Autonomic Nervous System and Hemodialysis Hypotensim

Autonomic Nervous System and Hemodialysis Hypotensim

Mark Travis and William L. Henrich

From the Department of Internal Medicine, University of Texas Southwestern Medical Center and Dallas Veterans Administration Medical Center, Dallas, Texas

The relationship between the autonomic nervous system and hemodynamic homeostasis was first de- scribed in detail by Bradbury in 1925 (1). He noted that the autonomic nervous system is intimately involved in the regulation of arterial blood pressure through baroreflex mechanisms. In subsequent years, the central and peripheral neuronal pathways which control vasomotor tone, heart rate, myocar- dial contractility, and venous capacitance have been delineated in greater detail (2-4).

The autonomic reflex arc is composed of an afferent limb, which consists of a network of neuronal fibers originating from the vascular tree, visceral organs, and skin which then enter the spinal cord and central nervous system (CNS). Arterial baroreceptors (located in aortic arch and left atrium) sense changes in blood pressure, and are also a part of the afferent limb. Within the CNS, integration of im- pulses between the brainstem, cerebellum, hypothal- amus, and cerebral hemispheres occurs; the efferent limb (both sympathetic and parasympathetic pathways) of the autonomic arc then exits the brainstem and spinal cord to travel to distal sites.

Primary disorders of the autonomic nervous system such as progressive autonomic failure (idi- opathic orthostatic hypotension), Shy-Drager syndrome, Parkinson’s disease, and multiple sclerosis are characterized by postural hypotension, a fixed heart rate, disordered sweat gland function, and im- potence. These degenerative disorders of the autonomic nervous system underscore its importance in the maintenance of adequate arterial perfusion. Spinal cord transections above the level of T6 are also associated with postural hypotension ( 5 ) and illustrate the key role of an integrated baroreflex mechanism for blood pressure control.

Hypotension during maintenance hemodialysis continues to occur in as many as 30% of all dialysis

Address correspondence to: William L. Henrich, MD. Chief, Nephrology Service, Dallas Veterans Administration Medical Center, 4500 South Lancaster (1 1 IGI), Dallas, TX 75216.

Seminars in Dialysis-Vol 2 , No 3 (July-Sept) 1989 pp 158- 162

158

sessions (6, 7). Table 1 lists several underlying etiol- ogies for hemodialysis hypotension. Goldberger (8) first emphasized the frequency of an autonomic neuropathy in uremia. In 1976 Lilley et al. (9) pro- posed that a defect in the baroreceptor reflex arc was a key factor in hemodialysis hypotension. More recently, Bondia et al. (10) studied 52 hernodialysis patients and confirmed the existence of a defect in the autonomic reflex arc in dialysis subjects; the defect was localized in the afferent pathway.

The purpose of this review is to examine the role of the autonomic nervous system in the context of the problem of hypotension during hemodialysis.

incidence of Autonomic Dysfunction in Dialysis Patients

Several investigators have measured the frequency of autonomic nervous system dysfunction in patients on hemodialysis. Soriano and Eisinger (1 1) noted a significant incidence of an attenuated blood pressure response during the Valsalva maneuver in dialysis patients. Ewing and Winney reported autonomic nervous system dysfunction in 45 to 50% of the patients on hemodialysis as ascertained by abnormal Valsalva and handgrip tests ( 1 2). They further suggested that screening for autonomic insufficiency in hemodialysis patients might disclose those patients who were at greatest risk of hypotensive epiosdes during dialysis.

