Tim M. Young

Water drinking in the management of orthostatic intolerance due to orthostatic hypotension, vasovagal syncope and the postural tachycardia syndrome

Water drinking recently has been shown to raise blood pressure in normal subjects and in patients with autonomic failure who have orthostatic hypotension. However, in normal young subjects, ingestion of approximately 500 ml has no pressor effect; but in older subjects there is an increase in blood pressure. An even greater rise in blood pressure occurs in cases with autonomic failure. The possible mechanisms responsible for the pressor response to water include neural and humoral factors; fluid redistribution also needs to be considered. This review will concentrate on the water pressor response in normal subjects and different groups of patients with autonomic diseases who have orthostatic intolerance, on the mechanisms that could be involved, and on whether this pressor response may be used in the management of orthostatic hypotension, vasovagal syncope and the postural tachycardia syndrome.

Skin vasomotor reflex responses in two contrasting groups of autonomic failure - Multiple system atrophy and pure autonomic failure

Background & AimA variety of stimuli such as deep inspiration, isometric exercise and mental arithmetic, result in a transient vasoconstriction,mediated by sympathetic efferent nerves, in the skin of the fingers and toes of healthy controls (Skin Vasomotor Reflex: SkVR). Multiple system atrophy (MSA) and pure autonomic failure (PAF) provide contrasting models of autonomic failure. In MSA the lesion is central and preganglionic, whilst in PAF the lesion site is peripheral and postganglionic. We evaluated the SkVR in response to various stimuli in MSA and PAF, to determine differences in skin vasomotor involvement between these two patient groups.Methods25 subjects (10 MSA, 7 PAF, 8 healthy controls) were studied. Baseline recordings of skin blood flow were obtained with a laser Doppler probe on the left index finger pulp and forearm. The subject then underwent a variety of stimuli with rest periods in between to reestablish baseline SkBF. These stimuli were: single deep inspiration (inspiratory gasp); mental arithmetic; bilateral leg elevation and cutaneous cold.ResultsHealthy control subjects demonstrated marked SkVRs on the finger pulp to each of the stimuli of a magnitude similar to those seen in previous studies, but no SkVRs on the forearm. In MSA SkVRs to inspiratory gasp on the finger pulp were reduced relative to controls. In PAF SkVRs were reduced relative to controls or MSA. The magnitude of SkVR response to gasp and cutaneous cold in PAF was significantly less than in healthy controls. In addition, the magnitude of the response in PAF was significantly less than in MSA for inspiratory gasp.ConclusionsPAF showed a decreased SkVR response to all 4 stimuli, the response being significantly less than controls (for inspiratory gasp and cutaneous cold) or MSA (cutaneous cold inspiratory gasp). The decreased responses in PAF may reflect the extensive postganglionic sympathetic denervation seen in this group. The measurement of SkVR may therefore provide a non-invasive aid to the differentiation of MSA and PAF.

The effect of different physiological stimuli on skin vasomotor reflexes above and below the lesion in human chronic spinal cord injury

Objective. Spinal cord injury (SCI) results in disruption of descending tonic activation of sympathetic circuits in the spinal cord. The authors determined whether different stimuli that increase sympathetic activity induced cutaneous vasoconstriction (skin vasomotor reflex, SkVR) above and below the level of lesion in subjects with clinically complete SCI. Methods. Baseline skin blood flow (SkBF) and SkVR reduction rate in the pulp of the finger and great toe was measured by laser Doppler probes in chronic complete SCI and in controls. Results. In the finger, baseline SkBF was similar in SCI and controls. The SkVR was elicited by all stimuli in controls but was significantly diminished to gasp, mental arithmetic, tactile stimulation, cutaneous cold, and deep breathing in high SCI compared to controls. In the toe, baseline SkBF was less stable in both controls and SCI. SkVR trends were identified in controls, and responses were not present or greatly reduced in high and low SCI. Conclusions. Measurements of skin vasomotor reflexes to physiological stimuli may be a noninvasive method to evaluate the extent of sympathetic adrenergic pathways in chronic SCI. This is of clinical relevance in monitoring recovery of sympathetic adrenergic function either spontaneously or following repair interventions.

