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Cardiovascular consequences of loss of supraspinal control of the sympathetic nervous system after spinal cord injury

  • Robert W. Teasell
    Affiliations
    Department of Physical Medicine and Rehabilitation (Dr. Teasell) and the Department of Medicine, Pharmacology, and Toxicology (Dr. Arnold), London Health Sciences Center; the Department of Physical Medicine and Rehabilitation, John P. Robarts Research Institute (Dr. Krassioukov); and the Department of Physical Medicine and Rehabilitation, Parkwood Hospital (Dr. Delaney), University of Western Ontario, London, Ontario, Canada
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  • J.Malcolm O. Arnold
    Affiliations
    Department of Physical Medicine and Rehabilitation (Dr. Teasell) and the Department of Medicine, Pharmacology, and Toxicology (Dr. Arnold), London Health Sciences Center; the Department of Physical Medicine and Rehabilitation, John P. Robarts Research Institute (Dr. Krassioukov); and the Department of Physical Medicine and Rehabilitation, Parkwood Hospital (Dr. Delaney), University of Western Ontario, London, Ontario, Canada
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  • Andrei Krassioukov
    Affiliations
    Department of Physical Medicine and Rehabilitation (Dr. Teasell) and the Department of Medicine, Pharmacology, and Toxicology (Dr. Arnold), London Health Sciences Center; the Department of Physical Medicine and Rehabilitation, John P. Robarts Research Institute (Dr. Krassioukov); and the Department of Physical Medicine and Rehabilitation, Parkwood Hospital (Dr. Delaney), University of Western Ontario, London, Ontario, Canada
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  • Gail A. Delaney
    Affiliations
    Department of Physical Medicine and Rehabilitation (Dr. Teasell) and the Department of Medicine, Pharmacology, and Toxicology (Dr. Arnold), London Health Sciences Center; the Department of Physical Medicine and Rehabilitation, John P. Robarts Research Institute (Dr. Krassioukov); and the Department of Physical Medicine and Rehabilitation, Parkwood Hospital (Dr. Delaney), University of Western Ontario, London, Ontario, Canada
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      Abstract

      Teasell RW, Arnold JMO, Krassioukov A, Delaney GA. Cardiovascular consequences of loss of supraspinal control of the sympathetic nervous system after spinal cord injury. Arch Phys Med Rehabil 2000;81:506-16. Spinal cord injury (SCI) with resultant quadriplegia or high paraplegia is associated with significant dysfunction of the sympathetic nervous system. This alteration of sympathetic nervous system activity occurs as a consequence of loss of supraspinal control of the sympathetic nervous system and is further complicated by at least three subsequent phenomena that occur below the level of SCI: reduced overall sympathetic activity, morphologic changes in sympathetic preganglionic neurons, and peripheral alpha-adrenoceptor hyperresponsiveness. Reduced sympathetic activity below the level of SCI appears to result in orthostatic hypotension, low resting blood pressure, loss of diurnal fluctuation of blood pressure, reflex bradycardia, and, rarely, cardiac arrest. Peripheral alpha-adrenoceptor hyperresponsiveness likely accounts for some, if not the majority, of the excessive pressor response in autonomic dysreflexia and may also contribute to decreased blood flow in the peripheral microcirculation, potentially increasing susceptibility to pressure sores. What has yet to be established is whether this alpha-adrenoceptor hyperresponsiveness is a consequence of receptor hypersensitivity or a failure of presynaptic reuptake of noradrenaline at the receptor level. Better understanding of the pathophysiology of sympathetic nervous system dysfunction after high-level SCI should allow development of more effective measures to manage clinical complications. © 2000 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

      Keywords

      SIGNIFICANT DYSFUNCTION of the sympathetic nervous system (SNS) is associated with spinal cord injuries (SCIs), particularly higher level SCIs. Cardiovascular deficits after SCI have been well documented in human studies as well as in animal models. However, little is actually known about the mechanisms underlying disordered cardiovascular control after SCI. Deranged cardiovascular control in paraplegic and quadriplegic individuals can be directly linked to abnormalities of SNS function. Multiple mechanisms have been considered to explain the development of these sympathetic/autonomic abnormalities. For instance, autonomic dysreflexia has been attributed to loss of tonic bulbospinal inhibitory inputs to spinal sympathetic neurons, the loss of baroreceptor reflexes, or as a consequence of hyperresponsiveness of peripheral alpha-adrenoceptors.
      • Arnold JM
      • Feng QP
      • Delaney GA
      • Teasell RW.
      Alpha-adrenoceptor hyperresponsiveness in quadriplegic patients with autonomic dysreflexia.
      • Naftchi NE.
      Mechanism of autonomic dysreflexia. Contributions of catecholamines and peptide neurotransmitters.
      In this review we will make the case that disruption of supraspinal control of the SNS after SCI results in clinical problems that can be attributed to the following related pathophysiologic phenomena occurring below the level of the lesion: (1) loss of supraspinal regulatory control; (2) reduced sympathetic activity; (3) morphologic changes in sympathetic preganglionic neurons; and (4) peripheral alpha-adrenoceptor hyperresponsiveness. This is an evolving area of SCI research and much work remains to be done.

      Sympathetic nervous system dysfunction in SCI

      Maintenance of homeostasis within the body is a function of the autonomic nervous system and is interrupted when central nervous system (CNS) communications are interrupted. With high-level SCIs, the SNS is disproportionately involved when compared with the parasympathetic nervous system. In a complete high-level SCI, functioning in the isolated spinal cord below the lesion becomes independent of supraspinal control and has been termed “decentralization” of the SNS.
      • Claus-Walker J
      • Halstead LS.
      Metabolic and endocrine changes in spinal cord injury: II (section 1). Consequences of partial decentralization of autonomic nervous system.
      Generally, the higher the level of the SCI, the more profound the effects of SNS dysfunction below the level of the injury.
      • Lehmann KG
      • Lane JG
      • Piepmeier JM
      • Batsford WP.
      Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
      Cardiovascular problems known to arise from SNS dysfunction include low resting blood pressure, orthostatic hypotension, autonomic dysreflexia, reflex bradycardia and cardiac arrest, limited cardiovascular responses to exercise, and likely changes to the skin microcirculation.
      • Frankel HL
      • Michaelis LS
      • Golding DR
      • Beral V.
      Blood pressure in paraplegia. I.
      • Erickson RP.
      Autonomic hyperreflexia: pathophysiology and medical management.
      • Braddom RL
      • Rocco JF.
      Autonomic dysreflexia: a survey of current treatment.
      • Corbett JL
      • Frankel HL
      • Harris PJ.
      Cardiovascular responses to tilting in tetraplegic man.
      • Krum H
      • Brown DJ
      • Rowe PR
      • Louis WJ
      • Howes LG.
      Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
      • Mathias CJ
      • Christensen NJ
      • Corbett JL
      • Frankel HL
      • Spalding JMK.
      Plasma catecholamines during paroxysmal neurogenic hypertension in quadriplegic man.
      • Mathias CJ
      • Frankel HL
      • Christensen NJ
      • Spalding JNK.
      Enhanced pressor response to noradrenaline in patients with cervical spinal cord transection.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.

       Loss of supraspinal control

      SNS dysfunction after SCI is attributable to loss of supraspinal control that occurs with disruption of spinal cord pathways. Loss of supraspinal control leads to dysregulation of those homeostatic mechanisms normally influenced by the SNS through loss of facilitation or lack of inhibition. Physiologic changes occur at the level of the isolated spinal cord and the peripheral SNS. The impact of loss of supraspinal control is a dynamic process that is related to alterations in both the central and peripheral SNS. Initially after SCI, individuals experience a period of “spinal shock.” In the motor system this is characterized by marked flaccidity or diminished muscular tone. As time progresses there is a gradual increase in muscle tone generally culminating in overactivity or hypertonicity, ie, spasticity. Likewise, with the SNS there is an initial period of markedly diminished sympathetic activity below the level of SCI, characterized by hypotension and reflex bradycardia/cardiac arrest, followed by a gradually increasing propensity to clinical bouts of apparent sympathetic hyperactivity, ie, autonomic dysreflexia, in those with SCI above thoracic level 6 (T6). This also suggests that loss of supraspinal control is not, in and of itself, sufficient to cause autonomic dysreflexia, because it does not occur immediately after SCI but rather after a delay of several weeks.
      Anatomically, SCI above the midthoracic SNS outflow is crucial to the development of clinical features of SNS dysfunction. It has been observed that the higher the level of the SCI, the greater the degree of clinical manifestations of SNS dysfunction.
      • Frankel HL
      • Michaelis LS
      • Golding DR
      • Beral V.
      Blood pressure in paraplegia. I.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      T6 appears to be the lowest level of injury in most individuals necessary for the development of the clinical sequelae of autonomic dysreflexia, although autonomic dysreflexia has been reported in some individuals with lesions as low as T8 to T10.
      • Gimovski ML
      • Ojeda A
      • Ozaki R
      • Zerne S.
      Management of autonomic hyperreflexia associated with a low thoracic spinal cord lesion.
      SCI above the level of T6 will result in significantly reduced SNS outflow and supraspinal control to the critical splanchnic bed as well as the lower extremity blood vessels.
      The medullary vasomotor center can no longer maintain sympathetically mediated efferent control of vasomotor tone, heart rate, and cardiac contractility after a high-level SCI. Peripheral alpha-adrenoceptors in sympathetically denervated vascular beds may subsequently become hyperresponsive, either as a consequence of receptor hypersensitivity because of up-regulation in response to reduced SNS efferent output or decreased presynaptic noradrenaline re-uptake.
      • Arnold JM
      • Feng QP
      • Delaney GA
      • Teasell RW.
      Alpha-adrenoceptor hyperresponsiveness in quadriplegic patients with autonomic dysreflexia.
      With SCIs below the level of T6 there is generally sufficient sympathetically innervated vasculature under supraspinal control, particularly in the important splanchnic blood vessels, to respond normally to baroreceptor mediated reflexes, limit clinically significant hemodynamic manifestations of SNS dysfunction, and maintain homeostasis.

       Reduced sympathetic activity below the level of SCI

      A high-level complete SCI results in reduced SNS efferent activity below the level of the SCI. Human findings during microneurographic recordings have demonstrated very sparse activity in cutaneous and muscle postganglionic axons that normally receive input from preganglionic neurons situated below the level of cord injury both in control conditions and during bladder stimulation.
      • Wallin BG
      • Stjernberg L.
      Sympathetic activity in man after spinal cord injury.
      • Stjernberg L
      • Blumberg H
      • Wallin BG.
      Sympathetic activity in man after spinal cord injury. Outflow to muscle below the lesion.
      Immediately after SCI, plasma adrenaline and noradrenaline and their urinary metabolites are usually in the low-normal range
      • Claus-Walker J
      • Valbona C
      • Carter RE
      • Lipscomb HS.
      Resting and stimulated endocrine function in human subjects with cervical spinal cord transection.
      and remain low as long as there is no stimulation below the level of SCI, such as with a full bladder.
      • Claus-Walker J
      • Halstead LS.
      Metabolic and endocrine changes in spinal cord injury: II (section 1). Consequences of partial decentralization of autonomic nervous system.
      • Krum H
      • Brown DJ
      • Rowe PR
      • Louis WJ
      • Howes LG.
      Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
      • Mathias CJ
      • Christensen NJ
      • Corbett JL
      • Frankel HL
      • Spalding JMK.
      Plasma catecholamines during paroxysmal neurogenic hypertension in quadriplegic man.
      • Claus-Walker J
      • Valbona C
      • Carter RE
      • Lipscomb HS.
      Resting and stimulated endocrine function in human subjects with cervical spinal cord transection.
      • DeBarge O
      • Christensen NJ
      • Corbett JL
      • Eidelman BH
      • Frankel HL
      • Mathias CJ.
      Plasma catecholamines in tetraplegics.
      • Frewin DM
      • Levitt M
      • Myers SJ
      • Co CC
      • Downey JA.
      Catecholamine responses in paraplegia.
      • Guttman L
      • Munro AF
      • Robinson R
      • Walsh JJ.
      Effect of tilting on cardiovascular responses and plasma catecholamine levels in spinal man.
      • Naftchi NE
      • Lowman EW
      • Sell GH
      • Rusk HA.
      Peripheral circulation and catecholamine metabolism in paraplegia and quadriplegia.
      • Vallbona C
      • Lipscomb HS
      • Carter RE.
      Endocrine responses to orthostatic hypotension in quadriplegia.
      Mathias and colleagues
      • Mathias CJ
      • Christensen NJ
      • Corbett JL
      • Frankel HL
      • Spalding JMK.
      Plasma catecholamines during paroxysmal neurogenic hypertension in quadriplegic man.
      reported that resting catecholamine levels in individuals with cervical SCIs were below normal when compared with normal controls and individuals with paraplegia. Krum and associates
      • Krum H
      • Brown DJ
      • Rowe PR
      • Louis WJ
      • Howes LG.
      Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
      reported that plasma noradrenaline levels and systolic/diastolic blood pressures were significantly lower in individuals with quadriplegia when compared with normal controls, while noradrenaline clearance was similar in both groups. Dopamine hydroxylase, an enzyme needed for the formation of noradrenaline from dopamine in nerve endings, has also been shown to be in the low-normal range in individuals with cervical SCI.
      • Kamelhar DL
      • Steel Jr, JM
      • Schact RG
      • Lowenstein J
      • Naftchi NE.
      Plasma renin and serum dopamine-beta-hydroxylase during orthostatic hypotension in quadriplegic man.
      • Levitt M
      • Frewin DB
      • Co CC
      • Luke WK
      • Downey JA.
      Plasma dopamine-beta-hydroxylase activity in paraplegic and quadriplegic subjects.
      • Naftchi NE
      • Wooten GF
      • Lowman EW
      • Axelrod J.
      Relationship between serum dopamine-B-hydroxylase activity, catecholamine metabolism, and hemodynamic changes during paroxysmal hypertension in quadriplegia.
      These findings support the concept of sympathetic hypoactivity below the level of high-level SCI when not being subjected to afferent stimuli below the level of SCI, such as a full bladder. One would therefore anticipate clinical sequelae of a hypoactive SNS on the cardiovascular system in high-level SCI.