The fact that the dysfunction of the autonomic nervous system was not a technical sequela of the hemodialysis process but a manifestation of the uremic syndrome was documented by Campese et al. ( 1 3). They studied 60 normal subjects, 2 1 predialysis patients, 16 dialysis patients, and 15 patients with chronic disease but without renal insufficiency. The autonomic nervous system was evaluted using the Valsalva ratio (the longest R-R interval after a tussive effort divided by the shortest R-R interval during the effort), hand-grip exercise and blood pressure resonse to a norepinephrine infusion. Both predialysis and dialysis patients had an abnormal Val- salva ratio and a blunted increase in blood pressure

C N S AND HEMODIALYSIS HYPOTENSION 159

TABLE 1. Contributing factors to dialysis hypotension

Procedural Rapid contraction of the ECF Rapid decreases in plasma osmolality Acetate

Diastolic dysfunction, hypertension Coronary artery disease Cardiomyopathy, uremia PericardiaJ tamponade Constrictive pencarditis Supravent~cular/ventricular dysrhythmias

Miscellaneous Antihypertensive medications Hypoxemia Anemia Endotoxemia Hemolysis, acute Hypokalemia, acidosis Autonomic insufficiency

Cardiac

during the hand grip exercise when compared to normal subjects and individuals with chronic illness. Norepinephine infusion produced a smaller increase in mean arterial pressure and heart rate of predialysis patients versus patients receiving regular hemodialysis or normal subjects. Taken as a whole, the increased incidence of autonomic nervous system dysfunction in predialysis as well as dialysis patients suggested that autonomic dysfunction is a manifestation of the uremic syndrome. Further, hemodialysis may actually ameliorate some aspects of the autonomic dysfunction. Unfortunately, the very large National Cooperative Dialysis Study ( 14) documented the presence of a peripheral neuropathy in many dialysis patients, but autonomic dysfunction was not directly assessed.

Characteristics of Autonomic Dysfunction in Dialysis Patients

Despite intensive investigation, the exact biochem- ical, cellular and molecular events which culminate in autonomic neuropathic dysfunction in uremia have not been elucidated. However, several well defined abnormalities within the autonomic arc are clear.

Reduced Baroreceptor Sensitivity

Guyton suggested that alterations in the integrity of baroreceptors could produce abnormal vascular responses (1 5) . Baroreceptors are generally assessed by studying the relationship between the increase in blood pressure (induced by pressor agents such as phenylephrine) and the normal reflex bradycardia. This type of maneuver tests high pressure barorecep tors; low pressure baroreceptors may be tested using amyl nitrite. Patients on hemodialysis often have an abnormal response to these types of tests (1 0).

Lilley et al. (9) used the cold pressor test (which tests the efferent limb of the autonomic arc) and the amyl nitrite inhalation test (a test of low pressure baroreceptors and the entire autonomic arc) in two groups of hemodialysis patients. One group exhibited

frequent episodes of hypotension (<70 mm Hg) during dialysis, whereas the other group was usually asymptomatic. The two groups had similar cold pressor tests, suggesting that the efferent limb of the autonomic arc was intact in both groups. However, the hypotension-prone group displayed a signifi- cantly blunted increase in heart rate with amyl nitrite-induced low blood pressure compared to the increase in heart rate seen in the nonhypotensive group. The authors therefore deduced that the afferent limb of the autonomic arc, (i.e., the barorecep tors) was the likely site of the defect in the autonomic nervous system. Furthermore, the hypotensive group had elevated plasma dopamine beta-hydroxylase concentrations, an enzyme released with norepinephrine from sympathetic nerve terminals, suggesting a general increase in efferent sympathetic activity. This subset of hypotensive patients also had higher mean supine blood pressures than the group of patients without frequent hemodialysis hypotension. In summary, these findings suggested that hemodialysis patients with baroreceptor arc dysfunction had a "deafferentation" of the autonomic system, leading to over-activity of the efferent limb (1 6). This study remains as the clearest investigation as- sociating autonomic neuropathy with dialysis hypotension.

Nies et al. (1 7) confirmed several of these earlier findings in five chronic hemodialysis patients with frequent episodes of hypotension. They also noted that the appropriate compensatory tachycardia expected during the hypotension was absent. The authors speculated that a baroreceptor defect was present since efferent sympathetic hnction by the cold pressor test was normal. These authors did not, however, link the presence of the autonomic lesion to overt hypotensive episodes during dialysis; rather, they clarified the location of the defect. More recently Ciccarelli et al. (18) also has noted a 20 to 40% prevalence of cardiac autonomic neuropathy in dialysis patients. In reality the incidence of autonomic neuropathy probably approaches 130% if the loss of beat to beat variability with respiratig n is taken as a diagnostic sign of autonomic dysfunction.

