should be secured gently so as to prevent falling.
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Tilt Angle and Duration
Risks and Complications
Tilt angles of 60 or 70 degrees should be used. Lesser degrees of tilt have been shown to have poor sensitivity. Tilt angles of 80 degrees or higher suffer from a lack of specificity. In terms of duration, current recommendations7 call for not less than 20 minutes and not greater than 45 minutes. In our laboratory the passive phase of the tilt is 20 minutes. At that time, if the patient has been asymptomatic, 0.4 mg of nitroglycerin is given sublingually. In children, a passive drug-free head-up tilt tends to be favored. In such cases (e.g., in the absence of pharmacological provocation), it may be necessary to extend tilt test duration to 45 or even 60 minutes.
The risks associated with head-up tilt table testing are minimal. A return to the supine position is typically all that is needed to avoid adverse events. As noted above, patients should be gently restrained to avoid falling. With respect to the active standing test, the risk of falling is the primary concern. The technical and nursing staff performing the active standing test should be aware of the “falls risk” possibility and should be authorized to return the patient to a supine or seated position promptly if a fall seems imminent. A chair at hand is usually adequate. Although none have yet been observed at our institution, there have been reports of ventricular arrhythmias with the use of isoproterenol. The decline in the use of isoproterenol as a provocative agent has reduced that risk even further. To our knowledge, there have been no reports of ventricular arrhythmias with use of nitroglycerine for provocation. Prolonged asystole has been reported during tilt testing, but long asystolic spells longer than 20 seconds are rare. Nevertheless, recognition of asystole is an important issue for the support staff. They need to be educated that asystole is selflimited and resolves with returning the patient to a supine position and that there is almost never any need for atropine, cardiopulmonary resuscitation, or transcutaneous pacing. It is prudent to warn staff new to tilt table testing that asystolic episodes can be very dramatic, with myotonic jerks and patients who appear to be in extremis. In almost all cases, overreacting to these events is likely to do more harm than good. Finally, we make it a point to warn patients that after a syncopal episode they may continue to feel unwell (fatigue, headache) for several hours. Although, medically, they could return to work or school, we advise against planning significant activity following the tilt study.
Personnel The Heart Rhythm Society has published staffing recommendations.24 In general, tilt table testing requires staffing similar to an exercise stress testing laboratory. The physician does not need to be in immediate attendance but does need to be in close proximity. The relationship of any induced symptoms to the patient’s spontaneous symptoms should be documented.
Active Standing Versus Head-up Tilt Test The active standing test complements head-up tilt table testing and can be undertaken in the laboratory at the same time, or separately in the clinic. In particular, the “initial” and “classic” forms of OH may be diagnosed by active standing (see definitions provided earlier). Beat-to-beat blood pressure recording is desirable during active standing as it is with tilt table testing, and testing may therefore be more suitable for the laboratory setting. The active standing test has the advantage of corresponding more closely to real-life situations than does tilt table testing. It is simple to perform in the clinic or the laboratory and does not require expensive equipment. However, a medical attendant should remain close to the patient to prevent a fall that could lead to injury. Clearly, active standing may not be possible in some circumstances, such as debilitated patients, patients with severe autonomic dysfunction, patients with muscular dystrophy, and so on.
Reproducibility of Head-up Tilt Table Testing and Active Standing Test A major issue with assessing reproducibility of a test utilizing orthostatic stress is how to control for variation in volume status prior to testing. Nevertheless, tilt-test reproducibility has been investigated using multiple tilts on the same day, a few days apart, and a few weeks apart. The experience in our laboratory suggests that the reproducibility of tilt-induced VVS is acceptable for use as a diagnostic test.45 The positivity or negativity of two sequential tests done 30 minutes apart was concordant in 87% of cases. In particular, a negative test has high reproducibility. In one study, none of the patients who were tilt-negative on the initial test developed syncope on repeat testing.45 The reproducibility of tilt testing with longer interest intervals is similar. Reproducibility with a 3- to 7-day separation was 90% in 21 patients (including isoproterenol provocation), although the level of provocation needed was different in 24%. At intervals of 1 to 6 weeks between testing (including isoproterenol provocation), there was 85% reproducibility in 46 patients who were initially tilt negative and 90% reproducibility in those who were initially tilt positive.46 Head-up tilt table testing using nitroglycerin for provocation also shows acceptable reproducibility.47,48 There has not been rigorous examination of the reproducibility of the active standing test.
Head-up Tilt Testing and Treatment of Vasovagal Syncope As noted in Table 67.3, the 2009 ESC guidelines7 do not view head-up tilt table testing as useful for the testing efficacy of therapy for VVS. This use of head-up tilt table testing for defining treatment was given a Class III indication. On the other hand, of interest is the recent observation that a negative tilt study appears to identify a subgroup of syncope patients, who, if found to have significant bradycardia or asystole as part of their clinical syncope picture (usually documented by long-term ambulatory ECG monitoring), are likely to benefit from permanent pacing.49 If this observation is confirmed, it would suggest a role for head-up tilt table testing for “pacemaker therapy stratification,” even if the VVS diagnosis was clear on clinical grounds.