       Morphologic changes in sympathetic neurons after SCI

      Clinical observations provide much of our current understanding of the characteristics of cardiovascular changes after SCI
      • Lehmann KG
      • Lane JG
      • Piepmeier JM
      • Batsford WP.
      Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
      • King ML
      • Lichtman SW
      • Pellicone JT
      • Close RJ
      • Lisanti P.
      Exertional hypotension in spinal cord injury.
      • Yekutiel M
      • Brooks ME
      • Ohry A
      • Yarom J
      • Carel R.
      The prevalence of hypertension, ischemic heart disease and diabetes in traumatic spinal cord injured patients and amputees.
      ; however, little is known about the morphologic changes that occur within the spinal cord structures that control the cardiovascular system. A substantial portion of the current literature on spinal cord pathology is focused on characterizing the changes at the site of injury. The majority of this work has described the extent of demyelination or cavitation within the human spinal cord, or defined complete or incomplete injuries of the spinal cord.
      • Biyani A
      • El Masry WS.
      Post-traumatic syringomyelia: a review of the literature.
      • Bunge RP
      • Puckett WR
      • Becerra JL
      • Macillo A
      • Quencer RM.
      Observation on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination.
      • Dimitrijevic MR.
      Residual motor functions in spinal cord injury.
      • Fehlings MG
      • Tator CH
      • Linden RD.
      The relationships among the severity of spinal cord injury, motor and somatosensory evoked potentials and spinal cord blood flow.
      • Tator CH.
      Update on the pathophysiology and pathology of acute spinal cord injury.
      After SCI, preservation of descending pathways through the area of cord injury or the maintenance of neuronal populations in the gray matter below the cord injury may play a crucial role in determining long-term neurologic outcome.
      • Tator CH.
      Update on the pathophysiology and pathology of acute spinal cord injury.
      • Ditunno JF
      • Formal CS.
      Chronic spinal cord injury.
      • Quencer RM
      • Bunge RP
      • Egnor M
      • Green BA
      • Puckett W
      • Naidich TP
      • et al.
      Acute traumatic central cord syndrome: MRI-pathological correlations.
      A recent study described changes in spinal sympathetic preganglionic neurons (SPNs) after SCI in an attempt to better understand mechanisms underlying the impaired cardiovascular control.
      • Krassioukov AC
      • Weaver LC.
      Morphological changes in sympathetic preganglionic neurons after spinal cord injury in rats.
      SPNs send efferent tonic signals from the CNS to different target organs such as blood vessels, the heart, and the adrenal medulla. These SPNs are therefore regarded as crucial for central cardiovascular control.
      • Calaresu FR
      • Yardley CP.
      Medullary basal sympathetic tone.
      • Chalmers J
      • Pilowsky P.
      Brainstem and bulbospinal neurotransmitter systems in the control of blood pressure.
      • Reis DJ
      • Morrison S
      • Ruggiero DA.
      The C1 area of the brainstem in tonic and reflex control of blood pressure.
      Previous research in animal models has demonstrated that after spinal cord transection, SPNs show signs of atrophy in the acute stage of SCI. With time, however, these SPNs regain their normal morphology.
      • Krassioukov AC
      • Weaver LC.
      Morphological changes in sympathetic preganglionic neurons after spinal cord injury in rats.
      The initial morphologic changes within the SPNs likely occur as a consequence of partial deafferentation from the loss of descending projections from medullary neurons because a portion of the descending medullary input is thought to synapse directly on SPNs.
      • Weaver LC
      • Polosa C.
      Spinal cord circuits providing control of sympathetic pregangionic neurones.
      Previously, neurons within the lateral horn of the human spinal cord had been studied only in cases with multiple system atrophy and autonomic failure.
      • Gray F
      • Vincent D
      • Hauw JJ.
      Quantitative study of lateral horn cells in 15 cases of multiple system atrophy.
      • Oppenheimer DR.
      Lateral horn cells in progressive autonomic failure.
      • Spokes EGS
      • Bannister R
      • Oppenheimer DR.
      Multiple system atrophy with autonomic failure.
      These changes have recently been studied in human SCI patients
      • Krassioukov AV
      • Bunge RP
      • Puckett WR
      • Bygrave M.
      The changes in human spinal cord sympathetic preganglionic neurons after spinal cord injury.
      ; in this study the soma area and diameter of SPNs was analyzed in one subject with an intact spinal cord and in two subjects after SCI, one acute and the other chronic. Morphology of SPNs were compared in the upper and middle thoracic segments in the control case and above and below the site of injury in the cord-injured cases. This neuronal population is crucial for cardiovascular control.
      • Weaver LC
      • Polosa C.
      Spinal cord circuits providing control of sympathetic pregangionic neurones.
      • Krassioukov AC
      • Weaver LC.
      Anatomy of the autonomic nervous system.
      Comparison of soma areas of the SPNs in the thoracic segments of the spinal cord of a person who died 2 weeks after spinal trauma showed a significant decrease in soma area below to the site of SCI (fig 1).
      Figure thumbnail gr1
      Fig. 1Haematoxylin/eosin stained sections through (A and B) the first and (C and D) the eighth thoracic segments of human spinal cord (person died 2 weeks after spinal injury). Panels B and D are the areas of intermediolateral nucleus (IML), with sympathetic neurons at higher magnification, that are outlined in panels A and C, respectively. (The IML is the nucleus within the lateral horn of the cord.) A small contusion hemorrhage within the dorsla funiculus is clearly present at T8 level (indicated by arrow on panel C). CC, central canal; T, thoracic level. Calibration line on panel C, for panels A and C, represents 1mm; calibration line on panel D, for panels B and D, represents 200μm.
      However, the soma area of the intermediolateral nucleus neurons within the upper and middle thoracic segments in an individual who died 23 years after SCI were similar to the SPNs in the spinal cord from the subject without a cord injury.
      The atrophy of the SPNs in the acute stage of SCI in humans may contribute to the condition of “spinal shock” observed immediately after the SCI in animals
      • Chiou-Tan FY
      • Lenz ML
      • Robertson CS
      • Grabois M.
      Pharmacologic treatment of autonomic dysreflexia in the rat.
      • Krassioukov AC
      • Weaver LC.
      Episodic hypertension due to autonomic dysreflexia in acute and chronic spinal cord injured rats.
      • Osborn JW
      • Taylor RF
      • Schramm LF.
      Determinants of arterial pressure after chronic spinal transection in rats.
      and humans.
      • Lehmann KG
      • Lane JG
      • Piepmeier JM
      • Batsford WP.
      Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
      • Green BA
      • Klose KJ.
      Acute spinal cord injury: emergency room care and diagnosis, medical and surgical management.
      • Levi L
      • Wolf A
      • Belzberg H.
      Hemodynamic parameters in patients with acute cervical cors trauma: description, intervention, and prediction of outcome.
      • Zipnick RI
      • Scalea TM
      • Trooskin SZ
      • Sclafani SJA
      • Emad B
      • Shah A
      • et al.
      Hemodynamic responses to penetrating spinal cord injuries.
      After acute SCI there is a flaccid paralysis, with urinary bladder atonia, paralytic bowel, and sympathetic underactivity resulting in low systemic arterial pressure. Besides the immediate depression of autonomic functions resulting from a loss of important excitatory input from the brain stem,
      • Calaresu FR
      • Yardley CP.
      Medullary basal sympathetic tone.
      the atrophy of SPNs likely contributes to the initial sympathetic atonia.
      With time after SCI, sustained excitatory responses develop that manifest as autonomic dysreflexia.
      • Naftchi NE.
      Mechanism of autonomic dysreflexia. Contributions of catecholamines and peptide neurotransmitters.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Kabalin JN
      • Lennon S
      • Gill HS
      • Wolfe V
      • Perkash I.
      Incidence and management of autonomic dysreflexia and other intraoperative problems encountered in spinal cord injury patients undergoing extracorporeal shock wave lithotripsy without anesthesia on a second generation lithotriptor.
      Autonomic dysreflexia is generally seen during the subacute and chronic stages of human SCI, becoming obvious within the first few months after cord injury in individuals with cervical or high to midthoracic cord injury.
      • Naftchi NE.
      Mechanism of autonomic dysreflexia. Contributions of catecholamines and peptide neurotransmitters.
      • Lindan R
      • Joiner E
      • Freehafter AA
      • Hazel C.
      Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury.
      • Cross LL
      • Meythaler JM
      • Tuel SM
      • Cross LA.
      Pregnancy, labor and delivery post spinal cord injury.
      • Finocchiaro DN
      • Herzfeld ST.
      Understanding autonomic dysreflexia.
      • Uozumi T
      • Nakano S
      • Matsunaga K
      • Tsuji S
      • Murai Y.
      Sudormotor potential evoked by magnetic stimulation of the neck.
      By the later stage of SCI, other mechanisms may contribute to impaired cardiovascular control. For example, in animals after SCI, dorsal root afferents have been shown to sprout
      • Murray M.
      Plasticity in the spinal cord: the dorsal root connection.
      and spinal neurons that initially lose synaptic inputs appear to have them replaced with synapses from a different source.
      • Beattie MS
      • Bresnahan JC
      • Leedy MG.
      Synaptic plasticity in the adult sacral spinal cord: effects of lesions and hormones. Trophic factors and the nervous system.
      Therefore, new inappropriate afferent inputs from different afferent sources could contribute to the later autonomic dysreflexia after SCI in humans. The return to normal morphologic appearance of SPNs at the chronic stage of SCI may be reflective of these changes. As mentioned previously, Krassioukov and colleagues
      • Krassioukov AV
      • Bunge RP
      • Puckett WR
      • Bygrave M.
      The changes in human spinal cord sympathetic preganglionic neurons after spinal cord injury.
      confirmed that in their case of chronic human cord injury, the morphology of SPNs was reestablished. To some extent a similar correlation in morphologic changes of SPNs was observed in previous animal studies. The reestablishment of the dendritic arbor and soma area at the chronic stage of SCI in animal models coincides with stable and intense autonomic dysreflexia.
      • Krassioukov AC
      • Weaver LC.
      Morphological changes in sympathetic preganglionic neurons after spinal cord injury in rats.
      Therefore, it is possible that the clinical functional changes seen are a consequence of reorganization within the spinal cord below the level of SCI.

