Peripheral, autonomic regulation of locus coeruleus noradrenergic neurons in brain: putative implications for psychiatry and psychopharmacology

the new data seem to allow a better understanding of how autonomic vulnerability or visceral dysfunction may precipitate or aggravate mental symptoms and disorder.

T. H. Svensson¹

(1)	Department of Pharmacology, Karolinska Institute, Box 60 400, S-104 01 Stockholm, Sweden

Received: 20 June 1986 Revised: 25 November 1986
Psychopharmacology

"Locus coeruleus (LC) is located in the ventrallateral side of the fourth ventricle in the pontine, most of which are noradrenergic neurons projecting to the cortex, cingulate cortex, amygdala nucleus, thalamus, hypothalamus, olfactory tubercles, hippocampus, cerebellum, and spinal cord (Swanson and Hartman, 1975). Norepinephrine (NE) released from the nerve terminal of LC neurons contributes to about 70% of the total extracellular NE in primates brain (Svensson, 1987). It plays important roles not only in arousal, attention, emotion control, and stress (reviewed in Aston-Jones and Cohen, 2005; Berridge and Waterhouse, 2003; Bouret and Sara, 2005; Nieuwenhuis et al., 2005; Sara and Devauges, 1989; Valentino and Van Bockstaele, 2008), but also in sensory information processing (Svensson, 1987). LC directly modulates the somatosensory information from the peripheral system. Under the stress condition, LC could completely inhibit the input from painful stimuli through the descending projection to the spinal cord (Stahl and Briley, 2004). Dys-regulations of LC neurotransmission have been suggested to be involved in physical painful symptoms, attention deficit hyperactivity disorder (ADHD), sleep/arousal disorder, post-traumatic stress disorder, depression, schizophrenia, and Parkinson's disease (reviewed in Berridge and Waterhouse, 2003; Grimbergen et al., 2009; Mehler and Purpura, 2009)."
http://journal.frontiersin.org/Journal/10.3389/fnmol.2012.00029/full

Anesthesiol Res Pract. 2013;2013:413985. doi: 10.1155/2013/413985. Epub 2013 Oct 23.

Supraventricular arrhythmias after thoracotomy: is there a role for autonomic imbalance?

Vretzakis G1, Simeoforidou M, Stamoulis K, Bareka M.

Author information

Abstract

Supraventricular arrhythmias are common rhythm disturbances following pulmonary surgery. The overall incidence varies between 3.2% and 30% in the literature, while atrial fibrillation is the most common form. These arrhythmias usually have an uneventful clinical course and revert to normal sinus rhythm, usually before patent's discharge from hospital. Their importance lies in the immediate hemodynamic consequences, the potential for systemic embolization and the consequent long-term need for prophylactic drug administration, and the increased cost of hospitalization. Their incidence is probably related to the magnitude of the performed operative procedure, occurring more frequently after pneumonectomy than after lobectomy. Investigators believe that surgical factors (irritation of the atria per se or on the ground of chronic inflammation of aged atria), direct injury to the anatomic structure of the autonomic nervous system in the thoracic cavity, and postthoracotomy pain may contribute independently or in association with each other to the development of these arrhythmias. This review discusses currently available information about the potential mechanisms and risk factors for these rhythm disturbances. The discussion is in particular focused on the role of postoperative pain and its relation to the autonomic imbalance, in an attempt to avoid or minimize discomfort with proper analgesia utilisation.

http://www.ncbi.nlm.nih.gov/pubmed/24235971

"Since changes in old age show some similarities with those following chronic sympathectomy"

"For the tracheobronchial tree. surgical (sympathectomy) and chemical (with 6-hydroxydopamine or reserpine) interventions lead to histological disappearance of the NA and NPY." (p.435)

" Prejunctional supersensitivity to norepinephrine after sympathectomy or cocaine treatment." (p. 410)

"Following chronic sympathectomy, substance P expression in presumptive sensory nerves....and NPY-expression in parasympathetic nerves ...to autonomically innervated tissues have both been shown to increase... Experiments using NGF and anti-NGF antibodies (Kessler et al., 1983) have suggested that competition between sympathetic and sensory fibers for target-derived growth factors could explain these apparently compensatory interactions,..." (p. 33)

"Since changes in old age show some similarities with those following chronic sympathectomy, it is tempting to consider whether alterations in one group of nerves in tissues with multiple innervations trigger reciprocal changes in other populations of nerves, perhaps through the mechanism of competition for common, target-produced growth factors. The nature of these changes is such that they could be nonadaptive and even destabilizing of cardiovascular homeostasis. (p. 34) 

Impairment of sympathetic and neural function has been claimed in cholesterol-fed animals (Panek et al., 1985). It has also been suggested that surgical sympathectomy may be useful in controlling atherosclerosis in certain arterial beds (Lichter et al., 1987). Defective cholinergic arteriolar vasodilation has been claimed in atherosclerotic rabbits (Yamamoto et al., 1988) and, in our laboratory, we have recently shown impairment of response to perivascular nerves supplying the mesenteric, hepatic, and ear arteries of Watanabe heritable hyperlipidemic rabbits (Burnstock et al., 1991). 
   Loss of adrenergic innervation has been reported in alcoholism (Low et al., 1975), amyloidosis (Rubenstein et al., 1983), orthostatic hypotension (Bannister et al., 1981), and subarachnoid haemorrhage (Hara and Kobayashi, 1988). Recent evidence shows that there is also a loss of noradrenergic innervation of blood vessels supplying malignant, as compared to benign, human intracranial tumours (Crockard et al., 1987). (p. 14)  