Heat-provoked skin vasodilatation in innervated and denervated trunk dermatomes in human spinal cord injury

Study design:Cross-sectional, observational, controlled study.Objective:High spinal cord injury (SCI) results in disruption of sympathetic vasomotor control. Vasodilatation as a response to local heating is a biphasic mechanism: the first phase (neurogenic) is mediated by the axon-reflex and is modulated by activity of sympathetic nerves. Our objective was to determine whether the response to heat provocation in trunk dermatomes may provide a measure of vasomotor sympathetic function in SCI.Setting:National Spinal Injuries Centre, Stoke Mandeville Hospital, Buckinghamshire, UK; Autonomic Unit, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Neurovascular Medicine Unit, Imperial College London at St Marys Hospital, UK.Subjects:A total of 30 subjects were studied; 18 had chronic complete SCI (level C6–T11) and 12 were healthy controls.Methods:Recordings of skin blood flow (SkBF) were obtained with thermostatic laser Doppler probes placed in the upper trunk (at C4) and lower trunk (T10 or T12) dermatomes.Results:SkBF at baseline (SkBFbas) and SkBF at the first peak of vasodilatation (SkBFmax) showed no significant differences between SCI and controls either in upper or lower trunk dermatomes. However, the ratio of SkBFmax/SkBFbas was significantly different in lower trunk dermatomes in SCI at C6–T5 level (7.5±3.5 PU) compared to SCI at T6-T11 level (3.5±1.5 PU) (P<0.01).Conclusion:Measurement of SkBF in response to local heating may provide a safe, noninvasive method to assess integrity of sympathetic spinal pathways to the local vasculature. This may aid the classification of the SCI lesions, as the autonomic component currently is not included in the accepted American Spinal Injury Association scoring.

Neuroendocrine and behavioural responses to CO2 inhalation in central versus peripheral autonomic failure

Multiple system atrophy (MSA) and pure autonomic failure (PAF) represent distinct pathological models of autonomic failure in humans. We have investigated the neuroendocrine, behavioural and autonomic cardiovascular responses to the 35% CO2 challenge. Nine patients with MSA, nine with PAF and five control subjects received a single breath of 35% CO2. Peripheral autonomic failure (i.e., PAF) was associated with significantly lower resting noradrenaline levels. All groups demonstrated a significant pressor response to CO2. In controls, the mean pressor response was +60.2 mm Hg, which was significantly smaller in both the PAF (+26.8 mm Hg, P < 0.01) and MSA (+18.3 mm Hg, P < 0.001) patients. In addition, the onset of the response was significantly delayed in both MSA (140.2 s) and PAF (154.2 s) patients compared with controls (32.4 s, P = 0.04 and P = 0.03, respectively). Noradrenaline levels increased only in controls. Central autonomic impairment (i.e., MSA) was associated with lower cortisol release (+8.8% in MSA compared with +35.2% in control and +23.7% in PAF) and fewer somatic symptoms of emotional arousal. Both MSA and PAF exhibit marked sympathetic autonomic impairment, however, residual (albeit differing) sympathetic pathways can still maintain a partial cardiovascular response. A central autonomic lesion, however, also appears to be associated with blunting of both cortisol and emotional responses to this stress paradigm.

Differences in overshoot of blood pressure after head-up tilt in two groups with chronic autonomic failure: pure autonomic failure and multiple system atrophy.

On head down tilt to the supine horizontal position (tilt reversal) after head up tilt (HUT), patients with orthostatic hypotension may show an increase in blood pressure (BP) relative to baseline readings. We assessed this BP overshoot in 8 patients with pure autonomic failure (PAF, 64±13 years) and 8 patients with multiple system atrophy (MSA, 66±10 years). BP was intermittently measured during pre-tilt supine, HUT (60°, 10 min), and post-tilt supine periods. In addition, beat-to-beat BP was measured continuously using the Portapres model 2 device to calculate stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR). There was systolic BP overshoot of ≥ 15mmHg after tilt reversal in 5 out of 8 PAF, but in only one of 8 MSA. A mean increase of systolic BP in PAF was significantly higher than that in MSA (p<0.01). TPR increased over baseline level after tilt reversal, although there was no significant difference. SV and CO levels during the post-tilt supine period were similar to baseline levels. In conclusion, BP overshoot was prominent in the PAF group but not in the MSA group. The phenomenon of BP overshoot while supine, especially in PAF, may have implications for long term cardiac and vascular damage in such patients.