       Hyperresponsiveness of peripheral alpha-adrenoceptors

      The fact that resting plasma catecholamine levels, in particular plasma noradrenaline, are often reduced in individuals with high SCI is consistent with the observation that peripheral vascular alpha-adrenoceptors become hyperresponsive below the level of SCI, possibly through an upregulatory or denervation supersensitivity mechanism.
      • Bloch RF.
      Autonomic dysfunction in management of spinal cord injuries.
      • Garnier VB
      • Gertsch R
      • Steinmann B.
      Vergleichende untersuchungen uber die wirkungen einer endogenen vegetativen erregung und intravenos verabriechten noradrenalins beim parplegiber.
      Evidence for hyperresponsiveness of vascular alpha-adrenoceptors comes from both animal and human studies. In animal experiments, section of preganglionic nerves (sympathetic decentralization) results in a supersensitivity response to noradrenaline.
      • Innes IR
      • Kosterlitz HW.
      The effects of preganglionic and postganglionic denervation on the responses of the nicitating membrane to sympathomimetic substances.
      It is also known that individuals with quadriplegia and cervical spinal cord transection have an enhanced pressor response to noradrenaline.
      • Mathias CJ
      • Frankel HL
      • Christensen NJ
      • Spalding JNK.
      Enhanced pressor response to noradrenaline in patients with cervical spinal cord transection.
      Moreover, circulating levels of noradrenaline in individuals with quadriplegia and controls are similar after identical infusions despite markedly different pressor responses.
      • Mathias CJ
      • Frankel HL
      • Christensen NJ
      • Spalding JNK.
      Enhanced pressor response to noradrenaline in patients with cervical spinal cord transection.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      Mathias and Frankel
      • Mathias CJ
      • Frankel HL.
      The neurological and hormonal control of blood vessels and heart in spinal man.
      note that this response is not likely due to impaired noradrenaline clearance in individuals with quadriplegia, an observation supported by Krum and colleagues,
      • Krum H
      • Brown DJ
      • Rowe PR
      • Louis WJ
      • Howes LG.
      Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
      suggesting peripheral alpha-adrenoceptor hyperresponsiveness likely accounts for a significant degree of the enhanced pressor response.
      Arnold and associates
      • Arnold JM
      • Feng QP
      • Delaney GA
      • Teasell RW.
      Alpha-adrenoceptor hyperresponsiveness in quadriplegic patients with autonomic dysreflexia.
      have demonstrated significant alpha-adrenoceptor–mediated hyperresponsiveness to infused noradrenaline in the dorsal foot veins of individuals with quadriplegia with a history of recurrent bouts of autonomic dysreflexia. The concentration of noradrenaline required to vasoconstrict the dorsal foot vein to half baseline value was six to seven times less in individuals with quadriplegia (1.6ng/min) than in controls (10.9ng/min, p <.02), demonstrating a hyperresponsiveness to noradrenaline presumably mediated by receptors in the blood vessel wall (fig 2).
      Figure thumbnail gr2
      Fig. 2Venous responsiveness to local infusion of increasing concentrations of noradrenaline using the dorsal foot vein of 6 quadriplegic patients was compared with 6 age- and sex-matched controls. A significant shift to the left of dose-response curve is seen in quadriplegic patients. The concentration of noradrenaline required to vasoconstrict the dorsal foot vein to half baseline value in quadriplegics (1.6ng/min) was less than controls (10.9ng/min, p <.02). (Reprinted with permission.
      • Arnold JM
      • Feng QP
      • Delaney GA
      • Teasell RW.
      Alpha-adrenoceptor hyperresponsiveness in quadriplegic patients with autonomic dysreflexia.
      )
      Because the study examined localized direct responses to noradrenaline while avoiding a significant pressor response, baroreceptor responses to an elevated blood pressure were eliminated. However, whether this hyperresponsiveness is a consequence of an increased number of receptors, abnormalities of postreceptor coupling mechanisms, or reduced presynaptic reuptake was not determined in this study. The aforementioned observation that noradrenaline clearance does not appear to be affected in quadriplegics
      • Krum H
      • Brown DJ
      • Rowe PR
      • Louis WJ
      • Howes LG.
      Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      would suggest one of the first two explanations.
      Evidence suggesting that there is an increased number of receptors comes from Rodriguez and colleagues,
      • Rodriguez GP
      • Claus-Walker J
      • Kent MC
      • Stal S.
      Adrenergic receptors in insensitive skin of spinal cord injury patients.
      who obtained skin biopsies from insensate areas of individuals with SCI. Alpha-adrenoceptor densities were significantly higher in early (<5yrs) cervical versus thoracic SCI individuals with a subsequent trend towards some decline in alpha-adrenoceptors over time, especially in the individuals with cervical cord injuries. Unfortunately, as the authors point out, sample sizes were small, there were no normal controls, and the radioliogic and assay procedures had inherently large errors. Thus, the results support, but do not provide definitive proof for, an upregulatory mechanism with an increase in the number of receptors contributing to the denervation hyperresponsiveness of alpha-adrenoceptors seen below the level of cervical SCI. Currently, there are no published studies looking at postreceptor coupling mechanisms.
      Osborn and colleagues
      • Osborn JW
      • Taylor RF
      • Schramm LF.
      Determinants of arterial pressure after chronic spinal transection in rats.
      • Osborn JW
      • Taylor RF
      • Schram LF.
      Chronic cervical spinal cord injury and autonomic hyperreflexia in rats.
      have challenged the concept of alpha-adrenoceptor hypersensitivity based on studies of rats with complete cervical spinal transections. They noted that there were no changes in pressor sensitivity to exogenous norepinephrine in these animals, an observation that argued against the concept of denervation supersensitivity. They suggested that this apparent lack of denervation supersensitivity after SCI may be caused by periodic episodes of SNS hyperactivity.
      • Osborn JW
      • Taylor RF
      • Schramm LF.
      Determinants of arterial pressure after chronic spinal transection in rats.
      Mallory
      • Mallory BS.
      Autonomic function in the isolated spinal cord.
      has proposed that the enhanced pressor response to noradrenaline in humans with cervical SCI reported by Mathias and associates
      • Mathias CJ
      • Frankel HL
      • Christensen NJ
      • Spalding JNK.
      Enhanced pressor response to noradrenaline in patients with cervical spinal cord transection.
      was a consequence of lack of baroreceptor-mediated sympathoinhibition because an exaggerated pressor response to noradrenaline does not occur in patients with chronic autonomic failure secondary to causes other than traumatic SCI (ie, multiple systems atrophy or parkinsonism). If loss of baroreceptor control was the principle mechanism, however, one might anticipate that autonomic dysreflexia would become a problem immediately after SCI; this is clearly not the case. Nevertheless, reorganization of spinal cord pathways and/or peripheral receptors combined with loss of baroreceptor control appears to be responsible for autonomic dysreflexia.
      In chronic high SCI there is often a paradox clinically whereby the individual may present with evidence of sympathetic hypoactivity at one time and then sympathetic hyperactivity at another, often within minutes of each other. The finding of local alpha-adrenoceptor hyperresponsiveness in human quadriplegics suggests that altered baroreflex control may not be the only or even the primary explanation for increased blood pressure responsiveness to noradrenaline in this condition.
      • Arnold JM
      • Feng QP
      • Delaney GA
      • Teasell RW.
      Alpha-adrenoceptor hyperresponsiveness in quadriplegic patients with autonomic dysreflexia.
      The development of autonomic dysreflexia over time provides support for both the concept of hypersensitization of peripheral vascular receptors and reorganization of spinal cord pathways below the level of SCI. The presence of alpha-adrenoceptor hyperresponsiveness may serve to better explain some of the clinical sequelae of high SCIs, in particular autonomic dysreflexia.

      Cardiovascular consequences of high SCI

       Reduced arterial pressure

      Low blood pressure is a problem in both acute and chronic high-level SCI patients. In recently injured individuals with quadriplegia still in the acute stage of spinal shock, blood pressure is much lower than in normal controls.
      • Mathias CJ
      • Christensen NJ
      • Frankel HL
      • Spalding JMK.
      Cardiovascular control in recently injured tetraplegics in spinal shock.
      This lower blood pressure is regarded as secondary to a reduction in SNS activity below the level of SCI.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      As Mathias and Frankel
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      have observed, it is unlikely that skeletal muscle paralysis accounts for low blood pressure as patients with flaccid quadriplegia secondary to poliomyelitis often have normal or even elevated blood pressure readings. In the later stages after SCI, both resting systolic and diastolic blood pressure in individuals with quadriplegia remain lower than in normal subjects.
      Frankel and colleagues
      • Frankel HL
      • Michaelis LS
      • Golding DR
      • Beral V.
      Blood pressure in paraplegia. I.
      recorded the “resting” blood pressure of 461 male patients with traumatic complete SCI. An inverse linear relationship between the level of SCI and resting blood pressure was recorded. The resting supine blood pressure of patients with complete cervical SCI was lower than that of normal individuals; the resting supine blood pressure of patients with lower thoracic and lumbar lesions was normal.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      Lehmann and colleagues
      • Lehmann KG
      • Lane JG
      • Piepmeier JM
      • Batsford WP.
      Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
      studied 71 consecutive patients admitted to a neurologic intensive care unit within 12 months of SCI. Hypotension, defined as at least two consecutive systolic blood pressure measurements of <90mmHg, was present in 21 of 31 (68%) individuals with quadriplegia with severe cervical injuries. In contrast, of the 40 patients with mild cervical and thoracolumbar SCIs, none had a diagnosis of hypotension.

       Orthostatic hypotension

      Orthostatic hypotension is a common problem in individuals with quadriplegia and paraplegia, particularly in the acute phase.
      • Corbett JL
      • Frankel HL
      • Harris PJ.
      Cardiovascular responses to tilting in tetraplegic man.
      • Cole TM
      • Kottke FJ
      • Olson M
      • Stradal L
      • Niederloh J.
      Alterations of cardiovascular control in high spinal myelomalacia.
      • Corbett JL
      • DeBarge O
      • Frankel HL
      • Mathias CJ.
      Cardiovascular responses in tetraplegic man to muscle spasm, bladder percussion and head-up tilt.
      • Downey JA
      • Chiodi HP
      • Miller JM.
      The effect of inhalation of 5 per cent carbon dioxide in air on postural hypotension in quadriplegia.
      • Koster M
      • Bethlem J.
      Paroxysmal hypertension in patients with spinal cord lesion (poikilopiesis spinalis).
      • Pollock LJ
      • Boshes B
      • Chor H
      • Finkelman I
      • Arieff AJ
      • Brown M.
      Defects in regulatory mechanisms of autonomic function in injuries to spinal cord.
      Patients may complain of dizziness, nausea, lightheadedness, a feeling of faintness, and even loss of consciousness. The true incidence and prevalence of orthostatic hypotension in this population are not known.
      • Bloch RF.
      Autonomic dysfunction in management of spinal cord injuries.
      Orthostatic hypotension appears to be related to pooling of blood in the viscera and dependent extremities in the absence of SNS efferent activity and reflex arterial and venous vasoconstriction in SCIs above the thoracic SNS outflow, ie, above the level of T5 to T8.
      • Bloch RF.
      Autonomic dysfunction in management of spinal cord injuries.
      In individuals with high SCIs at rest, loss of lower extremity muscle function combined with diminished SNS efferent activity results in excessive venous pooling in the lower extremities; as a consequence, blood volume is sequestered in the leg veins and mean systemic filling pressure at the heart is reduced.
      • Hopman MTE
      • Oeseburg B
      • Binkhorst RA.
      The effect of an anti-G suit on cardiovascular responses to exercise in persons with paraplegia.
      • Hopman MTE
      • Oeseburg B
      • Binkhorst RA.
      Cardiovascular responses in paraplegic subjects during arm exercise.
      • Hopman MTE
      • Oeseburg B
      • Binkhorst RA.
      Cardiovascular responses with paraplegia to prolonged arm exercise and thermal stress.
      • Davis GM
      • Servedio FJ
      • Glaser GM
      • Gupta SC
      • Suryaprasad AG.
      Cardiovascular responses to arm-cranking and FNS-induced leg exercise in paraplegics.
      • Figoni SF.
      Exercise responses and quadriplegia.
      • Sawka MN
      • Gonzalez RR
      • Drolet LL
      • Pandoff KB.
      Temperature regulation during upper body exercise: able-bodied and spinal cord injured.
      This in turn results in a decrease in end-diastolic filling volumes and stroke volume.
      • Hopman MTE
      • Oeseburg B
      • Binkhorst RA.
      Cardiovascular responses with paraplegia to prolonged arm exercise and thermal stress.
      Tachycardia may occur as a consequence of reduced vagal activity through the carotid sinus, but it is not sufficient to compensate for the diminished SNS response. Orthostatic hypotension does improve over time
      • Krebs M
      • Ragnarrson KT
      • Tuckman J.
      Orthostatic vasomotor response in spinal man.
      although the reasons for this improvement have not been clearly established; potential mechanisms include vascular wall receptor hypersensitivity, increased skeletal muscle tone, some recovery of postural reflexes at a spinal level, adaptation of the renin-angiotensin system, or some other, as yet undetermined, mechanism.

       Loss of diurnal variation in blood pressure

      Normal nocturnal decreases in blood pressure do not tend to occur in individuals with quadriplegia in comparison with neurologically intact subjects. Krum and colleagues
      • Krum H
      • Louis WJ
      • Brown DJ
      • Jackman GP
      • Howes LG.
      Diurnal blood pressure variation in quadriplegic chronic spinal cord injury patients.
      reported that systolic and diastolic pressures decreased significantly at night in orthopedic subjects but remained low in individuals with quadriplegia, with nighttime blood pressure being similar in both groups.
      • Krum H
      • Louis WJ
      • Brown DJ
      • Jackman GP
      • Howes LG.
      Diurnal blood pressure variation in quadriplegic chronic spinal cord injury patients.
      In contrast to studies in normal subjects in whom plasma noradrenaline peaks in the early morning and dips at night, the 24-hour plasma noradrenaline levels in individuals with SCI show no diurnal variation.
      • Claus-Walker J
      • Halstead LS.
      Metabolic and endocrine changes in spinal cord injury: II (section 1). Consequences of partial decentralization of autonomic nervous system.
      Together these findings suggest a link between diurnal variation in blood pressure and SNS activities in neurologically intact subjects, which is significantly diminished or completely absent in individuals with SCI.