Vascular Innervation and Receptor Mechanisms: New    Perspectives 

Rolf Uddman

Academic Press, 2 Dec 2012 - Medical - 498 pages

sympathectomy leads to fluctuation of vasoconstriction alternated with vasodilation in an unstable fashion. Following sympathectomy the involved extremity shows regional hyper - and hypothermia

"To quote Nashold, referring to sympathectomy, "Ill- advised surgery may tend to magnify the entire symptom complex"(38). Sympathectomy is aimed at achieving vasodilation. The neurovascular instability (vacillation and instability of vasoconstrictive function), leads to fluctuation of vasoconstriction alternated with vasodilation in an unstable fashion (39). Following sympathectomy the involved extremity shows regional hyper - and hypothermia in contrast, the blood flow and skin temperature on the non- sympathectomized side are significantly lower after exposure to a cold environment (39). This phenomenon may explain the reason for spread of CRPS. In the first four weeks after sympathectomy, the Laser Doppler flow study shows an increased of blood flow and hyperthermia in the extremity (40). Then, after four weeks, the skin temperature and vascular perfusion slowly decrease and a high amplitude vasomotor constriction develops reversing any beneficial effect of surgery (39). According to Bonica , "about a dozen patients with reflex sympathetic dystrophy (RSD) in whom I have carried out preoperative diagnostic sympathetic block with complete pain relief, sympathectomy produced either partial or no relief (40)"

Chronic Pain: 

 Reflex Sympathetic Dystrophy : Prevention and Management

Hooshang Hooshmand

CRC PressINC, 1993 - Medical - 202 pages

Despite the simplicity and rapidity of the procedure, some patients experience intense, in some cases persistent, postoperative pain

Jornal Brasileiro de Pneumologia - The incidence of residual pneumothorax after video-assisted sympathectomy with and without pleural drainage and its effect on postoperative pain:

"Anteroposterior chest X-ray in the orthostatic position, while inhaling, was absolutely normal in 18 patients (32.1%), and residual pneumothorax was detected in 17 patients (30.4%). When the patients were separated into two groups (those who had received drainage and those who had not), 25.9% (7 patients) and 34.4% (10 patients), respectively, presented residual pneumothorax, with no difference between the two groups (p = 0.48) (Figure 1).

The additional alterations were laminar atelectasis and emphysema of the subcutaneous cellular tissue.

Chest X-rays in the orthostatic position, while exhaling, revealed residual pneumothorax in 39.3% (22 patients) and was absolutely normal in 25% (14 patients). On the same X-rays, when patients were analyzed separately, residual pneumothorax was seen in 33.3% of the patients who had received drainage (9 patients) and in 44.8% (13 patients) of those who had not, with no difference between the two groups (p = 0.37) (Figure 1).

The low-dose computed tomography scans of the chest detected residual pneumothorax in 76.8% (43 patients). In the patients submitted to postoperative drainage, this rate was 70.3% (19 patients), compared with 82.7% (24 patients) in those without pleural drainage, with no difference between the two groups (p = 0.27) (Figure 1). Therefore, the overall rate of occult pneumothorax (only visible through tomography), revealed on anteroposterior X-rays was 35.7% (20 patients): 48.2% while patients were inhaling and 41.1% while patients were exhaling. The VAS score in the PACU ranged from 0 to 10, with a mean of 2.16 ± 0.35.

Regarding characteristics, 44.6% of the patients reported chest pain upon breathing and 32.1% reported retrosternal pain. The same evaluation performed in the infirmary, during the immediate postoperative period, ranged from 0 to 10, with a mean of 3.75 ± 0.30, being 69.6% of chest pain upon breathing and 78.6% of retrosternal pain. On postoperative day 7, according to VAS, pain ranged from 0 to 10, with a mean of 2.05 ± 0.31; regarding characteristics, it was continuous in 32.1% of the cases, and retrosternal in 26.8%. On postoperative day 28, pain ranged from 0 to 3, with a mean of 0.17 ± 0.08, 7.1% of mechanical rhythm and 5.4% upper posterior."

Jornal Brasileiro de Pneumologia

Print version ISSN 1806-3713

J. bras. pneumol. vol.34 no.3 São Paulo Mar. 2008

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1806-37132008000300003&lng=en&nrm=iso&tlng=en

Our data confirmed that sympathectomy in patients with EPH results in a disturbance of bronchomotor tone and cardiac function

Our study was composed of patients affected by EH, and thus having a dysfunction of sympathetic activity. The observed respiratory and clinical effects would probably not be observed in healthy individuals.

(ii) The cardio-respiratory effects were observed 6 months after operation. However, a longer postoperative period would be required to determine if they are long-term effects.