Plugging the leak

The kidneys and urinary tract have a rich autonomic nerve supply. Innervation of the juxtaglomerular apparatus influences renin release, that of the renal tubules controls excretion of water and ions such as sodium and chloride, and the dual innervation of the urinary bladder regulates its storage and emptying capabilities [1, 2]. With central autonomic neurodegeneration, which includes loss of vasopressin neurons in the suprachiasmatic nucleus in multiple system atrophy (MSA), there may be abnormal release of neurohormones, such as the antidiuretic hormone, arginine vasopressin [3–5]. Disorders of the autonomic nervous system, therefore, can result in a variety of abnormalities affecting fluid and electrolyte balance. Nocturnal polyuria is a common symptom in autonomic failure. This was first reported in patients with orthostatic hypotension by Bradbury and Eggleston [6] with detailed studies by Wilcox et al. [7]. In patients with urinary bladder involvement nocturia can be troublesome and considerably add to their disabilities. Nocturnal diuresis and natriuresis account for overnight weight loss that appears to worsen the extent of, and symptoms resulting from, orthostatic hypotension in the morning. Some patients are considerably incapacitated and find it difficult to function until late morning; even a light breakfast and minimal exertion can substantially worsen symptoms [8]. This partly may be helped by the use of head-up tilt at night. Alternative measures were considered by Mathias et al. [9] to reduce fluid loss overnight and improve morning orthostatic hypotension. They were aware that recumbency and restitution of blood pressure, sometimes with a degree of supine hypertension, increased sodium excretion [10]. The antidiuretic hormone vasopressin was a possible choice to reduce nocturnal polyuria, but it also had effects on vasopressin-1 receptors that result in an exaggerated pressor response in patients supersensitive to a variety of vasoactive agents [11]. Therefore, they chose the synthetic vasopressin analogue desmopressin which has minimal vasopressin-1 agonist activity and predominantly antidiuretic effects by acting on vasopressin-2 receptors on renal tubules. They administered desmopressin by intramuscular injection to 6 patients with primary autonomic failure; 4 had pure autonomic failure (PAF) and 2 had MSA [9]. Desmopressin was effective in reducing overnight urine volume and weight loss, and also improved morning orthostatic hypotension. Nocturnal polyuria probably results in redistribution of body fluids, reducing central filling pressure, stroke volume, cardiac output and thus blood pressure. This is consistent with recent studies confirming that orthostatic hypotension is worse in the morning and indicating that there are greater changes in stroke volume and cardiac output on standing in the morning compared to the evening [12]. The reduction in overnight fluid loss presumably reverses this cycle of events, thus reducing morning orthostatic hypotension. They suggested [9] there may be chronic fluid depletion in autonomic failure, with a reduced extracellular fluid compartment, thus accounting for absence of signs of fluid overload after desmopressin, despite a mean weight gain of over 1.5 kg. All benefited except for 1 who developed water intoxication and hyponatraemia (sodium C A R 92 Professor C. J. Mathias, DPhil, DSc, FRCP, FMedSci · Timothy M. Young, BSc, MRCP Autonomic Unit National Hospital for Neurology & Neurosurgery Queen Square & Institute of Neurology University College London London, UK

Hemodynamic effects of clonidine in two contrasting models of autonomic failure: Multiple system atrophy and pure autonomic failure