End Organ Resistance to Catecholamines

In keeping with the "dderentation" concept mentioned above, plasma catecholamine concentrations are increased in patients undergoing maintenance dialysis (19). It has been observed that these levels are also high in predialysis patients with renal insufficiency. Wehle et al. (20) and Chen et al. (21) both showed a decrease in the expected rise in peripheral vascular resistance during volume removal in hemodialysis patients. The implication from many studies is that the elevated plasma catecholamine concentration increases receptor occupancy leading to maximum peripheral vasoconstriction and a lack of response to further increments in norepinephrine concentration. This desensitization causes an inadequate vasomotor response to volume

160 Travis and Henrich

depletion and subsequent hemodialysis hypotension. Several explanations for the elevated level of nor-

epinephrine exist, including increased synthesis (due to deafferentation and increased sympathetic tone), decreased degradation and clearance (due to decreased renal clearance and diminished catechol-0- methyl-transferase levels), and independent down- regulation of catecholamine receptors. Campese and associates (1 3) have noted that norepinephrine resistance may improve with dialytic therapy.

Other Mechanisms of Autonomic Dysfunction

Jebson et al. (22) have suggested that substances other than urea and creatinine are important in the pathogenesis of uremic neuropathy. These “middle molecules” have clearances dependent on dialysis time and dialyzer permeability and membrane sur- face area. When the sera of uremic patients with and without uremic neuropathy were compared, a higher fraction of middle molecules were noted in patients with peripheral neuropathy (23). The middle molecule fraction of serum was then isolated and placed on an isolated (frog) surd nerve preparation. Incu- bation of the serum with the nerve reduced conduction velocity. Unfortunately, the precise identity of the middle molecules responsible for these findings has been elusive.

It has also been speculated that parathyroid hormone (PTH) may play a role in neuronal dysfunction in uremia. However, Arieff et al. (24) have pointed out that patients with elevated plasma levels of PTH from primary hyperparthyroidism have normal nerve conduction velocities without the neuropathy associated with uremia (24). Moreover, Bodia et al. ( 10) recently showed no correlation with the Valsalva index and serum PTH levels in patients on chronic hemodialysis. Altered neuronal calcium metabolism may play a role in uremic neuropathy, but its precise role and its relationship to PTH will require further clarification.

The parasympathetic component of the autonomic nervous system has also been suggested as playing a role in hemodialysis hypotension. The lack of cardioacceleration in patients with frequent episodes of hemodialysis hypotension has been postu- lated to result from a defect in vagal release. How- ever, few tests of autonomic function isolate parasympathetic activity; hence, its role in autonomic nervous system dysfunction remains poorly defined.

Autonomic Function Tests

Formal evaluation of the integrity of the autonomic arc requires a series of tests to evaluate sympathetic and parasympathetic function. Table 2 de- tails the purposes of a variety of autonomic function tests.

The goal of autonomic function tests is to identify specific abnormalities of the autonomic system. In the early 1970s, as more investigators examined the potential role of autonomic dysfunction in hemodi-

alysis hypotension, the utility of autonomic function testing and screening began to be appreciated. Tests exist for the integrity of the complete baroreaptor reflex arc, vasomotor center competence, the efferent limbs of the sympathetic and parasympathetic sys- tems, and extraadrenal catecholamine stores. How- ever, no one test strictly isolates the afferent limb of the autonomic arc. Hence, one must infer afferent defects by demonstrating a defect within the entire reflex arc but with an intact efferent and vasomotor limb. Currently, the only test of the vasomotor center in the CNS is the hyperventilation test. This test is not very reliable because variable responses in normal individuals without autonomic nervous system disease limit standardization. Clearly, better tests which specifically disect the components of the autonomic arc need to be developed and utilized.