(iii) The number of patients was too limited, thus our results should be corroborated by larger studies.

CONCLUSION

Our data confirmed that sympathectomy in patients with EPH results in a disturbance of bronchomotor tone and cardiac function.

1. 
   

   Eur J Cardiothorac Surg (2012)

   doi: 10.1093/ejcts/ezs071

Scientists have created a device that can beat arthritis agony - vagus nerve stimulation for arthritis and other disorders

Scientists have created a device that can beat arthritis agony | Health | Life & Style | Daily Express: "Tiny pacemaker-style devices embedded in the necks of patients with chronic rheumatoid arthritis "hacked" into their nervous systems.

The implant fires bursts of electrical impulses into a key nerve that relays brain signals to the body's vital organs.

Scientists, conducting a groundbreaking trial of the implant, say more than half found their condition dramatically improved.

More than 400,000 patients in the UK are affected by the debilitating disease. Now researchers believe the same technique, which can eliminate the need for a daily cocktail of drugs, could reverse conditions like asthma, obesity and diabetes.

The findings, revealed to Sky News, will be published in the new year.

We may be able to achieve remission in 20 to 30 per cent of patients
Paul-Peter Tak, Rheumatologist Professor
More than half the 20 patients taking part in tests at the Academic Medical Centre in Amsterdam have shown significant improvement.

Rheumatologist Professor Paul-Peter Tak said even for those unaffected by the most modern medicines, they saw an improvement.

"We may be able to achieve remission in 20 to 30 per cent of patients - a huge step forward in the treatment of rheumatoid arthritis," he added.

Doctors hope the implant could be widely used within a decade, but concede they do not yet fully understand how it has such a powerful effect. It stimulates the vagus nerve, which connects the brain to major organs.

By firing impulses for just three minutes a day, scientists were able to reduce the activity of the spleen, a key organ in the immune system.

Within a matter of days, the organ produced fewer chemicals and other immune cells that cause the abnormal inflammation in the joints of people with rheumatoid arthritis.

Kris Famm, who is leading the research, said: "I hope that in 10 to 20 years if you or I had diabetes, we would go to the doctor and there is an option for this sort of device."

Patient Monique Robroek was in so much pain she struggled to walk across a room, despite taking the strongest possible arthritis drugs.

She had an implant fitted under her skin a year ago and has now stopped taking medication and is pain free.

"I have my normal life back," she said. "Within six weeks I felt no pain. It is like magic.""



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"sympathicotomy may cause a temporary impairment of the caudal-to-rostral hierarchy of thermoregulatory control and changes in microcirculation"

Patients with palmar hyperhidrosis have been reported to have a much
more complex dysfunction of autonomic nervous system, involving compensatory high parasympathetic activity as well as sympathetic overactivity (13, 14), suggesting that sympathicotomy initially induces a sympathovagal imbalance with a parasympathetic predominance, and that this is restored on a long-term basis (14). Therefore, thoracic sympathicotomy may cause a temporary impairment of the caudal-to-rostral hierarchy of thermoregulatory control and changes in microcirculation.

The reduction of finger skin temperature on the non-denervated side may be due to either a decrease in the cross-
inhibitory effect or the abnormal control of the inhibitory fibers by the sudomotor center (6).
Vasoconstrictor neurons have been found to be largely under the inhibitory control of various afferent
input systems from the body surface, whereas sudomotor neurons are predominantly under excitatory
control (15). The basic neuronal network for this reciprocal organization is probably located in the spinal level (15). Therefore, the reduction in the contralateral skin temperature may be explained by cross-inhibitory control of various afferent in the spinal cord.
In particular, our study showed that, following bilateral T3 sympathicotomy, the skin temperatures on
the hands increased whereas the skin temperatures on the feet decreased. These findings suggest a
cross-inhibitory control between the upper and lower extremities. However, the pattern of skin
temperature reduction on the feet differed from that on the contralateral hand. The skin temperature on
the feet did not decrease after right T3 sympathicotomy but decreased significantly after bilateral T3
sympathicotomy.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722005/

functional abnormality detected in the small airway of patients who underwent bilateral dorsal sympathectomy to treat primary hyperhidrosis is still present 3 years after surgery

The main observation of our study was that the functional abnormality detected in the small airway of patients who underwent bilateral dorsal sympathectomy to treat primary hyperhidrosis is still present 3 years after surgery, although the patients remain clinically asymptomatic.

Studies to date evaluate alterations in lung function at 1, 3, and 6 months after sympathectomy. Only 1 recent study provides data 1 year after surgery. Ponce González et al¹⁰ studied a group of 37 patients who underwent forced spirometry before surgery, and at 3 months and 1 year after surgery. They observed a decrease in FVC, FEV₁, and FEF_25%-75% at 3 months, although FVC returned to baseline values at 12 months, whereas FEV₁ and FEF_25%-75% remained significantly low (-2.8% and -11.2%, respectively). These findings are consistent with ours, and corroborate the persistence of minimal bronchial obstruction 3 years after surgery. This appears to be associated with the influence of the sympathetic nervous system on bronchomotor tone.