       Bradycardia, reflex bradycardia, and cardiac arrest

      Lehmann and colleagues
      • Lehmann KG
      • Lane JG
      • Piepmeier JM
      • Batsford WP.
      Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
      studied 71 consecutive patients admitted to a neurologic intensive unit within 12 months of SCI. Persistent bradycardia, defined as mean heart rate for at least 1 day of <60 beats/min, was noted in 100% of individuals with quadriplegia with severe cervical lesions (Frankel A or B), 71% of those with quadriplegia with less severe cervical lesions (Frankel C or D), and in 13% of individuals with thoracolumbar spinal cord injuries (p <.00001). Marked bradycardia, defined as a heart rate of <45 beats/min, was present in 22 of 31 (71%) severe cervical SCI, compared with 2 of 17 (12%) milder cervical and 1 of 23 (4%) thoracolumbar SCIs. Twenty-nine percent of those with severe cervical SCIs required atropine or temporary transvenous pacemakers because of hemodynamic compromise, whereas none of the less severe cervical or thoracolumbar injuries needed these interventions. Bradycardia peaked at day 4 postinjury and then gradually resolved over the following 10 days in the majority of patients.
      • Lehmann KG
      • Lane JG
      • Piepmeier JM
      • Batsford WP.
      Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
      • Glenn MB
      • Bergman SB.
      Cardiovascular changes following spinal cord injury.
      In all patients with bradycardia, Lehmann and colleagues
      • Lehmann KG
      • Lane JG
      • Piepmeier JM
      • Batsford WP.
      Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
      reported the heart rate returned to normal 2 to 6 weeks after SCI.
      Dollfus and Frankel
      • Dollfus P
      • Frankel HL.
      Cardiovascular reflexes in tracheostomised tetaplegics.
      and Frankel and colleagues
      • Frankel HL
      • Mathias CJ
      • Spalding JMK.
      Mechanisms of reflex cardiac arrest in tetraplegic patients.
      have reported on reflex bradycardia and cardiac arrest during tracheal suction in recently injured individuals with quadriplegia who require intermittent positive pressure ventilation. This clinical phenomena was attributed to a vago-vagal reflex.
      • Frankel HL
      • Mathias CJ.
      The cardiovascular system in paraplegia and tetraplegia.
      In humans with an intact spinal cord, tracheal stimulation results in hypertension and tachycardia, a response dependent on sympathetic efferent pathways under supraspinal control.
      • Frankel HL
      • Mathias CJ.
      The cardiovascular system in paraplegia and tetraplegia.
      In individuals with quadriplegia, efferent cardiac parasympathetic nerve pathways remain intact in the presence of reduced SNS activity; this may predispose susceptible quadriplegic individuals to unopposed vagal overactivity with tracheal stimulation resulting in bradycardia and even cardiac arrest.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      Lehmann and colleagues
      • Lehmann KG
      • Lane JG
      • Piepmeier JM
      • Batsford WP.
      Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
      noted primary cardiac arrest occurred in 5 of 31 (16%) individuals in the severe cervical spinal cord injured group versus no episodes in the 40 patients with mild cervical and thoracolumbar SCIs (p <.05).

       Cardiovascular responses to exercise

      Active physical exercise is highly dependent on the SNS to compensate for cardiovascular and thermal stresses induced by aerobic and anaerobic activities. In normal humans, cardiac output is maintained as SNS vasoconstrictor responses serve to increase venous return and improve end-diastolic ventricular volume while heart rate and myocardial contractility increase. Neither of these first two mechanisms is available to the individuals with high-complete SCI who have reduced SNS efferent output, although a partial tachycardiac response can occur through a reduction in vagal activity. The end result contributes to exercise intolerance eventually leading to general deconditioning.
      • Figoni SF.
      Exercise responses and quadriplegia.
      Eriksson and colleagues
      • Eriksson P
      • Lofstrom L
      • Ekblom B.
      Aerobic power during maximal exercise in untrained and well-trained persons with quadriplegia and paraplegia.
      studied 58 men with traumatic SCIs from C4 to L4, including 25 well-trained “world-class athletes” and 33 untrained individuals with SCI, as well as 10 normal controls.
      • Eriksson P
      • Lofstrom L
      • Ekblom B.
      Aerobic power during maximal exercise in untrained and well-trained persons with quadriplegia and paraplegia.
      The mean heart rate achieved during maximal wheelchair exercise was 119 beats/min for untrained and 118 beats/min for trained individuals with quadriplegia, 138 beats/min for incompletely injured individuals with quadriplegia, and 183 to 186 beats/min for these same three categories of individuals with paraplegia. Untrained controls reached exercise heart rates of 155 beats/min while trained controls reached 164 beats/min. It was postulated that individuals with quadriplegia suffered loss of sympathetic innervation, which negatively affected cardiac performance (both contractility and chronotrophy); the end result was a maximal cardiac output that remained low. Similarly, Coutts and associates
      • Coutts KD
      • Rhodes EC
      • McKenzie DC.
      Maximal exercise responses of tetraplegics and paraplegics.
      studied individuals with quadriplegia and paraplegia with a continuous progressive loading exercise test to exhaustion on a wheelchair ergometer. Quadriplegic individuals had a significantly lower maximal heart rate (110 beats/min) compared with individuals with high and low paraplegia (175 and 190 beats/min, respectively). This suggests differential sympathetic activity in those with quadriplegia when compared with individuals with paraplegia and normal controls.
      A common practice among elite high-SCI athletes is the practice of “boosting,” whereby individuals intentionally increase their blood pressure or induce hyperreflexia to improve performance.
      • Burnham R
      • Wheeler G
      • Bhambhani Y
      • Belanger M
      • Eriksson P
      • Steadward R.
      Intentional induction of autonomic dysreflexia among quadriplegic athletes for performance enhancement: efficacy, safety and mechanism of action.
      Burnham and colleagues
      • Burnham R
      • Wheeler G
      • Bhambhani Y
      • Belanger M
      • Eriksson P
      • Steadward R.
      Intentional induction of autonomic dysreflexia among quadriplegic athletes for performance enhancement: efficacy, safety and mechanism of action.
      studied eight elite quadriplegic road racers and put them through exercise testing while in boosted or unboosted states. Race times were improved by 9.7% under boosted conditions (p <.05); however, the mechanism of improved performance was not entirely clear. With boosting there were significant increases in blood pressure, noradrenaline concentration, oxygen uptake, and arterial venous oxygen difference, as well as a reduction in stroke volume.

       Autonomic dysreflexia

      Autonomic dysreflexia is a symptom complex characterized by a sudden exaggerated increase in blood pressure accompanied by bradycardia in response to a stimulus originating below the level of the SCI. It commonly affects patients with SCI above the major SNS splanchnic outflow.
      • Braddom RL
      • Rocco JF.
      Autonomic dysreflexia: a survey of current treatment.
      It is generally confined to individuals with SCI at T5 to T6 or higher, although it has been reported in SCIs as low as T8 to T10.
      • Gimovski ML
      • Ojeda A
      • Ozaki R
      • Zerne S.
      Management of autonomic hyperreflexia associated with a low thoracic spinal cord lesion.
      • Kiker JD
      • Woodstide JR
      • Jelinek GE.
      Neurogenic pulmonary edema associated with autonomic dysreflexia.
      The higher the level of SCI, the more severe the bouts of autonomic dysreflexia, as measured by the level of hypertension.
      • Erickson RP.
      Autonomic hyperreflexia: pathophysiology and medical management.
      • Guttman L
      • Whitteridge D.
      Effects of bladder distention on autonomic mechanism after spinal cord injuries.
      Autonomic dysreflexia reportedly occurs in 48% to 90% of individuals with quadriplegia and high paraplegia
      • Erickson RP.
      Autonomic hyperreflexia: pathophysiology and medical management.
      • Lindan R
      • Joiner E
      • Freehafter AA
      • Hazel C.
      Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury.
      and has been reported after posterior fossa tumor resection.
      • Finestone HM
      • Teasell RW.
      Autonomic dysreflexia following brainstem tumor resection.