We assessed the effects of clonidine on blood pressure (BP) and heart rate (HR) in multiple system atrophy (MSA), where the autonomic nervous system lesion site is preganglionic, and in pure autonomic failure (PAF), where it is postganglionic. In normal subjects, intravenous infusion of the selective α2‐adrenoceptor agonist clonidine reduces BP and plasma noradrenaline (NA) levels by means of central α2‐adrenoceptor action, as well as inducing growth hormone (GH) release. Clonidine‐induced GH release is impaired in MSA but spared in PAF. However, the hemodynamic effects of clonidine have not been studied extensively in these disorders. We examined intravenous clonidine test results (performed in our autonomic laboratories using the London Autonomic Units protocol) in 58 patients: 39 with probable MSA and 19 with PAF. Systolic BP (SBP), diastolic BP (DBP), HR, and NA levels were measured supine at baseline and for up to 60 minutes after clonidine. Clonidine resulted in a significant BP fall in MSA patients, which occurred earlier (within 15 minutes of clonidine) and to a greater extent than seen in PAF patients. MSA and PAF patients showed reduction in HR after clonidine administration, although this finding was significantly greater in MSA than in PAF patients. NA levels decreased significantly after clonidine administration in both groups. Although basal NA levels were lower in PAF than in MSA patients, there was no difference in NA reduction relative to baseline between groups. MSA patients showed significant negative correlation between basal NA levels and BP response to clonidine. Clonidine infusion reduces BP and HR in both MSA and PAF groups but to a greater extent in MSA patients. The greater vasodepressor action of clonidine in MSA patients suggests that there is partial preservation of brainstem sympathetic outflow pathways in MSA and may reflect its action at sites in the brainstem and spinal cord that were in part functionally preserved in MSA. Despite similar degrees of NA reduction after clonidine administration, the vasodepressor effect of clonidine was attenuated in PAF compared with MSA patients. This attenuation in PAF patients may reflect greater peripheral α2‐adrenoceptor denervation supersensitivity due to the postganglionic lesion site. These BP differences, thus, may reflect the underlying lesion site in MSA and PAF, and the hemodynamic data after clonidine infusion may help differentiate these conditions.

Decompression Sickness: MRI of the Spinal Cord

Decompression sickness (DCS) typically causes changes in the white matter of the spinal cord on MR imaging. We present a case of DCS in a scuba diver with dorsal white matter lesions typical of venous infarction. In addition, some central gray matter involvement was noted. Characteristic features of venous spinal cord infarction can be recognized on MR imaging in DCS but may be more extensive in severe cases.

Metabolomic Profiling in Acute ST‐Segment–Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia–Reperfusion Injury

Background Ischemia–reperfusion injury following ST‐segment–elevation myocardial infarction (STEMI) is a leading determinant of clinical outcome. In experimental models of myocardial ischemia, succinate accumulation leading to mitochondrial dysfunction is a major cause of ischemia–reperfusion injury; however, the potential importance and specificity of myocardial succinate accumulation in human STEMI is unknown. We sought to identify the metabolites released from the heart in patients undergoing primary percutaneous coronary intervention for emergency treatment of STEMI. Methods and Results Blood samples were obtained from the coronary artery, coronary sinus, and peripheral vein in patients undergoing primary percutaneous coronary intervention for acute STEMI and in control patients undergoing nonemergency coronary angiography or percutaneous coronary intervention for stable angina or non‐STEMI. Plasma metabolites were analyzed by targeted liquid chromatography and mass spectrometry. Metabolite levels for coronary artery, coronary sinus, and peripheral vein were compared to derive cardiac and systemic release ratios. In STEMI patients, cardiac magnetic resonance imaging was performed 2 days and 6 months after primary percutaneous coronary intervention to quantify acute myocardial edema and final infarct size, respectively. In total, 115 patients undergoing acute STEMI and 26 control patients were included. Succinate was the only metabolite significantly increased in coronary sinus blood compared with venous blood in STEMI patients, indicating cardiac release of succinate. STEMI patients had higher succinate concentrations in arterial, coronary sinus, and peripheral venous blood than patients with non‐STEMI or stable angina. Furthermore, cardiac succinate release in STEMI correlated with the extent of acute myocardial injury, quantified by cardiac magnetic resonance imaging. Conclusion Succinate release by the myocardium correlates with the extent of ischemia.