As previously mentioned, the airway is innervated mainly by the parasympathetic nervous system. Sympathetic innervation, although scant, indirectly affects motor tone and could have caused the mild residual obstructive pattern after surgery. Despite the doubtful role of the sympathetic nervous system in the lung, a series of physiologic studies show the effect of sympathetic nervous activity after bilateral dorsal sympathectomy.^11,12 The first was by Noppen and Vincken⁴, who compared the results of lung function studies (spirometry, diffusion, and lung volumes using plethysmography) in 7 patients before dorsal sympathectomy performed using VATS, at 6 weeks, and at 6 months (previous studies had been performed using invasive techniques [thoracotomy]). A statistically significant decrease was observed in FEV₁, FEF_25%-75%, and total lung capacity 6 weeks after surgery. At 6 months, the authors again evaluated the 35 patients and found that total lung capacity had returned to normal values, whereas FEF_25%-75% remained low. They attributed the permanent decrease in FEF_25%-75% to the sympathetic denervation produced by surgery, and stressed that, in patients with primary hyperhidrosis, bronchomotor tone is influenced by the sympathetic nervous system. This contrasts with the common opinion that motor tone in the airway is not affected by this system. Both the study by Ponce González et al,¹⁰ who evaluated their patients at 1 year, and our study, in which we evaluated patients at 3 years, show that persistence of the decrease in FEF_25%-75% over time is related more to sympatholysis of the ganglia than to VATS.

http://www.archbronconeumol.org/en/bilateral-dorsal-sympathectomy-for-the/articulo/13147806/

Effect of ganglion blockade on cerebrospinal fluid norepinephrine

Prevention of ganglion blockade-induced hypotension using phenylephrine did not prevent the decrease in CSF NE caused by trimethaphan, and when phenylephrine was discontinued, the resulting hypotension was not associated with increases in CSF NE. The similar decreases in plasma NE and CSF NE during ganglionic blockade, and the abolition of reflexive increases in CSF NE during hypotension in ganglion-blocked subjects, cast doubt on the hypothesis that CSF NE indicates central noradrenergic tone and are consistent instead with at least partial derivation of CSF NE from postganglionic sympathetic nerve endings.

 http://www.mendeley.com/research/effect-of-ganglion-blockade-on-cerebrospinal-fluid-norepinephrine/

"sympathectomy, although having varying results, does seem to increase the severity of autoimmune disorders"

Allostasis - a state of imbalance responsible for Autoimmune disorders

In general, enhancing the sympathetic tone decreases both T0-cell and NK cell functions but not the proliferation of splenic B cells (Dowdell and Whitacre, 2000). In contrast, chemical sympathectomy, although having varying results, does seem to increase the severity of autoimmune disorders (Dowdell and Whitacre, 2000)
As far as metabolism, catecholamines promote mobilization of fuel stores at time of stress and act synergistically with glucocorticoids to increased glycogenolysis, gluconeogenesis, and lipolysis but exert opposing effects of protein catabolism, as noted earlier. One important aspect is regulation of body temperature (Goldsttein and Eisenhofer, 2000) Epinephrine levels are also positively related to serum levels of HDL cholesterol and negatively related to triglycerines. However, perturbing the balance of activity of various mediators or metabolism and body weight regulation can lead to well-known metabolic disorders such as type 2 diabetes and obesity.

At the same time, increased sympathetic activitation and nerephinephrine release is elevated in hypertensive individuals and also higher levels of insulin, and there are indications that insulin further increases sympathetic activity in a vicious cycle (Arauz-Pacheco et al.,1996)

As a result of either local production, cytokines often enter the the circultion and can be detected in plasma samples. Sleep deprivation and psychological stress, such as public speaking, are reported to elevate inflammatory cytokine level in blood (Altemus et al., 2001) Circulting levels of a number of inflammatory cytokines are elevated in relation to viral and other infections and contirbute to the feeling of being sick, as well as sleepiness, wiht both direct and indirect effects on the central nervous system (Arkins et al., 2000; Obal and Kueger, 2000)

Inflammatory autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes, reflect an allostatic state that consists of at least three principal causes: genetic risk factors, (...) factors that contribute to the development of tolerance of self-antigens (...) and the hormonal mikieu that regulates adaptive immunes responses (Dowdell and Whitacre, 2000)

Allostasis, homeostasis and the costs of physiological adaptation

By Jay SchulkinCambridge University Press, 2004

Allostasis is the process of achieving stability, or homeostasis, through physiological or behavioral change. This can be carried out by means of alteration in HPA axishormones, the autonomic nervous system, cytokines, or a number of other systems, and is generally adaptive in the short term ^[1]

Orthostatic syncope can occur after a spinal cord injury or sympathectomy

Neurocardiogenic syncope is also referred to as vasovagal, vasodepressor, neurally mediated, and reflex syncope. As the name implies, neurocardiogenic syncope involves the interaction of various autonomic nervous system reflexes, the central nervous system, and the cardiovascular system..sup.1,4,12-14 The Bezold-Harisch reflex is cited as the mechanism responsible for vasovagal syncope and has two components. There is "cardio-inhibitory syncope" due to a vagal (parasympathetic) mediated reflex causing bradycardia or even asystole, plus "vasodepressor syncope" from withdrawal of sympathetic input leading to a drop in PVR with venous pooling in the periphery leading to hypotension.

