What is the initial step in assessing a patient for orthostatic hypotension?

ASSESSMENT OF ORTHOSTATIC BLOOD PRESSURE

The measurement of orthostatic BP is an essential clinical tool for the assessment and management of patients suffering from many common medical disorders. The most common causes are volume depletion and autonomic dysfunction. According to Carlson (1999), orthostatic hypotension, which is a decline in BP when standing erect, is the “result of an impaired hemodynamic response to an upright posture or a depletion of intravascular volume. The measurement of orthostatic blood pressure can be done at the bedside and is therefore easily applied to several clinical disorders.”

Orthostatic hypotension is detected in 10% to 20% of community-dwelling older individuals (Mader, 1987). This condition is frequently asymptomatic, but disabling symptoms of light-headedness, weakness, unsteadiness, blurred vision, and syncope may occur.

The American Academy of Neurology's consensus statement (1996) defines orthostatic hypotension as a “reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing.”

Many clinicians use a combination of a decrease in BP combined with an increase in heart rate to determine the presence of orthostatic hypotension.

Performing these orthostatic measurements requires adequate techniques in BP measurement, appropriate positioning of the patient, and proper timing of the measurements.

Procedure for Measuring Orthostatic Blood Pressure

Ask the patient about his or her ability to stand.

Make sure the cuffed arm is positioned so that the brachial artery is held at the level of the heart.

After 5 to 10 minutes of supine rest, take a baseline BP and pulse.

Have the patient sit on the side of the bed with feet dangling for 2 to 3 minutes, then take BP and pulse.

Repeat the measurements immediately upon having the patient stand.

Repeat the measurements again 1 to 3 minutes after continued standing. When recording the measurements, include the position when you took the readings and any signs or symptoms developed with postural changes.

Throughout the procedure assess the patient for dizziness, light-headedness, pallor, sweating, or syncope. If any of these occur, return the patient to a supine position.

Clinical presentation

Based on hemodynamic and temporal changes in orthostatic BP, there are three different clinical variants of OH that have been proposed, namely, initial, classic, and delayed forms (Moya et al., 2009; Wieling and Schatz, 2009). Initial OH is exclusively associated with active standing and is defined as a transient decrease of systolic BP > 40 mmHg and/or diastolic BP decrease > 20 mmHg within 30 s of standing. Diagnosing initial OH can be challenging and often requires tilt table testing with continuous BP monitoring. The postulated mechanism involves a transient mismatch between cardiac output and systemic vascular resistance (Wieling et al., 2007; Fedorowski and Melander, 2013). Classic OH is defined as a sustained reduction in systolic BP of at least 20 mmHg and/or a decrease in diastolic BP of at least 10 mmHg within 3 min of standing compared with BP from the sitting or supine position. In patients with supine hypertension, a reduction in systolic BP of at least 30 mmHg is considered more appropriate criteria for OH (Freeman et al., 2011). Delayed OH results from a progressive drop in BP beyond 3 min and sometimes up to 45 min. It is defined by a decrease in systolic/diastolic BP of at least 20/10 mmHg in normotensive patients and at least 30/15 mmHg in patients with hypertension. Patients with delayed OH often have milder, but prolonged prodromal symptoms. It is often seen in the older patient with age-related impairment of compensatory reflexes, frequent use of vasodilators and diuretics and associated comorbidities (e.g., diabetes, hypertension, and heart failure) (Gibbons and Freeman, 2006; Madhavan et al., 2008; Moya et al., 2009).

Characteristic symptoms of OH include lightheadedness, visual blurring, dizziness, leg buckling, generalized weakness, “coat hanger” ache, cognitive slowing, and gradual or sudden loss of consciousness. Most patients with OH however, are asymptomatic or have limited nonspecific symptoms. Thus, OH is often unrecognized or misdiagnosed.