Autonomic tests also need to be practical. Solders (25) examined a battery of autonomic function tests in both normal and nondiabetic uremic subjects. The author concluded that the assessment of the loss of beat to beat respiratory variability and the Val- salva maneuver were reliable and simple tests for the evaluation of autonomic dysfunction. Ewing et al. ( 12) and Ciccarelli et al. (1 8) have also noted the utility of the Valsalva test and the loss of beat to beat variation in heart rate in providing evidence of the presence of an autonomic lesion.

More widespread and specific testing of autonomic nervous system function in patients on hemodialysis is needed before the natural history of the lesion is known. The use of the Valsalva test, the cold pressor test and documentation of the loss of beat to beat heart rate variability are the best and most practical comprehensive screening tests of autonomic integrity.

Treatment

A specific treatment is lacking for dialysis patients with autonomic neuropathy and frequent episodes of dialysis hypotension. Therefore, other treatable factors which contribute to the occurrence of dialysis hypotension (see Table 1) are addressed. For exam- ple, antihypertensive or antianginal medication should, if possible, be withheld prior to dialysis. An increased dialysate sodium concentration reduces the decline in plasma osmolality and stablizes dec- rements in blood pressure during dialysis (20, 26, 27). Presently, a dialysate sodium concentration of 140 to 145 meq/L is commonly used initially to reduce the frequency of episodes of hypotension in patients with autonomic nervous system defects.

The frequency of hypotensive episodes may also be diminished if ultrafiltration is separated from diffusional solute loss (28). Extracellular fluid contraction during ultrafiltration results in greater increases in peripheral vascular resistance and higher blood pressures than with standard dialysis. A major advance in dialytic therapy is the accurate, propor- tioned volume removal now available with newer dialysis machines.

CNS A N D HEMODIALYSIS HYPOTENSION 161

TABLE 2. Cbmmon autonomic function tests

Tests Pathway Tested Normal Resmnse Tests of the entire autonomic arc

Valsalva maneuver

Amy1 nitrite inhalation

Tilt-table (head up 60' angle)

Phenylephrine hydrochloride (50- 100 pg) or angiotensin I1 (0.25-2.0 pg) injection

High pressure baroreceptors

Efferent sympathetic limb Cold pressor test

Mental arithmetic with harassment

Efferent parasympathetic limb

CNS integrative test Hyperventilation

Atropine (0.02 mg/kg)

Afferent visceral receptors + vasomotor center ( C N S ) + efferent sympathetic pathway and efferent parasympathetic pathway + end organ response

Afferent visceral receptor + vasomotor center (CNS) + efferent sympathetic pathway + end organ response

Same as Amy1 nitrite response

Arterial baroreceptors -D afferent sympathetic pathways (through cranial nerve IX) + vasomotor center -., efferent parasympathetin + end organ response

efferent sympathetics + end organ response

Cortical function -D vasomotor center +

end organ response

Afferent pain fibers + spinal cord +

Efferent parasympathetic fibers + end

1 Vasomotor center response -1 effer-

organ response

ent svmoathetic tone

CPhase response with arterial pressure overshoot and bradycardia

A heart rate/A arterial blood pressure (BP) = 1.0

510 mm Hg decrease in systolic and diastolic B P heart rate increases 10 bpm

t Arterial pressure and bradycardia (7 RR mterval/systolic pressure = slope of 12.8)

2 I5 mm Hg increase in systolic and diastolic BP

>I0 mm Hg in systolic BP

t Increase in heart rate 2 20% of control

Decrease in arterial pressure 10-20 mm Hg

Pharmacologic intervention to augment arterial blood pressure may be necessary in a few patients. Norepinephrine or dopamine infusions may be used for particularly difficult, hernodynamically tenuous patients. The use of bicarbonate dialysate may also be beneficial in avoiding potential vasodilation caused by acetate dialysate buffer.

A combination of these therapies is possible with the newer dialysis machines. The ability to directly alter sodium dialysate concentration during dialysis, bicarbonate buffered dialysate, constant and predict- able ultrafiltration rates, and stable plasma osmolal- ities provide safeguards against frequent hypotensive episodes. Finally, Mallanaci et al. (29) have noted the resolution of autonomic neuropathy following renal allograft transplantation, suggesting that even severe lesions are reversible with removal of the uremic milieu.