Vasovagal syncope can occur in heart transplant patients, suggesting that the Bezold-Harisch reflex or vagal stimulation plus sympathetic withdrawal as the only factor may be a somewhat simplistic explanation, and that other variables may also play a role.

Although there are many causes of cardiovascular syncope, the final common mechanism is a decrease in cardiac output causing a decrease in cerebral perfusion.
Orthostatic syncope can occur after a spinal cord injury or sympathectomy, which eliminates
the vasopressor reflexes, and in patients on certain medications, commonly antihypertensive and
vasodilator drugs.
http://www.thefreelibrary.com/Syncope+in+Pediatric+Patients-a0217945432

"Similar low values are observed in patients with sympathectomy and in patients with tetraplegia"

"Patients with progressive autonomic dysfunction (including diabetes) have little or no increase in plasma noradrenaline and this correlates with their orthostatic intolerance (Bannister, Sever and Gross, 1977). In patients with pure autonomic failure, basal levels of noradrenaline are lower than in normal subjects (Polinsky, 1988). Similar low values are observed in patients with sympathectomy and in patients with tetraplegia. (p.51)

The finger wrinkling response is abolished by upper thoracic sympathectomy. The test is also abnormal in some patients with diabetic autonomic dysfunction, the Guillan-Barre syndrome and other peripheral sympathetic dysfunction in limbs. (p.46)

Other causes of autonomic dysfunction without neurological signs include medications, acute autonomic failure, endocrine disease, surgical sympathectomy . (p.100)

Anhidrosis is the usual effect of destruction of sympathetic supply to the face. However about 35% of patients with sympathetic devervation of the face, acessory fibres (reaching the face through the trigeminal system) become hyperactive and hyperhidrosis occurs, occasionally causing the interesting phenomenon of alternating hyperhidrosis and Horner's Syndrome (Ottomo and Heimburger, 1980). (p.159)



Disorders of the Autonomic Nervous System
By David Robertson, Italo Biaggioni
Edition: illustrated
Published by Informa Health Care, 1995
ISBN 3718651467, 9783718651467"

Patients with surgical sympathectomies have low plasma levels of DA and NE [49], whereas EPI:NE ratios are increased

Patients with surgical sympathectomies have low plasma levels of DA and NE [49], whereas EPI:NE ratios are increased (unpublished observations), suggesting decreased sympathetically mediated exocytosis and compensatory adrenomedullary activation.   

Catecholamines 101, David S. Goldstein Clin Auton Res (2010) 20:331–352

sympathectomy results in a pronounced increase of cerebrospinal fluid production

Electrical stimulation of the sympathetic nerves, which originate in the superior cervical ganglia, induces as much as 30% reduction in the net rate of cerebrospinal fluid (CSF) production, while sympathectomy results in a pronounced increase, about 30% above control, in the CSF formation. There is strong reason to believe that the choroid plexus is under the influence of a considerable sympathetic inhibitory tone under steady-state conditions.

http://ukpmc.ac.uk/abstract/MED/6276421

"Sympathectomy is a destructive procedure that interrupts the sympathetic nervous system"

Cervico-thoracic or lumbar sympathectomy for neuropathic pain | Cochrane Summaries: "Sympathectomy is a destructive procedure that interrupts the sympathetic nervous system. Chemical sympathectomies use alcohol or phenol injections to destroy sympathetic nervous tissue (the so-called "sympathetic chain" of nerve ganglia). Surgical ablation can be performed by open removal or electrocoagulation (destruction of tissue with high-frequency electrical current) of the sympathetic chain, or by minimally invasive procedures using thermal or laser interruption. Nerve regeneration commonly occurs following both surgical or chemical ablation, but may take longer with surgical ablation.

This systematic review found only one small study (20 participants) of good methodological quality, which reported no significant difference between surgical and chemical sympathectomy for relieving neuropathic pain. Potentially serious complications of sympathectomy are well documented in the literature, and one (neuralgia) occurred in this study.

The practice of sympathectomy for treating neuropathic pain is based on very weak evidence. Furthermore, complications of the procedure may be significant."



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The biology and control of surface overhealing

Lesions of “surface overhealing” include keloid, hypertrophic scar, and burn scar. All are characterized by overabundant collagen deposition. The biology of these lesions is reviewed, suggesting that abnormal collagen metabolism results from alterations in the inflammatory/immune response. Practical and theoretical treatment plans are outlined based on methods that alter collagen metabolism, the inflammatory/immune system or rely on physical alterations (surgery, pressure).

http://www.springerlink.com/content/3g2mr5r32m438125/

Blood diverted from muscle to skin after sympathectomy

However, the clinical results of both surgical and neurolityc sympathectomy are uncertain. Indeed these procedures lead to a redistribution of the blood flow in the lower limbs from the muscle to the skin, with a concomitant fall of the regional resistance, mainly in undamaged vessels. The blood flow will be diverted into this part of the vascular tree, so that a "stealing" of the blood flow may occur.