Patients with OH may experience abnormal responses to pharmacologic or physiologic challenges (Grubb, 2005; Kanjwal et al., 2015). Heat, fever, alcohol, postexercise period, and immobilization are all conditions that may predispose patients to peripheral venous pooling and worsening tolerance of orthostatic stress. Symptoms are usually more common in the morning and after waking up. Morning intake of antihypertensive medications and postprandial hypotension often contribute to the problem in the early hours of the day resulting in syncope, falls, dizziness, weakness, angina pectoris, and stroke (Zanasi et al., 2012). Patients with AUD may be more susceptible to hypotension after consumption of large meals rich in carbohydrates (Jansen and Lipsitz, 1995). Possible contributors to postprandial hypotension include inadequate sympathetic nervous system compensation for meal-induced splanchnic blood pooling; inadequate postprandial increases in cardiac output; impairments in baroreflex function and peripheral vasoconstriction; insulin-induced vasodilation, and release of vasodilatory gastrointestinal peptides (Trahair et al., 2014).

HYPOTENSIVE ACTIVITY

Cannabis and cannabinoids are known to reduce orthostatic blood pressure[144]. The literature up to 1986 on the cardiovascular effects has been reviewed by Graham [161]. Δ9-THC (up to 5 mg/kg) administered i.v. to anaesthetized rats caused a profound decrease in mean arterial blood pressure in a dose-dependent manner [162]. Yet very little has been published on this topic. One of the reasons may be that the acute cardiovascular changes, including decreased standing blood pressure or increased supine blood pressure are of ‘little consequence for users without cardiovascular disease’ [163]. From the point of view of the medicinal chemist, this field apparently did not look promising as it was assumed that the lowering of blood pressure was of central origin and therefore it would be accompanied by the THC-type side-effects, although it was shown 20 years ago that a synthetic isomer of CBD, namely (29), which is not psychotropic, is hypotensive [164]. Several 9-azacannabinoids [such as (30) and (31)] were prepared in order to test their antihypertensive effects [165]. The most potent compound, the benzopyran (30), was less psychoactive than Δ9-THC. However, on chronic administration to dogs, rapid tachyphylaxis was noted and apparently no further work was undertaken. It should be of interest to take a second look at these azacannabinoids.

In a recent publication, the effects of HU-210 on blood pressure are discussed [166]. It was noted that this very potent psychotropic agent also caused long-lasting hypotension (as well as bradycardia) in rats in doses between 10 and 1000 μg/kg. With Δ9-THC, an initial pressor effect was found, but with HU-210, this effect was not observed.

In several papers the Kunos group has reported observations that may represent a starting point for novel medicinal chemistry research in this area [167,168]. Anandamide (i.v. bolus; 4 mg/kg) caused a triphasic blood pressure response, brief hypotension, followed by a transient pressor and then a prolonged depressor phase. The hypotensive effect was not initiated in the CNS, but was due to a presynaptic action that inhibited norepinephrine release from sympathetic nerve terminals in the periphery (heart and vasculature). The inhibitory effect (but not the pressor effect) was antagonized by SR141716A, indicating that this peripheral action was mediated by CB1 receptors.

In a late 1997 paper, the Kunos group reported that activation of peripheral CB1 receptors contributes to haemorrhagic hypotension, and that the anandamide produced by macrophages may be a mediator of this effect [168a]. In a series of publications, Randall has proposed that anandamide (or a related cannabinoid) is a long-looked for endothelium-derived hyper-polarizing factor, EDHF [65, 168b]. EDHF relaxes vascular smooth muscle through activation of ATP-dependent potassium channels. As mentioned above, anandamide, like Δ9-THC, induces vasodilation in cerebral arteries [62]. Randall has now shown that in rat mesenteric arteries (treated with inhibitors of NO synthase and cyclo-oxygenase), the CB1 antagonist SR141716A inhibits endothelium-dependent relaxations evoked by carbachol. Such relaxations are produced by anandamide. As in most types of hypertension, endothelium-dependent relaxations are curtailed due to lowered production or activity of endothelium-derived NO and EDHF. The above observations may be of central importance in the development of anandamide-type drugs against hypertension [168c].

On-Treatment Management

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General management on treatment should include at least weekly vital signs including orthostatic blood pressure readings to monitor for dehydration and accurate weight to monitor for accelerated weight loss.

Skin changes like erythema and dry desquamation should be managed with topical emollients.

Though uncommon in doses such as these, moist desquamation should be treated with antimicrobial topical agents such as silver sulfadiazine.