Conclusions

Some patients with frequent episodes of hemodialysis hypotension have been shown to have a defect in the afferent limb of their autonomic reflex arc. Given the high prevalence of autonomic neuropathy in dialysis patients and the frequency of dialysis hypotension, it is surprising more studies have not been able to link the two as causally related. Thus, uncertainty exists as to the importance of autonomic neuropathy as a contributing factor in dialysis hypotensive syndromes. The exact mechanisms for the autonomic defect remain unknown. A variety of autonomic tests are welldescribed and are useful in identifying the sites of abnormalities. Therapeutic interventions for treatment of autonomic neuropa-

thy are usually nonspecific and are directed at sta- bilizing those factors known to contribute to dialysis hypotension.

The development of simple autonomic tests which localize defects in the afferent, vasomotor and parasympathetic limbs would be helpful. In addition, natural history studies which track the changes in lesions once an autonomic defect is found in a dialysis patient would also be useful. Finally, hture studies need to directly focus on the pathogenetic importance of autonomic neuropathy as a co-factor in dialysis hypotension. Such studies will obviously need to address the severity and loci of the autonomic lesions. This knowledge is important because it is possible that some autonomic lesions (or com- binations of lesions) might be associated with greater hemodynamic instability than others. At present, it is probably most accurate to conclude that autonomic neuropathy is an important co-factor in dialysis hypotension in a minority of dialysis patients. Clearly more work is needed to define the exact importance of these defects in the vexing problem of dialysis hypotension.

References

1. Bradbury S, Egglcston C: Postural hypotension: Report of three cases. Am Hean J 1 :73-86, 1925

2. Rowel1 L B Reflex control of regional circulation in humans: J Au- tonomNervSys 11:101-114, 1984

3. Damprey RAL, Goodchild AK, Robertson LG, Montgomery W Role of ventrolaterol medulla in vasomotor regulation, correlative, anatom- ical. and physiological study. Bruin Res 249:223-235, 1982

4. Bannister R: Autonomic Failure. Oxford. Oxford University, 1983 5. M c L e d JG, Tuck R R Disordcn of the autonomic nervous system:

Part I: Pathophysiology and clinical features. Ann Neurol21:419-427. 1987

162 Travis and Henrich

6. Azancot I, Degoulet P, Juillet Y. Rottenbourg J. Legrain M: Hem* dynamic evaluation of hypotension during chronic hemodialysis. Clin Nephrol8:3 12-3 16, 1977

7. Rubin U Gutman RA: Hypotension during hemodialysis. Kidney I1:21-24, 1978

8. Goldberger: Autonomic nervous dysfunction in chronic renal failure. CIin Res 19531-534, 1973

9. Lilley U, Golden J. Stone RA: Adrenergic regulation of blood pressure in chronic renal failure. J Clin Invest 57: 1190-1200, 1976

10. Bondia A. Tabernero JM. Macias JF, Martin-Luengo C Autonomic nervous system in haemodialysis. Nephrol Dial Transplant 2: 174-1 80, 19x11 .___

1 1. Soriano G, Eisinger R P Abnormal response to the Valsalva maneuver in patients on chronic hemodialysis. Nephron 9:25 1-256, 1972

12. Ewing DJ, Winney R: Autonomic function in patients with chronic renal failure on intermittent haemodialysis. Nephron lk424-429, 1975

13. Campese VM, Romoff MS, Levitan D, Lane K, Massry SG: Mecha- nisms of autonomic nervous system dysfunction in uremia. Kidney Int 20246-253, 1981