       Clinical picture

      Tabled 1Table 1: Clinical manifestations of autonomic dysreflexia
      Throbbing headache, especially in the occiput and frontal regions
      Marked hypertension
      Bradycardia
      Pupillary dilitation
      Above the SCI: pallor initially, followed by flushing of face and neck and sweating in areas above and around the lesion
      Below the SCI: cold peripheries, piloerection
      Contraction of urinary bladder and large bowel
      Penile erection and seminal fluid emission
      During an episode of autonomic dysreflexia, vasodilatation (flushing of face, neck, upper chest, and upper arms), profuse sweating, increased cutaneous temperature, and nasal congestion are seen above the level of SCI. Headaches are common and are regarded as a consequence of dilation of pain-sensitive intracranial arteries. The profuse sweating above the level of the SCI has been described as a consequence of sympathetic cholinergic hyperactivity.
      • Colachis SC.
      Autonomic hyperreflexia with spinal cord injury.
      Trop and Bennett
      • Trop CS
      • Bennett CJ.
      Autonomic dysreflexia and its urological implications: a review.
      have noted that afferent outflow from aortic arch and carotid sinus baroreceptors to the medullary vasomotor center results in vasodilitation in the head and neck. Headaches have not been shown to correlate with the severity of hypertension. Other symptoms include nausea, respiratory distress, hyperreflexia with increased spasticity, and cardiac abnormalities.
      More severe, but fortunately rare, complications associated with the severe hypertension of autonomic dysreflexia include myocardial infarction and neurologic disorders such as seizures, visual deficits, and cerebral hemorrhage.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Eltorai I
      • Kim P
      • Vulpe M
      • Kasravi H
      • Ho W.
      Fatal cerebral hemorrhage due to autonomic dysreflexia in a tetraplegic patient: case report and review.
      Autonomic dysreflexia occurs during labor in approximately two thirds of pregnant women with SCI above the level of T6.
      • Trop CS
      • Bennett CJ.
      The evaluation of autonomic dysreflexia.
      • Crosby E
      • St-Jean B
      • Reid D
      • Elliott RD.
      Obstetric forum.
      The long-term consequences of repeated episodes of severe hypertension in individuals with high-level SCIs has yet to be determined.
      Tabled 1Table 2: Stimuli and conditions associated with the development of autonomic dysreflexia in SCI patients
      Urogenital System
       Bladder distension
      • Lindan R
      • Joiner E
      • Freehafter AA
      • Hazel C.
      Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury.
      • Kewalramani LS.
      Autonomic dysreflexia in traumatic myelopathy.
      • Kursh ED
      • Freehafer A
      • Persky L.
      Complications of autonomic dysreflexia.
      • Sommers DK.
      Paroxysmal neurogenic hypertension and its prevention in patients with cervical spinal cord lesions.
       Urethral distension
      • Bors E
      • French JD.
      Management of paroxysmal hypertension following injuries to cervical and upper thoracic segments of the spinal cord.
       Urodynamics/cystoscopy
      • Lindan R
      • Joiner E
      • Freehafter AA
      • Hazel C.
      Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury.
      • Kursh ED
      • Freehafer A
      • Persky L.
      Complications of autonomic dysreflexia.
      • Barton CH
      • Kohonsari F
      • Vaziri ND
      • Byrne C
      • Gordon S
      • Friis R.
      The effect of modified transurethral sphincterotomy on autonomic dysreflexia.
      • Broecker BH
      • Hranowsky N
      • Hackler RH.
      Low spinal anesthesia for the prevention of autonomic dysreflexia in the spinal cord injury patient.
      • Brown BT
      • Carrion HM
      • Politano VA.
      Guanethidine sulfate in the prevention of autonomic hyperreflexia.
      • Dykstra DD
      • Sidi AA
      • Anderson LC.
      The effect of nifedipine on cystoscopy-induced autonomic hyperreflexia in patients with high spinal cord injuries.
      • Snow JC
      • Siderpoulos HP
      • Kripke BJ
      • Freed MM
      • Shah NK
      • Schlesinger RM.
      Autonomic hyperreflexia during cystoscopy in patients with high spinal cord injuries.
       Urinary tract infections
      • Cole TM
      • Kottke FJ
      • Olson M
      • Stradal L
      • Niederloh J.
      Alterations of cardiovascular control in high spinal myelomalacia.
      • Sizemore GW
      • Winternitz WW.
      Autonomic hyperreflexia—suppression with alpha-adrenergic blocking agents.
      • Thompson CE
      • Witham AC.
      Paroxysmal hypertension in spinal cord injuries.
       Epididymitis
      • Kursh ED
      • Freehafer A
      • Persky L.
      Complications of autonomic dysreflexia.
       Renal calculus
      • Cole TM
      • Kottke FJ
      • Olson M
      • Stradal L
      • Niederloh J.
      Alterations of cardiovascular control in high spinal myelomalacia.
       Electroejaculation
      • Frankel HL
      • Mathias CJ.
      Severe hypertension in patients with spinal cord lesions undergoing electroejaculation—management with prostaglandin E2.
      • Steinberger RE
      • Ohl DA
      • Bennett CJ
      • McCabe M
      • Wange SC.
      Nifedipine pretreatment for autonomic dysreflexia during electroejaculation.
       Coitus
      • Scott MB
      • Morrow JW.
      Phenoxybenzamine in neurogenic bladder dysfunction after spinal cord injury.
       Penile stimulation to obtain reflex erection
      • Erickson RP.
      Autonomic hyperreflexia: pathophysiology and medical management.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
       Vaginal dilation
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
       Uterine contractions
      • Cross LL
      • Meythaler JM
      • Tuel SM
      • Cross LA.
      Pregnancy, labor and delivery post spinal cord injury.
      • Finocchiaro DN
      • Herzfeld ST.
      Understanding autonomic dysreflexia.
      • Trop CS
      • Bennett CJ.
      The evaluation of autonomic dysreflexia.
      • Crosby E
      • St-Jean B
      • Reid D
      • Elliott RD.
      Obstetric forum.
      • Abouleish EI
      • Hanely ES
      • Palmer SM.
      Can epidural fentanyl control autonomic hyperreflexia in a quadriplegic patient?.
      • Guttman L
      • Frankel HL
      • Paeslack V.
      Cardiac irregularities during labor in paraplegic women.
      • Katz VL
      • Thorp Jr, JM
      • Cefalo RC.
      Epidural analgesia and autonomic hyperreflexia: a case report.
      • Tabsh KMA
      • Brinkman CRI
      • Reff RA.
      Autonomic dysreflexia in pregnancy.
       Testicular torsion
      • Vapnek TM.
      Autonomic dysreflexia.
      Gastrointestinal System
       Bowel distension
      • Lindan R
      • Joiner E
      • Freehafter AA
      • Hazel C.
      Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury.
      • Kewalramani LS.
      Autonomic dysreflexia in traumatic myelopathy.
       Anal fissures
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
       Esophageal reflux
      • Donald IP
      • Gear MWL
      • Wilkinson SP.
      A life threatening respiratory complication of gastroesophageal reflux in a patient with tetraplegia.
       Enemas
      • Head H
      • Riddoch G.
      The automatic bladder, excessive sweating and some other reflex conditions in gross injuries of the spinal cord.
       Gastric dilatation
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
       Gastric ulcer
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
       Cholecystitis or cholelithiasis
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      Skin/musculoskeletal
       Cutaneous stimulation
      • Kursh ED
      • Freehafer A
      • Persky L.
      Complications of autonomic dysreflexia.
      • Jane MJ
      • Freehafer AA
      • Hazel C
      • Lindan R
      • Joiner E.
      Autonomic dysreflexia. A cause of morbidity and mortality in orthopedic patients with spinal cord injury.
       Sunburns
      • Finocchiaro DN
      • Herzfeld ST.
      Understanding autonomic dysreflexia.
      • Scott MB
      • Morrow JW.
      Phenoxybenzamine in neurogenic bladder dysfunction after spinal cord injury.
       Pressure sores
      • Cole TM
      • Kottke FJ
      • Olson M
      • Stradal L
      • Niederloh J.
      Alterations of cardiovascular control in high spinal myelomalacia.
      • Scott MB
      • Morrow JW.
      Phenoxybenzamine in neurogenic bladder dysfunction after spinal cord injury.
      • Hall PA
      • Young JV.
      Autonomic hyperreflexia in spinal cord injured patients: trigger mechanism-dressing changes of pressure sores.
       Ingrown toenails
      • Lindan R
      • Joiner E
      • Freehafter AA
      • Hazel C.
      Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury.
       Functional electrical stimulation
      • Ashley EA
      • Laskin JJ
      • Olenik LM
      • Burnham R
      • Steadward RD
      • Cumming DC
      • et al.
      Evidence of autonomic dysreflexia during functional electrical stimulation in individuals with spinal cord injuries.
       Spasticity
      • Maynard FM.
      Early clinical experience with clonidine in spinal spasticity.
      Surgical procedures/conditions
       Surgical procedures
      • Broecker BH
      • Hranowsky N
      • Hackler RH.
      Low spinal anesthesia for the prevention of autonomic dysreflexia in the spinal cord injury patient.
      • Lambert DH
      • Deane RS
      • Mazuzan JE.
      Anesthesia and the control of blood pressure in patients with spinal cord injury.
      • Nieder RM
      • O'Higgins JW
      • Aldrete JA.
      Autonomic hyperreflexia in urologic surgery.
      • Schonwald G
      • Fish KJ
      • Perkash I.
      Cardiovascular complications during anesthesia in chronic spinal cord injured patients.
      • Stowe DF
      • Bernstein JS
      • Madsen KE
      • McDonald DJ
      • Ebert TJ.
      Autonomic hyperreflexia in spinal cord injured patients during extracoroporeal shock wave lithotripsy.
       Radiological procedures
      • Scher AT.
      Autonomic hyperreflexia. A serious complication of radiologic procedures in patients with cervical or upper thoracic spinal cord lesions.
       Deep venous thromboses
      • Scott MB
      • Morrow JW.
      Phenoxybenzamine in neurogenic bladder dysfunction after spinal cord injury.
      • Jane MJ
      • Freehafer AA
      • Hazel C
      • Lindan R
      • Joiner E.
      Autonomic dysreflexia. A cause of morbidity and mortality in orthopedic patients with spinal cord injury.
       Pulmonary emboli
      • Scott MB
      • Morrow JW.
      Phenoxybenzamine in neurogenic bladder dysfunction after spinal cord injury.
      • Colachis SC.
      Autonomic hyperreflexia in spinal cord injury associated with pulmonary embolism.
       Fracture site manipulation
      • Givre S
      • Freed HA.
      A potentially fatal complication of somatic stress in quadriplegics.
      Miscellaneous
       Range of motion exercises
      • McGarry J
      • Woolsey RM
      • Thompson CW.
      Autonomic hyperreflexia following passive stretching to the hip joint.
       Position changes
      • Arnold JM
      • Feng QP
      • Delaney GA
      • Teasell RW.
      Alpha-adrenoceptor hyperresponsiveness in quadriplegic patients with autonomic dysreflexia.
      • Naftchi NE.
      Mechanism of autonomic dysreflexia. Contributions of catecholamines and peptide neurotransmitters.
      • Claus-Walker J
      • Halstead LS.
      Metabolic and endocrine changes in spinal cord injury: II (section 1). Consequences of partial decentralization of autonomic nervous system.
      • Lehmann KG
      • Lane JG
      • Piepmeier JM
      • Batsford WP.
      Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
      • Frankel HL
      • Michaelis LS
      • Golding DR
      • Beral V.
      Blood pressure in paraplegia. I.
      • Abouleish EI
      • Hanely ES
      • Palmer SM.
      Can epidural fentanyl control autonomic hyperreflexia in a quadriplegic patient?.
      • Khurana RK.
      Orthostatic hypotension—induced autonomic dysreflexia.
       Medications
      • Wineinger MA
      • Basford JR.
      Autonomic dysreflexia due to medication: misadventure in the use of an isometheptene combination to treat migraine.
       Emergence in cold water
      • Kurnick NB.
      Autonomic hyperreflexia and its control in patients with spinal cord lesions.
      Advantages
       Self-induced autonomic dysreflexia (intentional boosting)
      • Burnham R
      • Wheeler G
      • Bhambhani Y
      • Belanger M
      • Eriksson P
      • Steadward R.
      Intentional induction of autonomic dysreflexia among quadriplegic athletes for performance enhancement: efficacy, safety and mechanism of action.
      • Harris P.
      Self-induced autonomic dysreflexia (“boosting”) practised by some tetraplegic athletes to enhance their athletic performance.
       Signal of onset of serious medical complications
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      Complications
       Seizures
      • Lindan R
      • Joiner E
      • Freehafter AA
      • Hazel C.
      Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury.
      • Cole TM
      • Kottke FJ
      • Olson M
      • Stradal L
      • Niederloh J.
      Alterations of cardiovascular control in high spinal myelomalacia.
      • Kursh ED
      • Freehafer A
      • Persky L.
      Complications of autonomic dysreflexia.
      • Thompson CE
      • Witham AC.
      Paroxysmal hypertension in spinal cord injuries.
       Retinal or subarachnoid hemorrhages
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Kursh ED
      • Freehafer A
      • Persky L.
      Complications of autonomic dysreflexia.
      • Brown BT
      • Carrion HM
      • Politano VA.
      Guanethidine sulfate in the prevention of autonomic hyperreflexia.
       Cerebral vascular accidents
      • Kursh ED
      • Freehafer A
      • Persky L.
      Complications of autonomic dysreflexia.
      • Guttman L
      • Frankel HL
      • Paeslack V.
      Cardiac irregularities during labor in paraplegic women.
       Death
      • Lindan R
      • Joiner E
      • Freehafter AA
      • Hazel C.
      Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury.
      • Kursh ED
      • Freehafer A
      • Persky L.
      Complications of autonomic dysreflexia.