Overview of Uses for Head-up Tilt Table Testing Established indications for head-up tilt table testing were noted earlier7 and in Table 67.3. Additionally, head-up tilt table testing has been used (albeit with less supportive evidence) in (1) chronic fatigue syndrome, (2) POTS, (3) recurrent vertigo, (4) recurrent transient ischemic attacks, and (5) conduction system disease that, at electrophysiological testing, does not appear severe enough to explain syncope. With the possible exception of POTS, we do not advocate these other applications, and the existing practice guidelines do not provide support for such use.
Conclusions Head-up tilt table testing, either drug-free or if necessary with pharmacological provocation (most often nitroglycerine) has
HEAD-UP TILT TABLE TESTING
proven to be a useful, readily available, and safe modality for identifying susceptibility to VVS and confirming suspected OH. However, tilt testing has not been shown to be a reliable means of testing the efficacy of therapeutic interventions. Additionally, head-up tilt table testing is not known to be helpful in evaluating other forms of reflex syncope, with the possible exception of clarifying the hemodynamic impact of carotid sinus stimulation in patients with suspected carotid sinus syndrome. Head-up tilt table testing has been the subject of numerous studies, resulting in the development of widely accepted protocols. These protocols offer a level of reproducibility, sensitivity, specificity, and predictive value on par with other widely used cardiovascular tests, such as exercise testing.
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Finally, head-up tilt table testing is finding new roles in the evaluation in distinguishing between epilepsy and syncope, detecting psychogenic pseudosyncope/pseudoseizures, and in the assessment of patients initially considered having epilepsy but in whom confirmation of the diagnosis has been elusive. In all of these cases, the tilt test is best combined with ancillary testing, particularly the video-EEG.
Acknowledgment Dr Benditt is supported in part by a grant in support of heartbrain research from the Dr. Earl E. Bakken family.
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36. Sinkovec M, Grad A, Rakovec P. Role of endogenous adenosine in vasovagal syncope. Clin Auton Res. 2001;11:155–161. 37. Shen WK, Hammill SC, Munger TM, et al. Adenosine: potential modulator for vasovagal syncope. J Am Coll Cardiol. 1996;28:146–154. 38. Brignole M; Gaggioli G; Menozzi C; et al. Adenosineinduced atrioventricular block in patients with unexplained syncope: the diagnostic value of ATP testing. Circulation. 96:3921–3927. 39. Flammang D, Erickson M, McCarville S, Church T, Hamani D, Donal E. Contribution of head-up tilt testing and ATP testing in assessing the mechanisms of vasovagal syndrome: preliminary results and potential therapeutic implications. Circulation. 1999;99:2427–2433. 40. Flammang D, Church TR, De Roy L, et al. ATP Multicenter Study. Treatment of unexplained syncope: a multicenter, randomized trial of cardiac pacing guided by adenosine 5’-triphosphate testing. Circulation. 2012;125:31–63. 41. Adkisson WO, Benditt DG. Syncope due to autonomic dysfunction: diagnosis and management. Med Clin North Am. 2015;99:691–710. 42. Adkisson WO, Benditt DG. Treatment of ‘refractory’ epilepsy: syncope incognito unmasked by implantable ambulatory electrocardiographical recordings. Europace. 2012;14:1540–1542. 43. Rangel I, Freitas J, Correia AS, et al. The usefulness of the head-up tilt test in patients with suspected epilepsy. Seizure. 2014;23:367–370. 44. van Dijk JG, Thijs RD, van Zwet E, et al. The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes. Brain. 2014;137:576–585. 45. Chen MY, Goldenberg IF, Milstein S, et al. Cardiac electrophysiologic and hemodynamic correlates of neurally mediated syncope. Am J Cardiol. 1989;63:66–72. 46. Sheldon R, Splawinski J, Killam S. Reproducibility of isoproterenol tilt-table tests in patients with syncope. Am J Cardiol. 1992;69:1300–1305. 47. Del Rosso A, Bartoletti A, Bartoli P, et al. Methodology of head-up tilt testing potentiated with sublingual nitroglycerin in unexplained syncope. Am J Cardiol. 2000;85:1007–1011. 48. Foglia-Manzillo G, Giada F, Beretta S, Corrado G, Santarone M, Raviele A. Reproducibility of head-up tilt testing potentiated with sublingual nitroglycerin in patients with unexplained syncope. Am J Cardiol. 1999;84:284–288. 49. Brignole M, Donateo P, Tomaino M, et al. International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3). Circ Arrhythm Electrophysiol. 2014;7:10–16.
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