Radiation-induced esophagitis

Can be managed with topical analgesics such as viscous lidocaine alone or in mixtures with antacids and antihistamines (occasionally referred to as “magic mouthwash” or “oncology mouthwash”). These often offer only temporary relief of esophagitis symptoms but can be effective if optimally timed for meals or oral intake.

Escalated pain symptoms in this setting sometime require narcotics for management. Transdermal narcotics can be effective at providing long-acting analgesia without requiring oral administration.

Overuse of narcotics should be regarded with caution given the potential for respiratory depression in a population that may have significant dyspnea at baseline.

Occasionally costochondritis can develop and cause mechanical chest pain.

This may be more common with SBRT and can be acute or subacute (6 months to 1 year) after treatment.

Usually conservative measures including over-the-counter nonsteroidal antiinflammatory medications are adequate to treat this until they resolve spontaneously.

Acute cardiac toxicities are uncommon, and may manifest as pericarditis or pericardial effusion.

If pericarditis is suspected on the basis of chest pain or hemodynamic changes, evaluation by cardiology or emergency medicine is recommended.

Pericardial friction rub on exam and diffuse ST segment elevations on electrocardiogram are characteristics. This can usually be managed conservatively with antiinflammatories.

Constraints proposed by an MD Anderson review of pericardial effusion in treatment of esophageal tumors with definitive radiation include mean dose <26 Gy and V30 <46% [46], though these may not be directly applicable to the various dose regimens and fraction sizes used in palliative thoracic radiation.

Another study pooling protocol patients at a single institution reported an actuarial rate of 3.9% for pericarditis at 6 months, which suggested that fraction size may predict development of pericarditis or effusion [47].

Possibly the most challenging on-treatment toxicities to manage are those related to the patients’ respiratory symptoms.

Patients may present with a history of respiratory issues and are often receiving palliative radiation due to an acute exacerbation of these symptoms.

Worsening dyspnea or cough on treatment could represent radiation toxicity, tumor progression, embolism, infection, or development of a pleural effusion.

As these are all managed in very different ways, there should be a low threshold to order repeat diagnostic imaging or infectious workups while on treatment.

Depending on etiology, a trial of inhaled bronchodilators may be useful.

As earlier, concurrent steroids may be effective in reducing transient tumor swelling when treating compression-related symptoms. Working closely with the patient’s pulmonologist is advised (Table 14.2).

Table 14.2. On-Treatment and Chronic Management of Toxicities

21 What is the significance of autonomic dysfunction? How might you tell if a patient has autonomic dysfunction?

Patients with autonomic dysfunction tend to have severe hypotension intraoperatively. Evaluation of changes in orthostatic blood pressure and heart rate is a quick and effective way of assessing autonomic dysfunction. If the autonomic nervous system is intact, an increase in heart rate of 15 beats/min and an increase of 10 mm Hg in diastolic blood pressure are expected when changing position from supine to sitting. Autonomic dysfunction is suggested whenever there is a loss of heart rate variability, whatever the circumstances. Autonomic dysfunction includes vasomotor, bladder, bowel, and sexual dysfunction. Other signs include blurred vision, reduced or excessive sweating, dry or excessively moist eyes and mouth, cold or discolored extremities, incontinence or incomplete voiding, diarrhea or constipation, and impotence. Although there are many causes, it should be noted that people with diabetes and chronic alcoholics are patient groups well known to demonstrate autonomic dysfunction.

Neurologic

The major neurological complications of AN are seizures (caused by electrolyte disturbances) and syncope (caused by orthostatic blood pressure changes). Structural brain changes have been observed on brain imaging studies (Golden et al., 1996; Katzman et al., 1996) and neuropsychological testing has demonstrated impairment of attention, concentration and memory. Early studies demonstrated reduced grey and white matter volumes that improved with weight restoration (Golden et al., 1996; Katzman et al., 1997; Van Den Eynde et al., 2012). More recent structural and functional studies have focused on the insula, striatum and orbitofrontal cortex and have demonstrated alteration in the taste reward circuitry (Frank et al., 2013).