       Pathophysiology

      Possible pathophysiological mechanisms accounting for autonomic dysreflexia included loss of supraspinal inhibitory control; denervation hypersensitivity of sympathetic spinal, ganglionic, or peripheral receptor sites; and the formation of abnormal synaptic connections due to axonal sprouting.
      • Bloch RF.
      Autonomic dysfunction in management of spinal cord injuries.
      Sympathetic preganglionic neurons, which are responsible for the maintenance of sympathetic tone, undergo significant morphologic changes with time after SCI.
      • Krassioukov AV
      • Bunge RP
      • Puckett WR
      • Bygrave M.
      The changes in human spinal cord sympathetic preganglionic neurons after spinal cord injury.
      Moreover, reactive astrogliosis observed in animal and human spinal cords after SCI could contribute to plastic changes in the neurophil that affect the sympathetic neurons.
      • Bunge RP
      • Puckett WR
      • Becerra JL
      • Macillo A
      • Quencer RM.
      Observation on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination.
      • Krassioukov AC
      • Weaver LC.
      Morphological changes in sympathetic preganglionic neurons after spinal cord injury in rats.
      Finally, enhanced expression of synaptophysin in the gray matter caudal to a cord injury is consistent with fiber outgrowth leading to new synaptic formation.
      • Krassioukov AC
      • Weaver LC.
      Morphological changes in sympathetic preganglionic neurons after spinal cord injury in rats.
      The major splanchnic outflow of the SNS occurs from T5 to L2
      • Trop CS
      • Bennett CJ.
      The evaluation of autonomic dysreflexia.
      • Eade NM.
      Paroxysmal hypertension in spinal cord injuries (autonomic hyperreflexia).
      and can be modulated through inhibition by supraspinal centers.
      • Trop CS
      • Bennett CJ.
      The evaluation of autonomic dysreflexia.
      In the past, the prevailing viewpoint has been that SNS outflow is excessive below the level of cord injury because of lack of central inhibition, which results in prolonged vasoconstriction and subsequent hypertension.
      • Braddom RL
      • Rocco JF.
      Autonomic dysreflexia: a survey of current treatment.
      Wallin and Stjernberg,
      • Wallin BG
      • Stjernberg L.
      Sympathetic activity in man after spinal cord injury.
      using microelectrodes to measure SNS activity in humans after SCI, found various visceral and somatic stimuli caudal to the cord injury led to spontaneous SNS activity. The duration of the resulting vasoconstriction was prolonged when compared to normals.
      • Bloch RF.
      Autonomic dysfunction in management of spinal cord injuries.
      Studies have shown, however, that during autonomic dysreflexia only a mild to moderate increase in catecholamine release occurs.
      • Krum H
      • Brown DJ
      • Rowe PR
      • Louis WJ
      • Howes LG.
      Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
      It continues to be widely believed that in autonomic dysreflexia the vasoconstriction, hypertension, piloerection, and other sympathetic effects seen below the level of SCI are mediated via SNS postganglionic fiber release of noradrenaline with predominantly alpha-adrenergic smooth muscle receptor activity in the absence of restraining supraspinal vasomotor reflexes.
      • Erickson RP.
      Autonomic hyperreflexia: pathophysiology and medical management.
      • Krum H
      • Brown DJ
      • Rowe PR
      • Louis WJ
      • Howes LG.
      Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
      However, plasma noradrenaline levels, even at the height of hypertension and despite their twofold or threefold increases over the same individuals with SCI at rest, were at best similar to the resting basal levels of normal subjects.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      Krum and colleagues
      • Krum H
      • Louis WJ
      • Brown DJ
      • Howes LG.
      Pressor doses responses and baroreflex sensitivity in quadriplegic spinal cord injury patients.
      studied pressor dose responsiveness in individuals with SCI and quadriplegia and normal controls to a variety of adrenergic agonists. Increased responsiveness to alpha-1– and alpha-2–adrenoceptor agonists and to angiotensin II was noted in quadriplegic spinal cord injured individuals when compared with controls.
      • Krum H
      • Louis WJ
      • Brown DJ
      • Howes LG.
      Pressor doses responses and baroreflex sensitivity in quadriplegic spinal cord injury patients.
      Indeed, the amount of noradrenaline infused into the circulation necessary to produce hypertension similar to that seen during autonomic dysreflexia in the quadriplegic individuals
      • Mathias CJ
      • Christensen NJ
      • Corbett JL
      • Frankel HL
      • Spalding JMK.
      Plasma catecholamines during paroxysmal neurogenic hypertension in quadriplegic man.
      was 8 to 37 times greater than that actually measured in SCI patients during a regular bout of autonomic dysreflexia.
      • Krum H
      • Brown DJ
      • Rowe PR
      • Louis WJ
      • Howes LG.
      Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
      This suggested that noradrenaline elicits a greater pressor response when it is released at a local (neuron terminal) level directly onto the peripheral receptor. Nevertheless, studies have shown spinal cord injured individuals with quadriplegia have an increased blood pressure response to exogenous noradrenaline infusion.
      • Mathias CJ
      • Christensen NJ
      • Corbett JL
      • Frankel HL
      • Spalding JMK.
      Plasma catecholamines during paroxysmal neurogenic hypertension in quadriplegic man.
      This increased pressor responsiveness could be due to increased reactivity of resistant vessels or decreased neuronal reuptake from the synaptic cleft.
      Krum and associates
      • Krum H
      • Louis WJ
      • Brown DJ
      • Clarke SJ
      • Fleming JA
      • Howes LG.
      Cardiovascular and vasoactive hormone responses to bladder distension in spinal cord normal man.
      subjected high and low SCI and control patients to slow bladder filling/distension. In high SCI subjects, systolic and diastolic blood pressure increased significantly while heart rates decreased. In contrast, low SCI subjects and normal controls demonstrated no significant changes. There were no significant changes in plasma levels of noradrenaline, renin, aldosterone, vasopressin, arginine, or atrial naturetic peptide in the high SCI group. The authors concluded that these major differences in blood pressure in high SCI subjects supported the concept that SNS efferents below the level of cord transection were associated with increased vascular sensitivity, which most likely mediated blood pressure elevations in response to bladder distension in high SCI subjects.
      • Krum H
      • Brown DJ
      • Rowe PR
      • Louis WJ
      • Howes LG.
      Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
      • Mathias CJ
      • Frankel HL
      • Christensen NJ
      • Spalding JNK.
      Enhanced pressor response to noradrenaline in patients with cervical spinal cord transection.
      To understand how this might develop, one must understand the development of autonomic dysreflexia. Initially, in recently injured individuals with quadriplegia in spinal shock, there is often no change in blood pressure or heart rate during stimulation (principally bladder stimulation) below the level of SCI.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      • Mathias CJ
      • Frankel HL.
      The neurological and hormonal control of blood vessels and heart in spinal man.
      The syndrome of autonomic dysreflexia typically is not present initially. Stimuli that readily elicit autonomic dysreflexia or an increase in blood pressure in chronic high-level spinal cord injured individuals fail to elicit any cardiovascular response in acute spinal cord injured individuals
      • Corbett JL
      • Frankel HL
      • Harris PJ.
      Cardiovascular responses to tilting in tetraplegic man.
      suggesting loss of supraspinal inhibitory influences is not the only, or even the key factor, in the development of paroxysmal hypertension. Rather, it would appear that autonomic dysreflexia develops over time, suggesting peripheral (and/or central) receptor hypersensitization, which would develop over time. Alternatively, SCI may result in decreased neuronal reuptake of noradrenaline, resulting in increased synaptic levels of noradrenaline. This could lead to increased vascular responsiveness in the absence of a change in postsynaptic receptors or postreceptor coupling mechanisms.
      Autonomic dysreflexia is basically confined to cord injuries above the level of T6. Lesions below the level of T6 generally allow enough supraspinal neural control of SNS efferent flow to the large and crucial splanchnic circulatory bed. Alpha-adrenoceptor–mediated hypersensitivity could potentially occur below the level of SCI in individuals with lower paraplegia but the volume of affected blood vessels would be small enough to be counteracted by the larger volume of unaffected blood vessels.
      Krum and colleagues
      • Krum H
      • Louis WJ
      • Brown DJ
      • Howes LG.
      A study of the alpha-1 adrenoceptor blocker prazosin in the prophylactic management of autonomic dysreflexia in high spinal cord injury patients.
      studied the response to prazosin (an alpha-adrenceptor antagonist) or a placebo in 16 consecutive spinal cord injured individuals with lesions above the level of T6 who were at least 3 months postinjury and who had at least two episodes of symptomatic autonomic dysreflexia in the preceding 7 days. The authors reported that those individuals in the prazosin group suffered fewer severe episodes of autonomic dysreflexia with significant reductions in average increase of blood pressure and shorter and less severe symptoms.

       Pressure sores

      Pressure sores pose a serious potential complication in persons with SCIs. Sympathetic denervation is considered to be a contributing factor in the development of diabetic neuropathic foot ulceration. Animal studies have shown that somatic nerve denervation alone was insufficient to result in a neuropathic foot ulcer and additional sympathetic denervation must also be present.
      • Ryder REJ
      • Kennedy RL
      • Newrick PG
      • Wilson RM
      • Ward JD
      • Hardisty CA.
      Autonomic denervation may be a prerequisite of diabetic neuropathic foot ulceration.
      Arteriovenous shunting has also been reported in the lower extremities of patients with diabetic neuropathy, presumably due to involvement of the SNS.
      • Boulton AJM
      • Scarpello JHB
      • Ward JD.
      Venous oxygenation in the diabetic neuropathic foot: evidence of arteriovenous shunting?.
      This arteriovenous shunting would be expected to increase susceptibility to local ischemia with prolonged pressure, increasing susceptibility to skin ulceration.
      Similar arteriovenous shunting has been reported in individuals with quadriplegia.
      • Van Dan Hoogen F
      • Brawn LA
      • Sherriff S
      • Watson N
      • Ward JD.
      Arteriovenous shunting in quadriplegia.
      Transcutaneous oxygen tension is reportedly significantly lower in individuals with SCI than in controls, especially in the supine position.
      • Mawson AR
      • Siddiqui FH
      • Connolly BJ
      • Sharp CJ
      • Summer WR
      • Biundo JJ.
      Sacral transcutaneous oxygen tension levels in spinal cord injured: risk factors for pressure ulcers?.
      As mentioned previously, individuals with high cord injuries suffer reduced resting blood pressure. Schubert and Fagrell
      • Schubert V
      • Fagrell B.
      Postocclusive reactive hyperemia and thermal response in the skin microcirculation of subjects with spinal cord injury.
      found that skin blood flow occlusion occurred at lower externally applied pressures in individuals with SCI when compared with controls. The same study found that increased skin blood flow during the occlusive (recovery) reactive hyperemia phase was lower in individuals with SCI when compared with controls.
      • Schubert V
      • Fagrell B.
      Postocclusive reactive hyperemia and thermal response in the skin microcirculation of subjects with spinal cord injury.
      This propensity toward pressure-induced skin blood flow occlusion only heightens the risk of pressure sores, particularly over insensate regions. This propensity for increased pressure-induced local ischemia could be accounted for by increased alpha-adrenoceptor hyperresponsiveness to released noradrenaline, assuming it also involves the arterial system, as suggested by Mathias and Frankel.
      • Mathias CJ
      • Frankel HL.
      Autonomic disturbances in spinal cord lesions.
      • Mathias CJ
      • Frankel HL.
      The cardiovascular system in tetraplegia and paraplegia.
      This would help explain some of the propensity to pressure ulceration not only in individuals with SCI but also in advanced diabetic peripheral neuropathy.

      Summary

      Cervical and high thoracic SCIs invariably result in significant SNS dysfunction. This SNS dysfunction can be largely attributed to several pathophysiological phenomena which occur below the level of SCI: (1) loss of supraspinal regulatory control; (2) reduced SNS outflow; (3) morphologic changes in sympathetic preganglionic neurons; and (4) peripheral alpha-adrenoceptor hyperresponsiveness. Reduced SNS outflow results in low resting blood pressure, orthostatic hypotension, reflex bradycardia, and rarely cardiac arrest. Loss of supraspinal inhibitory influences in combination with peripheral alpha-adrenoceptor hyperresponsiveness result in autonomic dysreflexia and we hypothesize that the latter may also contribute to a greater susceptibility to pressure sores. Better understanding of the pathophysiology of SNS changes in higher level SCIs should eventually lead to improved treatment directed at those abnormalities.