Vito A. Peduto, Giancarlo Boero, Antonio Marchi, Riccardo Tani

Bilateral extensive skin necrosis of the lower limbs following prolonged epidural blockade

Anaesthesia 1976; 31: 1068-75.

sympathectomy must somehow quiet the contralateral spread of spinal cord hyperexcitability underlying mirror-image pain

Blocking sympathetic function, whether by surgical sympathectomy, systemic phentolamine, or systemic guanethidine, relieves partial nerve injury-induced neuropathic pain in laboratory animal models as well as humans (8, 35, 146, 239, 278). Indeed, sympathectomy does not just relieve pathological pain in the body region ipsilateral to the CRPS-initiating event; rather, it also relieves pain arising from anatomically impossible mirror-image sites, that is, the identical body region contralateral to the initiating event (278). Thus sympathectomy must somehow quiet the contralateral spread of spinal cord hyperexcitability underlying mirror-image pain. 

Alterations in sympathetic fibers rapidly follow peripheral nerve injury. This occurs as sprouting of sympathetic fibers, creating aberrant communication pathways from the new sympathetic terminals to sensory neurons (35). Sympathetic sprouting has been documented in the region of peripheral terminal fields of sensory neurons (262), at the site of nerve trauma (57), and within the dorsal root ganglia (DRG) containing cell bodies of sensory neurons (248, 343). Each of these sites develops spontaneous activity and sensitivity for catecholamines and sympathetic activation (8, 53). 

The clearest evidence that immune activation participates in sympathetic sprouting comes from studies of the DRG. DRG cells receive signals that peripheral nerve injury has occurred via retrograde axonal transport from the trauma site. These retrogradely transported signals trigger sympathetic nerve sprouting into DRG (205, 308). As a result of nerve damage-induced retrogradely transported signals, glial cells within the DRG (called satellite cells) proliferate (248) and become activated (343); macrophages are recruited to the DRG as well (63, 176). In turn, the activated satellite glial cells (and, presumably, the macrophages) release proinflammatory cytokines and a variety of growth factors into the extracellular fluid of the DRG (206, 246 –248, 258, 277, 308, 358). These substances stimulate and direct the growth of sympathetic fibers, which form basket-like terminals around the satellite cells that, in turn, surround neuronal cell bodies (247, 248, 343). 

Until recently, the sympathetic sprouting, rather than the glial (satellite cell) activation, has attracted the attention of pain researchers. The satellite cells were ignored as they were thought to be irrelevant to the creation of exaggerated pain states. However, it may be speculated that the satellite cells, rather than the sympathetic sprouts, have the most impact on pain.

Physiol Rev • VOL 82 • OCTOBER 2002 • www.prv.org

Beyond Neurons: Evidence That Immune and Glial Cells 

Contribute to Pathological Pain States 

LINDA R. WATKINS AND STEVEN F. MAIER 

Department of Psychology and the Center for Neuroscience, 

University of Colorado at Boulder, Boulder, Colorado 

RA, lupus and other connective tissue disorders may have abnormalities of sympathetic postganglionic function

Rheumatoid arthritis, systemic lupus erythematosus, and other connective tissue disorders may have abnormalities of sympathetic postganglionic function. Some of these patients may have autoantibodies to ganglionic acetylcholine receptors. Autoimmune thyroiditis, as with chronic thyroiditis and Hashimoto thyroiditis, can be associated with some features of Sjögren syndrome such as xerostomia. Patients with systemic sclerosis and mixed connective tissue disorder may have abnormalities of autonomic functioning of esophageal motor activity.

http://www.emedicine.com/NEURO/topic720.htm

The sympathetic nervous system stimulates anti-inflammatory B cells in collagen-type II-induced arthritis

Ann Rheum Dis 2012;71:432–439. doi:10.1136/ard.2011.153056 

Ablation of the Sympathetic Nervous System Decreases Gram-Negative and Increases Gram-Positive Bacterial Dissemination: Key Roles for Tumor Necrosis Factor/Phagocytes and Interleukin-4/Lymphocytes

In both models, the peritoneal wall was the critical border for systemic infection. These results show the dual role of the sympathetic nervous system in sepsis. It can be favorable or unfavorable, depending on the innate immune effector mechanisms necessary to overcome infection

There is now agreement that sepsis and the systemic inflammatory response syndrome are accompanied by a dysregulation of the inflammatory response. During the onset of sepsis, the inflammatory system becomes hyperactive, evoking a strong anti-inflammatory feedback response by the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). 

http://jid.oxfordjournals.org/content/192/4/560.full

• Oxford Journals
• Medicine & Health
• The Journal of Infectious Diseases
• Volume 192, Issue 4
• Pp. 560-572.

peripheral sympathectomy causes a dramatic increase in NGF levels in the denervated organs