14. Lowrie EG,' Laird NM: National Cooperative Dialysis Study. Kidney Inl 20246-253. 1981

15. Guyton A C Cardiac Output and Its Regulation. Philadelphia, WB

16. Henderson L W Symptomatic hypotension during hemodialysis. Kid-

17. N i a AS, Robertson D. Stone WJ: Hemodialysis hypotension is not the

Saunders, 1973. pp. 36 1-362

ney Int 17571-576. 1980

result of uremic peripheral autonomic neuropathy. J Lab Clin Med 94395-402. 1979

18. Ciccarelli LL. Ford CM, Tsueda K: Autonomic neuropathy in a

diabetic patient with renal failure: Anesihesiology 64283-287, 1986 19. Henrich WL. h t z FH. Molinoff PB, Schrier R W Competitive effects

of hypoMemia and volume depletion on plasma renin mivitv. abm terone, and catecholamine concentrations in hemdialysis ktia& Kidney I ~ I 12279-284, 1977

20. Wehle B, Asaba H, Castenfon J, et al: Hemdynamic c b g a during sequential ultrafiltration and dialysis. Kidney In1 15:411418. 1979

2 1. Chen W, Chaignon M. Tarazi R, et ak Hemodynamia of postdialysis hypotension (abstr). Kidney Int 12:493, 1977

22. Jebsen RH, Tenckhoff H, Honet J C U m i c p~lyneu-&y a d effects of dialysis: N Engl J M e d 277:327-331, 1967

23. Funck-Brrntano JL, Cueille GF, Man NK: Defense of the mid& molecule hypothesis Kidney Int 13:8, $31, 1978

24. Arieff AI, Massry S G Calcium metabolism of brain in acute renal failurecffects of uremia. hemodialysis and parathyroid hormone. J Clin Invest 53:387-392. 1974

25. S o l d m G Autonomic function tests in healthy controlsand in terminal uraemia. Acta NeurolScand 7T638-639, 1986

26. Rodtigo F, Shipeman J, McHugh R, Buselmeir T, Kjellscrand C: Osmolality change during hemodialysis. Ann Iniern Med 86:554-56 I, 1977

27. Hampl H, Paeprer H, Unger V. Kesel M Hemodynamic studia during hemodialysis in comparison to sequential ultrafiltration and hemodialysis. J Dial 351-55. 1979

28. Bergstrom J: Ultrafiltration without dialysis for removal of fluid and solutesin uremia. CIin Neph 9:156-164, 1978

29. Mallanaci F, Zocalli C, Cicarrelli M, Briggs JD. Autonomic funtion in uremic patients treated by hemodialysis or CAPD and in transplant patients. Clin Neph 25: 175- 180, I986

Any Volunteers?

In the controlled environment of a metabolic ward, Dr. Carmelo Giordano of Naples fed a synthetic diet of carbohydrates, fats, and essential amino acids to eight azotemic patients, six of whom were clinically uremic.

"Experiments reported here provide evidence that urea is potentially utilizable for protein synthesis and that azotemic patients can use their accumulated urea nitrogen for anabolic purposes, provided that a diet adequate in calories with nitrogen supplied by minimal amounts of essential amino acids be allowed. Utilization of urea, as of other body-retained nitrogenous substances, parallels a progressive clinical improvement in uremic patients, the significance of which is under study as a possible metabolic treatment of renal failure."

A 3 I-year-old normal volunteer also ingested the 3100-calorie synthetic diet:

"Three-fourths of the calories were derived from sugar and starch taken in equal amounts and the remaining 25% was supplied either as margarine or vegetable oil. The above dietary components, to which amino acids and colored flavor were added, were mixed with hot water and heated gently for 15 minutes, forming a pudding. Twenty milliliters of either rum or anise was added before transference to a cake-shaped container. The pudding was distributed in three to four meals. One-hundred grams of fresh lettuce and 150 g of apple, respectively, were given during the second and third meal."

For 53 days, Carmelo Giordano, in the honored tradition of medical self-experimentation, remained on this diet, eschewing fine Neopolitan cuisine. Then he wrote the paper.

Giordano C: Use of exogenous and endogenous urea for protein synthesis in normal and uremic subjects. J Lab Clin Med 1963; 62:231-246 (used with permission of the C. V. Mosby Company).

Autonomic Nervous System and Hemodialysis Hypotensim

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