      References

        • Arnold JM
        • Feng QP
        • Delaney GA
        • Teasell RW.
        Alpha-adrenoceptor hyperresponsiveness in quadriplegic patients with autonomic dysreflexia.
        Clin Auton Res. 1995; 5: 267-270
        • Naftchi NE.
        Mechanism of autonomic dysreflexia. Contributions of catecholamines and peptide neurotransmitters.
        Ann N Y Acad Sci. 1990; 579 ([review]): 133-148
        • Claus-Walker J
        • Halstead LS.
        Metabolic and endocrine changes in spinal cord injury: II (section 1). Consequences of partial decentralization of autonomic nervous system.
        Arch Phys Med Rehabil. 1982; 63: 569-575
        • Lehmann KG
        • Lane JG
        • Piepmeier JM
        • Batsford WP.
        Cardiovascular abnormalities accompanying acute spinal cord injuries in humans: incidence, time course and severity.
        J Am Coll Cardiol. 1987; 10: 46-52
        • Frankel HL
        • Michaelis LS
        • Golding DR
        • Beral V.
        Blood pressure in paraplegia. I.
        Paraplegia. 1972; 10: 193-200
        • Erickson RP.
        Autonomic hyperreflexia: pathophysiology and medical management.
        Arch Phys Med Rehabil. 1980; 61: 431-440
        • Braddom RL
        • Rocco JF.
        Autonomic dysreflexia: a survey of current treatment.
        Am J Phys Med Rehabil. 1991; 70: 234-241
        • Corbett JL
        • Frankel HL
        • Harris PJ.
        Cardiovascular responses to tilting in tetraplegic man.
        J Physiol (Lond). 1971; 215: 411-431
        • Krum H
        • Brown DJ
        • Rowe PR
        • Louis WJ
        • Howes LG.
        Steady state plasma (3H) noradrenaline kinetics in quadriplegic spinal cord injury patients.
        J Auton Pharmacol. 1990; 10: 221-226
        • Mathias CJ
        • Christensen NJ
        • Corbett JL
        • Frankel HL
        • Spalding JMK.
        Plasma catecholamines during paroxysmal neurogenic hypertension in quadriplegic man.
        Circ Res. 1976; 39: 204-208
        • Mathias CJ
        • Frankel HL
        • Christensen NJ
        • Spalding JNK.
        Enhanced pressor response to noradrenaline in patients with cervical spinal cord transection.
        Brain. 1976; 99: 757-770
        • Mathias CJ
        • Frankel HL.
        Autonomic disturbances in spinal cord lesions.
        in: 3rd ed. Autonomic failure. Oxford University Press, Oxford1992: 839-881
        • Mathias CJ
        • Frankel HL.
        The cardiovascular system in tetraplegia and paraplegia.
        in: Spinal cord trauma. handbook of clinical neurology. Elsevier Science Publishers, Amsterdam1992: 435-456
        • Gimovski ML
        • Ojeda A
        • Ozaki R
        • Zerne S.
        Management of autonomic hyperreflexia associated with a low thoracic spinal cord lesion.
        Am J Obstet Gynecol. 1985; 153: 223-224
        • Wallin BG
        • Stjernberg L.
        Sympathetic activity in man after spinal cord injury.
        Brain. 1984; 107: 183-198
        • Stjernberg L
        • Blumberg H
        • Wallin BG.
        Sympathetic activity in man after spinal cord injury. Outflow to muscle below the lesion.
        Brain. 1986; 109: 695-715
        • Claus-Walker J
        • Valbona C
        • Carter RE
        • Lipscomb HS.
        Resting and stimulated endocrine function in human subjects with cervical spinal cord transection.
        J Chron Dis. 1971; 24: 193-207
        • DeBarge O
        • Christensen NJ
        • Corbett JL
        • Eidelman BH
        • Frankel HL
        • Mathias CJ.
        Plasma catecholamines in tetraplegics.
        Paraplegia. 1978; 12: 44-49
        • Frewin DM
        • Levitt M
        • Myers SJ
        • Co CC
        • Downey JA.
        Catecholamine responses in paraplegia.
        Paraplegia. 1973; 11: 238-244
        • Guttman L
        • Munro AF
        • Robinson R
        • Walsh JJ.
        Effect of tilting on cardiovascular responses and plasma catecholamine levels in spinal man.
        Paraplegia. 1963-64; 1: 4-18
        • Naftchi NE
        • Lowman EW
        • Sell GH
        • Rusk HA.
        Peripheral circulation and catecholamine metabolism in paraplegia and quadriplegia.
        Arch Phys Med Rehabil. 1972; 53 (372): 357-361
        • Vallbona C
        • Lipscomb HS
        • Carter RE.
        Endocrine responses to orthostatic hypotension in quadriplegia.
        Arch Phys Med Rehabil. 1966; 47: 412-421
        • Kamelhar DL
        • Steel Jr, JM
        • Schact RG
        • Lowenstein J
        • Naftchi NE.
        Plasma renin and serum dopamine-beta-hydroxylase during orthostatic hypotension in quadriplegic man.
        Arch Phys Med Rehabil. 1978; 59: 212-216
        • Levitt M
        • Frewin DB
        • Co CC
        • Luke WK
        • Downey JA.
        Plasma dopamine-beta-hydroxylase activity in paraplegic and quadriplegic subjects.
        Aust N Z Med. 1974; 4: 48-52
        • Naftchi NE
        • Wooten GF
        • Lowman EW
        • Axelrod J.
        Relationship between serum dopamine-B-hydroxylase activity, catecholamine metabolism, and hemodynamic changes during paroxysmal hypertension in quadriplegia.
        Circ Res. 1974; 35: 850-861
        • King ML
        • Lichtman SW
        • Pellicone JT
        • Close RJ
        • Lisanti P.
        Exertional hypotension in spinal cord injury.
        Chest. 1994; 106: 1166-1171
        • Yekutiel M
        • Brooks ME
        • Ohry A
        • Yarom J
        • Carel R.
        The prevalence of hypertension, ischemic heart disease and diabetes in traumatic spinal cord injured patients and amputees.
        Paraplegia. 1989; 27: 58-62
        • Biyani A
        • El Masry WS.
        Post-traumatic syringomyelia: a review of the literature.
        Paraplegia. 1994; 32: 723-731
        • Bunge RP
        • Puckett WR
        • Becerra JL
        • Macillo A
        • Quencer RM.
        Observation on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination.
        in: Advances in neurology. Raven Press Ltd, New York1993: 75-88
        • Dimitrijevic MR.
        Residual motor functions in spinal cord injury.
        in: 4th ed. Functional recovery in neurological disease. Raven Press, New York1988: 139-155
        • Fehlings MG
        • Tator CH
        • Linden RD.
        The relationships among the severity of spinal cord injury, motor and somatosensory evoked potentials and spinal cord blood flow.
        Electroencephalogr Clin Neurophysiol. 1989; 74: 241-259
        • Tator CH.
        Update on the pathophysiology and pathology of acute spinal cord injury.
        Brain Pathol. 1995; 5 ([review]): 407-413
        • Ditunno JF
        • Formal CS.
        Chronic spinal cord injury.
        N Engl J Med. 1994; 330: 550-556
        • Quencer RM
        • Bunge RP
        • Egnor M
        • Green BA
        • Puckett W
        • Naidich TP
        • et al.
        Acute traumatic central cord syndrome: MRI-pathological correlations.
        Neuroradiology. 1992; 34: 85-94
        • Krassioukov AC
        • Weaver LC.
        Morphological changes in sympathetic preganglionic neurons after spinal cord injury in rats.
        Neuroscience. 1996; 70: 211-226
        • Calaresu FR
        • Yardley CP.
        Medullary basal sympathetic tone.
        Ann Rev Physiol. 1988; 50 ([review]): 511-524
        • Chalmers J
        • Pilowsky P.
        Brainstem and bulbospinal neurotransmitter systems in the control of blood pressure.
        J Hypertens. 1991; 9: 675-694
        • Reis DJ
        • Morrison S
        • Ruggiero DA.
        The C1 area of the brainstem in tonic and reflex control of blood pressure.
        Hypertension. 1988; 11: I8-I13
        • Weaver LC
        • Polosa C.
        Spinal cord circuits providing control of sympathetic pregangionic neurones.
        in: The autonomic nervous system: control of autonomic functions. Harwood Academic Publishers, London1994
        • Gray F
        • Vincent D
        • Hauw JJ.
        Quantitative study of lateral horn cells in 15 cases of multiple system atrophy.
        Acta Neuropathol. 1988; 75: 513-518
        • Oppenheimer DR.
        Lateral horn cells in progressive autonomic failure.
        J Neurol Sci. 1980; 46: 37-45
        • Spokes EGS
        • Bannister R
        • Oppenheimer DR.
        Multiple system atrophy with autonomic failure.
        J Neurol Sci. 1979; 43: 59-82
        • Krassioukov AV
        • Bunge RP
        • Puckett WR
        • Bygrave M.
        The changes in human spinal cord sympathetic preganglionic neurons after spinal cord injury.
        Spinal Cord. 1997; 37: 6-13
        • Krassioukov AC
        • Weaver LC.
        Anatomy of the autonomic nervous system.
        Phys Med Rehabil State of the Art Rev. 1996; 10: 1-14
        • Chiou-Tan FY
        • Lenz ML
        • Robertson CS
        • Grabois M.
        Pharmacologic treatment of autonomic dysreflexia in the rat.
        Am J Phys Med Rehabil. 1994; 73: 251-255
        • Krassioukov AC
        • Weaver LC.
        Episodic hypertension due to autonomic dysreflexia in acute and chronic spinal cord injured rats.
        Am J Physiol. 1995; 268: H2077-H2083
        • Osborn JW
        • Taylor RF
        • Schramm LF.
        Determinants of arterial pressure after chronic spinal transection in rats.
        Am J Physiol. 1989; 256: R666-R673
        • Green BA
        • Klose KJ.
        Acute spinal cord injury: emergency room care and diagnosis, medical and surgical management.
        in: Intensive care for neurological trauma and disease. Academic Press, New York1982: 249-269
        • Levi L
        • Wolf A
        • Belzberg H.
        Hemodynamic parameters in patients with acute cervical cors trauma: description, intervention, and prediction of outcome.
        Neurosurgery. 1993; 33: 1007-1017
        • Zipnick RI
        • Scalea TM
        • Trooskin SZ
        • Sclafani SJA
        • Emad B
        • Shah A
        • et al.
        Hemodynamic responses to penetrating spinal cord injuries.
        J Trauma. 1993; 35: 578-583
        • Kabalin JN
        • Lennon S
        • Gill HS
        • Wolfe V
        • Perkash I.
        Incidence and management of autonomic dysreflexia and other intraoperative problems encountered in spinal cord injury patients undergoing extracorporeal shock wave lithotripsy without anesthesia on a second generation lithotriptor.
        J Urol. 1993; 149: 1064-1067
        • Lindan R
        • Joiner E
        • Freehafter AA
        • Hazel C.
        Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury.
        Paraplegia. 1980; 18: 285-292
        • Cross LL
        • Meythaler JM
        • Tuel SM
        • Cross LA.
        Pregnancy, labor and delivery post spinal cord injury.
        Paraplegia. 1992; 30: 890-902
        • Finocchiaro DN
        • Herzfeld ST.
        Understanding autonomic dysreflexia.
        Am J Nursing. 1990; 90: 56-59
        • Uozumi T
        • Nakano S
        • Matsunaga K
        • Tsuji S
        • Murai Y.
        Sudormotor potential evoked by magnetic stimulation of the neck.
        Neurology. 1993; 43: 1397-1400
        • Murray M.
        Plasticity in the spinal cord: the dorsal root connection.
        Restorative Neurol Neurosci. 1980; 46: 393-404
        • Beattie MS
        • Bresnahan JC
        • Leedy MG.
        Synaptic plasticity in the adult sacral spinal cord: effects of lesions and hormones. Trophic factors and the nervous system.
        Raven Press Ltd, New York1990
        • Bloch RF.
        Autonomic dysfunction in management of spinal cord injuries.
        in: Management of spinal cord injuries. Williams & Wilkins, Baltimore1986: 149-163
        • Garnier VB
        • Gertsch R
        • Steinmann B.
        Vergleichende untersuchungen uber die wirkungen einer endogenen vegetativen erregung und intravenos verabriechten noradrenalins beim parplegiber.
        Cardiologia (Basel). 1964; 44: 167-176
        • Innes IR
        • Kosterlitz HW.
        The effects of preganglionic and postganglionic denervation on the responses of the nicitating membrane to sympathomimetic substances.
        J Physiol (Lond). 1954; 124: 25-43
        • Mathias CJ
        • Frankel HL.
        The neurological and hormonal control of blood vessels and heart in spinal man.
        J Autonom Nerv Syst. 1986; : 457-464
        • Rodriguez GP
        • Claus-Walker J
        • Kent MC
        • Stal S.
        Adrenergic receptors in insensitive skin of spinal cord injury patients.
        Arch Phys Med Rehabil. 1986; 67: 177-180
        • Osborn JW
        • Taylor RF
        • Schram LF.
        Chronic cervical spinal cord injury and autonomic hyperreflexia in rats.
        Am J Physiol. 1990; 258: R169-R174
        • Mallory BS.
        Autonomic function in the isolated spinal cord.
        in: 2nd ed. The physiological basis of rehabilitation medicine. Butterworth-Heinemann, Boston1994: 519-541
        • Mathias CJ
        • Christensen NJ
        • Frankel HL
        • Spalding JMK.
        Cardiovascular control in recently injured tetraplegics in spinal shock.
        Q J Med. 1979; 48: 273-287
        • Cole TM
        • Kottke FJ
        • Olson M
        • Stradal L
        • Niederloh J.
        Alterations of cardiovascular control in high spinal myelomalacia.
        Arch Phys Med. 1967; 48: 359-368
        • Corbett JL
        • DeBarge O
        • Frankel HL
        • Mathias CJ.
        Cardiovascular responses in tetraplegic man to muscle spasm, bladder percussion and head-up tilt.
        Clin Exp Pharmacol Physiol. 1975; : 189-193
        • Downey JA
        • Chiodi HP
        • Miller JM.
        The effect of inhalation of 5 per cent carbon dioxide in air on postural hypotension in quadriplegia.
        Arch Phys Med Rehabil. 1966; 47: 422-426
        • Koster M
