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

"Norepinephrine (NE) released from the nerve terminal of locus coeruleus (LC) neurons contributes to about 70% of the total extracellular NE in primates brain. In addition, LC neurons also release NE from somatodendritic sites. Quantal NE release from soma of LC neurons has the characteristics of long latency, nerve activity-dependency, and autoinhibition by α2-adrenergic autoreceptor. The distinct kinetics of stimulus-secretion coupling in somata is regulated by action potential patterns. The physiological significance of soma and dendritic release is to produce negative-feedback and to down-regulate neuronal hyperactivity, which consequently inhibit NE release from axon terminal of LC projecting to many brain areas. Recent discoveries about the LC somatodendritic release may provide new insights into the pathogenesis of clinic disease involving LC-NE system dysfunction, and may help developing remedy targeted to the LC area."
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

Acute pain pain following needlescope-VATS (nVATS) sympathectomy for palmar hyperhidrosis

"...recently Sihoe et al. [10] have reported that pre-emptive wound infiltration with a local anaesthetic reduces the postoperative wound pain following needlescope-VATS (nVATS) sympathectomy for palmar hyperhidrosis. The concept of pre-emptive analgesia has gained popularity following
experimental work, demonstrating that early control of pain can alter its subsequent evolution as well as the recognition that nociception produces important physiological responses, even in adequately anaesthetised individuals, and the understanding that for many individuals the minimisation of pain can improve clinical outcomes [11].
The pre-emptive analgesia is based on the intuitive idea that if pain is treated before the injury occurs, the nociceptive system will perceive less pain than if analgesia is given after the injury has already occurred. The preoperative administration of analgesic will modify the afferent nociceptive barrage from the site of injury, thus preventing the development of central sensitisation and hyperalgesia [12].
Thus, we have focussed on this argument in the aim of the present study, which is to determine whether pre-emptive local analgesia (PLA) has an effect to reduce acute postoperative pain following standard-VATS (s-VATS) sympathectomy, in view of n-VATS being considered less painful
than the s-VATS procedure [4,5]."

http://ejcts.oxfordjournals.org/content/37/3/588.full.pdf+html
European Journal of Cardio-thoracic Surgery 37 (2010) 588—593
Pre-emptive local analgesia in video-assisted thoracic surgery sympathectomy

Alfonso Fiorelli, Giovanni Vicidomini, Paolo Laperuta, Luigi Busiello,
Anna Perrone, Filomena Napolitano, Gaetana Messina, Mario Santini*
Thoracic Surgery Unit, Second University of Naples, Naples, Italy
Received 28 March 2009; received in revised form 21 July 2009; accepted 31 July 2009; Available online 12 September 2009

"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/

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

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/

Evidence based medicine is broken and corrupted - BMJ

"How many people care that the research pond is polluted,5 with fraud, sham diagnosis, short term data, poor regulation, surrogate ends, questionnaires that can’t be validated, and statistically significant but clinically irrelevant outcomes? Medical experts who should be providing oversight are on the take. Even the National Institute for Health and Care Excellence and the Cochrane Collaboration do not exclude authors with conflicts of interest, who therefore have predetermined agendas.6 7 The current incarnation of EBM is corrupted, let down by academics and regulators alike.8"



http://www.bmj.com/content/348/bmj.g22

"decrease in cardiac output causing a decrease in cerebral perfusion"

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"