Contraindications

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Unstable angina

Resting systolic blood pressure >200 mm Hg or diastolic BP >110 mm Hg

Orthostatic blood pressure drop of >20 mm Hg with symptoms

Moderate to severe aortic stenosis

Acute systemic illness or fever

Uncontrolled atrial or ventricular arrhythmias

Uncontrolled tachycardia (>120 beats/min)

Uncompensated congestive heart failure

Third-degree heart block (without pacemaker)

Active pericarditis or myocarditis

Recent embolism

Thrombophlebitis

Resting ST displacement (>2 mm)

Uncontrolled diabetes

Orthopedic problems that prohibit exercise

Other metabolic conditions such as thyroiditis, hypokalemia, hyperkalemia, or hypovolemia

Physical Findings

The physical examination should include height, weight after voiding in a gown facing backwards on the scale, and orthostatic blood pressure and pulse measurements. Some centers do not weigh patients backwards, preferring “open weights” for all, but for those individuals limited cognitively by brain starvation, the numbers can trigger increasing dieting or disordered eating attitudes and behaviors. Those clinicians who know by experience which of their patients do well with that knowledge and which will find the numbers triggering can use their individual judgment case by case; but nursing staff may support care better by making it a universal procedure to be discreet with all patients, using words such as, “It is our policy to weigh all new patients backwards on the scale after voiding, and you may discuss this further with Dr. __,” clearly and respectfully. Clinicians should also be alert to the possibility of weight manipulations, either via water loading to falsely elevate weight, use of weights in underwear or various orifices, or other strategies. For these reasons, many centers insist on the weight in a gown, often after a “pat down” with patients known or suspected of hiding weights, after voiding, with urinalysis checking for specific gravity, protein, and ketosis. Dehydration may result in an accelerated heart rate, masking a sinus bradycardia as a result of a feeding disorder.

Other aspects of the physical examination include a thorough head-to-toe examination, with attention to the parotid glands (looking for parotitis from vomiting), dental erosions on the lingual and occlusal surfaces, Russell sign (callus of the knuckle from hitting it with teeth during purging; see Figure 16-1), bradycardia, hypothermia, and orthostatic hypotension by pulse (an increase in heart rate greater than or equal to 20 when going from horizontal to vertical) or by blood pressure (diastolic dropping by 10 points from lying to standing), Tanner staging of breasts and pubic hair (genitals and pubic hair in boys), noting atrophy of breasts, abdominal masses (including palpable loops of stool from constipation), scaphoid appearance, swelling of extremities, acrocyanosis, and edema in dependent areas. Examination of optic disks can also help to rule out blurred disk margins, with a full neurologic examination necessary to elicit any positive findings requiring brain imaging to identify a brain tumor, low in likelihood but a concern in boys in whom the prevalence of eating disorders is less likely than in girls and in any girl with positive neurologic findings. A summary of physical findings can be found in Table 16-4.

Contraindications to exercise

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Unstable angina.

Resting SBP >200 mmHg or resting diastolic BP (DBP) >110 mmHg.

Orthostatic BP drop >20 mmHg with symptoms.

Critical aortic stenosis.

Acute systemic illness or fever.

Uncontrolled atrial or ventricular arrhythmias.

Uncontrolled sinus tachycardia.

Uncompensated chronic heart failure.

Third degree heart block.

Active pericarditis or myocarditis.

Recent embolism.

Thrombophlebitis.

Resting ST segment displacement >2 mm on electrocardiograph (ECG).

Uncontrolled diabetes (resting blood glucose >400 mg/dL).

Hypotension

The hypotensive effects of the monoamine oxidase inhibitors differ from those of the tricyclic antidepressants, inasmuch as the former affect supine as well as orthostatic blood pressure. This was confirmed in a study involving tranylcypromine [16] and in an evaluation of blood pressure changes in 14 patients who took phenelzine at an average dose of 65 mg/day for at least 3 weeks [17]. The drug-free mean supine systolic blood pressure was 127 mmHg and it fell significantly (mean drop 5 mmHg) by the end of the first week. By contrast, an increase in the orthostatic drop from the mean predrug baseline of 2 mmHg did not reach significance until the end of the second week of treatment, after which the blood pressure continued to fall. Two patients developed profound orthostatic falls of up to 50 mmHg after more than 2 weeks of treatment. In one patient the hypotension and related symptoms (light-headedness and ataxia) improved with fludrocortisone, but not in the other, who required drug withdrawal. The authors commented that because orthostatic hypotension can develop late, cautious long-term monitoring is required.