        • Bethlem J.
        Paroxysmal hypertension in patients with spinal cord lesion (poikilopiesis spinalis).
        Arch Psychiatr Neurol Scand. 1960; 36: 347-368
        • Pollock LJ
        • Boshes B
        • Chor H
        • Finkelman I
        • Arieff AJ
        • Brown M.
        Defects in regulatory mechanisms of autonomic function in injuries to spinal cord.
        J Neurophysiol. 1951; 14: 85-93
        • Hopman MTE
        • Oeseburg B
        • Binkhorst RA.
        The effect of an anti-G suit on cardiovascular responses to exercise in persons with paraplegia.
        Med Sci Sports Exerc. 1992; 24: 984-999
        • Hopman MTE
        • Oeseburg B
        • Binkhorst RA.
        Cardiovascular responses in paraplegic subjects during arm exercise.
        Eur J Appl Physiol. 1992; 65: 73-78
        • Hopman MTE
        • Oeseburg B
        • Binkhorst RA.
        Cardiovascular responses with paraplegia to prolonged arm exercise and thermal stress.
        Med Sci Sports Exerc. 1993; 25: 577-583
        • Davis GM
        • Servedio FJ
        • Glaser GM
        • Gupta SC
        • Suryaprasad AG.
        Cardiovascular responses to arm-cranking and FNS-induced leg exercise in paraplegics.
        J Appl Physiol. 1990; 69: 671-677
        • Figoni SF.
        Exercise responses and quadriplegia.
        Med Sci Sports Exerc. 1993; 25: 433-441
        • Sawka MN
        • Gonzalez RR
        • Drolet LL
        • Pandoff KB.
        Temperature regulation during upper body exercise: able-bodied and spinal cord injured.
        Med Sci Sports Exerc. 1989; 21: 132-140
        • Krebs M
        • Ragnarrson KT
        • Tuckman J.
        Orthostatic vasomotor response in spinal man.
        Paraplegia. 1983; 21: 72-80
        • Krum H
        • Louis WJ
        • Brown DJ
        • Jackman GP
        • Howes LG.
        Diurnal blood pressure variation in quadriplegic chronic spinal cord injury patients.
        Clin Science. 1991; 80: 271-276
        • Glenn MB
        • Bergman SB.
        Cardiovascular changes following spinal cord injury.
        Top Spinal Cord Inj Rehabil. 1997; 2: 47-53
        • Dollfus P
        • Frankel HL.
        Cardiovascular reflexes in tracheostomised tetaplegics.
        Paraplegia. 1965; 2: 227-235
        • Frankel HL
        • Mathias CJ
        • Spalding JMK.
        Mechanisms of reflex cardiac arrest in tetraplegic patients.
        Lancet. 1975; ii: 1183-1195
        • Frankel HL
        • Mathias CJ.
        The cardiovascular system in paraplegia and tetraplegia.
        in: Handbook of clinical neurology.Vol. 26. North-Holland, Amsterdam1976: 313-333 (Injuries of the spine and spinal cord, part I)
        • Eriksson P
        • Lofstrom L
        • Ekblom B.
        Aerobic power during maximal exercise in untrained and well-trained persons with quadriplegia and paraplegia.
        Scand J Rehabil Med. 1988; 20: 141-147
        • Coutts KD
        • Rhodes EC
        • McKenzie DC.
        Maximal exercise responses of tetraplegics and paraplegics.
        J Appl Physiol. 1983; 55: 479-482
        • Burnham R
        • Wheeler G
        • Bhambhani Y
        • Belanger M
        • Eriksson P
        • Steadward R.
        Intentional induction of autonomic dysreflexia among quadriplegic athletes for performance enhancement: efficacy, safety and mechanism of action.
        Clin J Sport Med. 1994; 4: 1-10
        • Kiker JD
        • Woodstide JR
        • Jelinek GE.
        Neurogenic pulmonary edema associated with autonomic dysreflexia.
        J Urol. 1982; 128: 1038-1039
        • Guttman L
        • Whitteridge D.
        Effects of bladder distention on autonomic mechanism after spinal cord injuries.
        Brain. 1947; 70: 361-404
        • Finestone HM
        • Teasell RW.
        Autonomic dysreflexia following brainstem tumor resection.
        Am J Phys Med Rehabil. 1993; 72: 395-397
        • Bors E
        • Comarr AE.
        Neuroanatomy and neurophysiology.
        in: Neurological urology. University Park Press, New York1971: 61-125
        • Colachis SC.
        Autonomic hyperreflexia with spinal cord injury.
        J Am Paraplegia Soc. 1992; 15 ([review]): 171-186
        • Trop CS
        • Bennett CJ.
        Autonomic dysreflexia and its urological implications: a review.
        J Urol. 1991; 146: 1461-1469
        • Eltorai I
        • Kim P
        • Vulpe M
        • Kasravi H
        • Ho W.
        Fatal cerebral hemorrhage due to autonomic dysreflexia in a tetraplegic patient: case report and review.
        Paraplegia. 1992; 30: 355-360
        • Trop CS
        • Bennett CJ.
        The evaluation of autonomic dysreflexia.
        Semin Urol. 1992; 10 ([review]): 95-101
        • Crosby E
        • St-Jean B
        • Reid D
        • Elliott RD.
        Obstetric forum.
        Can J Anaesth. 1992; 39: 487-494
        • Kewalramani LS.
        Autonomic dysreflexia in traumatic myelopathy.
        Am J Phys Med Rehabil. 1980; 59: 1-21
        • Kursh ED
        • Freehafer A
        • Persky L.
        Complications of autonomic dysreflexia.
        J Urol. 1977; 118: 70-72
        • Sommers DK.
        Paroxysmal neurogenic hypertension and its prevention in patients with cervical spinal cord lesions.
        S Afr Med J. 1979; 56: 14-18
        • Bors E
        • French JD.
        Management of paroxysmal hypertension following injuries to cervical and upper thoracic segments of the spinal cord.
        Arch Surg. 1997; 64: 83-85
        • Barton CH
        • Kohonsari F
        • Vaziri ND
        • Byrne C
        • Gordon S
        • Friis R.
        The effect of modified transurethral sphincterotomy on autonomic dysreflexia.
        J Urol. 1986; 135: 83-85
        • Broecker BH
        • Hranowsky N
        • Hackler RH.
        Low spinal anesthesia for the prevention of autonomic dysreflexia in the spinal cord injury patient.
        J Urol. 1979; 122: 366
        • Brown BT
        • Carrion HM
        • Politano VA.
        Guanethidine sulfate in the prevention of autonomic hyperreflexia.
        J Urol. 1979; 122: 55-57
        • Dykstra DD
        • Sidi AA
        • Anderson LC.
        The effect of nifedipine on cystoscopy-induced autonomic hyperreflexia in patients with high spinal cord injuries.
        J Urol. 1987; 138: 1155-1157
        • Snow JC
        • Siderpoulos HP
        • Kripke BJ
        • Freed MM
        • Shah NK
        • Schlesinger RM.
        Autonomic hyperreflexia during cystoscopy in patients with high spinal cord injuries.
        Paraplegia. 1977; 15: 327-332
        • Sizemore GW
        • Winternitz WW.
        Autonomic hyperreflexia—suppression with alpha-adrenergic blocking agents.
        New Engl J Med. 1970; 282: 795
        • Thompson CE
        • Witham AC.
        Paroxysmal hypertension in spinal cord injuries.
        New Engl J Med. 1948; 239: 291-294
        • Colachis SC.
        Autonomic hyperreflexia with spinal cord injury.
        J Am Paraplegia Soc. 1997; 15: 171-186
        • Frankel HL
        • Mathias CJ.
        Severe hypertension in patients with spinal cord lesions undergoing electroejaculation—management with prostaglandin E2.
        Paraplegia. 1980; 18: 293-299
        • Steinberger RE
        • Ohl DA
        • Bennett CJ
        • McCabe M
        • Wange SC.
        Nifedipine pretreatment for autonomic dysreflexia during electroejaculation.
        Urology. 1990; 36: 228-231
        • Scott MB
        • Morrow JW.
        Phenoxybenzamine in neurogenic bladder dysfunction after spinal cord injury.
        J Urol. 1978; 119: 483-484
        • Abouleish EI
        • Hanely ES
        • Palmer SM.
        Can epidural fentanyl control autonomic hyperreflexia in a quadriplegic patient?.
        Anesth Analg. 1989; 68: 523-526
        • Guttman L
        • Frankel HL
        • Paeslack V.
        Cardiac irregularities during labor in paraplegic women.
        Paraplegia. 1965; 3: 141-151
        • Katz VL
        • Thorp Jr, JM
        • Cefalo RC.
        Epidural analgesia and autonomic hyperreflexia: a case report.
        Am J Obstet Gynecol. 1990; 162: 471-472
        • Tabsh KMA
        • Brinkman CRI
        • Reff RA.
        Autonomic dysreflexia in pregnancy.
        Obstet Gynecol. 1982; 60: 119-121
        • Vapnek TM.
        Autonomic dysreflexia.
        Top Spinal Cord Inj Rehabil. 1997; 2: 54-63
        • Donald IP
        • Gear MWL
        • Wilkinson SP.
        A life threatening respiratory complication of gastroesophageal reflux in a patient with tetraplegia.
        Postgrad Med J. 1987; 63: 397-399
        • Head H
        • Riddoch G.
        The automatic bladder, excessive sweating and some other reflex conditions in gross injuries of the spinal cord.
        Brain. 1917; 40: 188-263
        • Jane MJ
        • Freehafer AA
        • Hazel C
        • Lindan R
        • Joiner E.
        Autonomic dysreflexia. A cause of morbidity and mortality in orthopedic patients with spinal cord injury.
        Clin Orthop Rel Res. 1982; 169: 151-154
        • Hall PA
        • Young JV.
        Autonomic hyperreflexia in spinal cord injured patients: trigger mechanism-dressing changes of pressure sores.
        J Trauma. 1983; 23: 1074-1075
        • Ashley EA
        • Laskin JJ
        • Olenik LM
        • Burnham R
        • Steadward RD
        • Cumming DC
        • et al.
        Evidence of autonomic dysreflexia during functional electrical stimulation in individuals with spinal cord injuries.
        Paraplegia. 1993; 31: 593-605
        • Maynard FM.
        Early clinical experience with clonidine in spinal spasticity.
        Paraplegia. 1986; 24: 175-182
        • Lambert DH
        • Deane RS
        • Mazuzan JE.
        Anesthesia and the control of blood pressure in patients with spinal cord injury.
        Anesth Analg. 1982; 61: 344-348
        • Nieder RM
        • O'Higgins JW
        • Aldrete JA.
        Autonomic hyperreflexia in urologic surgery.
        JAMA. 1970; 213: 867-869
        • Schonwald G
        • Fish KJ
        • Perkash I.
        Cardiovascular complications during anesthesia in chronic spinal cord injured patients.
        Anesthesia. 1981; 55: 550-558
        • Stowe DF
        • Bernstein JS
        • Madsen KE
        • McDonald DJ
        • Ebert TJ.
        Autonomic hyperreflexia in spinal cord injured patients during extracoroporeal shock wave lithotripsy.
        Anesth Analg. 1989; 68: 788-791
        • Scher AT.
        Autonomic hyperreflexia. A serious complication of radiologic procedures in patients with cervical or upper thoracic spinal cord lesions.
        S Afr Med J. 1978; 53: 208-210
        • Colachis SC.
        Autonomic hyperreflexia in spinal cord injury associated with pulmonary embolism.
        Arch Phys Med Rehabil. 1991; 72: 1014-1016
        • Givre S
        • Freed HA.
        A potentially fatal complication of somatic stress in quadriplegics.
        J Emerg Med. 1989; 7: 461-463
        • McGarry J
        • Woolsey RM
        • Thompson CW.
        Autonomic hyperreflexia following passive stretching to the hip joint.
        Phys Ther. 1982; 62: 30-31
        • Khurana RK.
        Orthostatic hypotension—induced autonomic dysreflexia.
        Neurology. 1987; 37: 1221-1224
        • Wineinger MA
        • Basford JR.
        Autonomic dysreflexia due to medication: misadventure in the use of an isometheptene combination to treat migraine.
        Arch Phys Med Rehabil. 1985; 66: 645-646
        • Kurnick NB.
        Autonomic hyperreflexia and its control in patients with spinal cord lesions.
        Ann Intern Med. 1956; 44: 678-686
        • Harris P.
        Self-induced autonomic dysreflexia (“boosting”) practised by some tetraplegic athletes to enhance their athletic performance.
        Paraplegia. 1994; 32: 289-291
        • Eade NM.
        Paroxysmal hypertension in spinal cord injuries (autonomic hyperreflexia).
        N Z Med J. 1964; 63: 574-580
        • Krum H
        • Louis WJ
        • Brown DJ
        • Howes LG.
        Pressor doses responses and baroreflex sensitivity in quadriplegic spinal cord injury patients.
        J Hypertension. 1992; 10: 245-250
        • Krum H
        • Louis WJ
        • Brown DJ
        • Clarke SJ
        • Fleming JA
        • Howes LG.
        Cardiovascular and vasoactive hormone responses to bladder distension in spinal cord normal man.
        Paraplegia. 1992; 30: 348-354
        • Krum H
        • Louis WJ
        • Brown DJ
        • Howes LG.
        A study of the alpha-1 adrenoceptor blocker prazosin in the prophylactic management of autonomic dysreflexia in high spinal cord injury patients.
        Clin Auton Res. 1992; 2: 83-88
        • Ryder REJ
        • Kennedy RL
        • Newrick PG
        • Wilson RM
        • Ward JD
        • Hardisty CA.
        Autonomic denervation may be a prerequisite of diabetic neuropathic foot ulceration.
        Diabetic Med. 1990; 7: 726-730
        • Boulton AJM
        • Scarpello JHB
        • Ward JD.
        Venous oxygenation in the diabetic neuropathic foot: evidence of arteriovenous shunting?.
        Diabetologia. 1982; 22: 6-8
        • Van Dan Hoogen F
        • Brawn LA
        • Sherriff S
        • Watson N
        • Ward JD.
        Arteriovenous shunting in quadriplegia.
        Paraplegia. 1986; 24: 282-286
        • Mawson AR
        • Siddiqui FH
        • Connolly BJ
        • Sharp CJ
        • Summer WR
        • Biundo JJ.
        Sacral transcutaneous oxygen tension levels in spinal cord injured: risk factors for pressure ulcers?.
        Arch Phys Med Rehabil. 1993; 74: 745-751
        • Schubert V
        • Fagrell B.
        Postocclusive reactive hyperemia and thermal response in the skin microcirculation of subjects with spinal cord injury.
        Scand J Rehabil Med. 1991; 23: 33-40