Increased Nerve Growth Factor Messenger RNA and Protein

Peripheral NGF mRNA and protein levels following sympathectomy
It has been shown previously that peripheral sympathectomy
causes a dramatic increase in NGF levels in the denervated
organs (Yap et al., 1984; Kanakis et al., 1985; Korsching and
Thoenen, 1985).
Increased ,&Nerve Growth Factor Messenger RNA and Protein
Levels in Neonatal Rat Hippocampus Following Specific Cholinergic
Lesions
Scott R. Whittemore,” Lena Liirkfors,’ Ted Ebendal,’ Vicky R. Holets, 2,a Anders Ericsson, and HBkan Persson
Departments of Medical Genetics and’ Zoology, Uppsala University, S-751 23 Uppsala, Sweden, and *Department of
Histology, Karolinska Institute, S-104 01 Stockholm, Sweden

Permanent pain following sympathectomy

The mean inpatient pain scores were significantly higher in the biportal group (1.2±0.6) than that in the uniportal group (0.8±0.5, P=0.025). For the first three weeks after operation, four out of 20 (20%) patients in the uniportal group constantly suffered from mild or moderate residual pain while eight out of 25 (32%) cases in the biportal group (P=0.366). Among them, two cases in the uniportal group and five cases in the biportal group need to take analgesics.
Chinese Medical Journal, 2009, Vol. 122 No. 13 : 1525-1528

sympathectomy affects the heart, sweating, and circulation

heart rate was significantly reduced at rest (14%), at sub-maximal exercise (12.3%), and at peak exercise (5.7%), together with a significant increase in oxygen pulse (11.8, 12.7, and 7.8%, respectively). The rate pressure product (RPP) was also significantly reduced following the surgical procedure at all three study stages, while all other physiological variables measured remained unchanged. It is suggested that thoracic-sympathetic denervation affects the heart, sweating, and circulation of the respective denervated region

Eur J Appl Physiol. 2008 Sep;104(1):79-86. Epub 2008 Jun 10.

significant adverse effects on cardiopulmonary physiology

Because of technologic advances and improved postoperative recovery, endoscopic surgery has become the technique of choice for many thoracic surgical procedures^6and 25; however, endoscopic visualization of intrathoracic structures requires retraction or collapse of the ipsilateral lung, which can have significant adverse effects on cardiopulmonary physiology. These cardiopulmonary changes can be further affected by the pathophysiologic changes associated with the disease process requiring the surgical procedure.

Because acute changes in cardiopulmonary function can compromise patient safety severely, a clear understanding of the dynamic interaction between the anesthetic–surgical technique and patient physiology is essential. This article discusses the effect of thoracoscopic surgery and the impact of various anesthetic interventions on cardiovascular and pulmonary physiology. In addition, some recommendations for “damage control” are made.

Anesthesiology Clinics of North America
Volume 19, Issue 1, 1 March 2001, Pages 141-152

Removal of noradrenergic innervation by sympathectomy enhanced the severity of symptoms in EAE

Sympathetic regulation of Autoimmune Disease

In animal models of human autoimmune disease, alterations in sympathetic innervation, NE concentration and lymphocyte AR expression have been demonstrated. ....reduced splenic noradrenergic innervation and decreased splenic NE concentration were apparent before the onset os disease symptoms. In myelin basic protein-induced EAE and MS-like disease, a reduction in splenic NE concentration was reported at the time of maximal antigen-induced lymphocyte proliferation and was accompanied by an increase in the density of of splenic lymphocyte beta-AR. In chronic/relapsing EAE (CREAE) induced in rats, splenocyte beta-AR density correlated positively with the severity of CREAE. Removal of noradrenergic innervation by chemical sympathectomy with 6-OHDA enhanced the severity of symptoms in EAE...

Neuropsychiatry  By Randolph B. Schiffer, Stephen M. Rao, Barry S. Fogel Published 2003 Lippincott Williams & Wilkins

Postsympathectomy pain of such severity that parenteral narcotics afforded no relief

Fifty-six consecutive patients who subsequently underwent ninety-six lumbar sympathectomies were studied prospectively with regard to the development of postoperative pain. Pain after operation was observed in thirty-four extremities by twenty-five of the patients (35 per cent). It began abruptly an average of twelve days after operation and was often accentuated nocturnally. The pain was almost always described as a deep, dull ache and persisted two to three weeks before spontaneously remitting. Postsympathectomy pain of such severity that parenteral narcotics afforded no relief developed in two of these fifty-six patients and in nine additional patients. Treatment with carbamazepine produced dramatic reduction in the intensity of pain in seven of these nine patients within twenty-four hours after the institution of therapy. Two patients were given intravenous diphenylhydantoin and both experienced immediate relief of pain. The mechanisms of the syndrome and of the action of these drugs are uncertain.

http://www.sciencedirect.com/science/article/pii/0002961074902384

Sympathetic denervation leads to loss of an important regulatory mechanism in immune system physiology

Sympathectomy decreased CD4+ T-cells in lymph nodes Alterations in lymphocyte activity does not always correlate with changes in the proportions of T- or B-lymphocyte subsets. Sympathetic denervation leads to loss of an important regulatory mechanism in immune system physiology. This is apparently site specific in that both lymph node and spleen T-cell proliferative responses are reduced.
Article by Dr. Brian A. Smith
http://home.earthlink.net/~doctorsmith/hivandchiro.htm

Degeneration patterns of postganglionic fibers following sympathectomy

In the muscle nerves the first signs of an axonal degeneration of the sympathetic fibers can be recognized 4 days after surgery. The signs of axonal degeneration are most striking about 8 days p.o. They have more or less disappeared another week later. The reactions of the Schwann cells also start on the fourth day but outlast the degenerative processes by some 8 days. Thus the degenerative and reactive processes in the reg precede those in the muscle nerves by 2 days early after surgery and by 6 days 3 weeks later. Seven weeks after surgery, fragments of folded basement lamella and Remak bundles with condensed cytoplasm and numerous flat processes are persisting signs of the degeneration.
K. H. Andres, M. von Düring, W. Jänig and R. F. Schmidt
Anatomy and Embryology
Springer Berlin / Heidelberg
Volume 172, Number 2 / August, 1985
http://www.springerlink.com/content/m21m2612n2147011/

Pain in the form of intercostal neuralgia with dysesthesia at the site of trocar insertion is rarely documented but more frequent than generally recognized

Pain in the form of intercostal neuralgia with dysesthesia at the site of trocar insertion is rarely documented but more frequent than generally recognized. Many centres perform short-stay surgery that may lead to underestimation of pain results. In most series pain resolves within months, but Walles and colleagues could detect a persistence for years (Walles et al., 2008).

http://www.intechopen.com/books/topics-in-thoracic-surgery/surgical-management-of-primary-upper-limb-hyperhidrosis-a-review

Patients with surgical sympathectomies have low plasma levels of DA and NE [49], whereas EPI:NE ratios are increased

Patients with surgical sympathectomies have low plasma levels of DA and NE [49], whereas EPI:NE ratios are increased (unpublished observations), suggesting decreased sympathetically mediated exocytosis and compensatory adrenomedullary activation.

Catecholamines 101, David S. Goldstein
Clin Auton Res (2010) 20:331–352

The mechanisms by which sympathectomy leads to increased local bone loss is unknown

In vivo effects of surgical sympathectomy on intra... [Am J Otol. 1996] - PubMed - NCBI: "Am J Otol. 1996 Mar;17(2):343-6.

In vivo effects of surgical sympathectomy on intramembranous bone resorption.
Sherman BE1, Chole RA.
Author information
1Department of Otolaryngology--Head and Neck Surgery, School of Medicine, University of California, Davis, USA.
Abstract
Bone modeling and remodeling are highly regulated processes in the mammalian skeleton. The exact mechanism by which bone can be modeled at a local site with little or no effect at adjacent anatomic sites is unknown. Disruption of the control of modeling within the temporal bone may lead to various bone disease such as otosclerosis, osteogenesis imperfecta, Paget's disease of bone, fibrous dysplasia, or the erosion of bone associated with chronic otitis media. One possible mechanism for such delicate control may be related to the ubiquitous and rich sympathetic innervation of all periosteal surfaces. Previous studies have indicated that regional sympathectomy leads to qualitative alterations in localized bone modeling and remodeling. In this study, unilateral cervical sympathectomy resulted in significant increases in osteoclast surface and osteoclast number within the ipsilateral bulla of experimental animals. The mechanisms by which sympathectomy leads to increased local bone loss is unknown. Potential mechanisms include disinhibition of resorption, secondary to the elimination of periosteal sympathetics, as well as indirect vascular effects."

Endoscopic Thoracic Sympathectomy (ETS) is major surgery with a high possibility of permanent damage and irreversible side effects

http://www.hyperhidrosisuk.org/treatment-options.html

change in sympathetic nervous system activity after thoracic sympathectomy

The photoplethysmographic (PPG) signal, which measures cardiac-induced changes in tissue blood volume by light transmission measurements, shows spontaneous fluctuations. In this study, PPG was simultaneously measured in the right and left index fingers of 16 patients undergoing thoracic sympathectomy, and, from each PPG pulse, the amplitude of the pulse (AM) and its maximum (BL) were determined. The parameter AM/BL is proportional to the cardiac-induced blood volume increase, which depends on the arterial wall compliance. AM/BL increased after the thoracic sympathectomy treatment (for male patients, from 2.60±1.49% to 4.81±1.21%), as sympathetic denervation decreases arterial tonus in skin. The very low-frequency (VLF) fluctuations of BL or AM showed high correlation (0.90±0.11 and 0.92±0.07, respectively) between the right and left hands before the thoracic sympathectomy, and a significant decrease in the right-left correlation coefficient (to 0.54±0.22 and 0.76±0.20, respectively) after the operation. The standard deviation of the BL or AM VLF fluctuations also reduced after the treatment, indicating sympathetic mediation of the VLF PPG fluctuations. The study also shows that the analysis of the PPG signal and the VLF fluctuations of the PPG parameters enable the assessment of the change in sympathetic nervous system activity after thoracic sympathectomy.

Medical and Biological Engineering and Computing

2001, Volume 39, Issue 5, pp 579-583
http://link.springer.com/article/10.1007%2FBF0234514