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Background: To investigate the pathophysiology of temperature hypersensitivity in neuropathic pain rodent models, it is essential to be able to quantify the phenotype as objective as possible. Current temperature sensitivity measuring paradigms are performed during exposure to external factors, i.e. light, sound and smell, which modulate behavior significantly. In addition the present outcome measure for temperature hypersensitivity in rodents is the examination of the hind paw lift upon exposure to a certain temperature, which reflects more a reflex-flexion than an experience of pain., New Method: Therefore the Rotterdam Advanced Multiple Plate (RAMP) was developed to assess cold hyperalgesia and allodynia objectively in freely behaving neuropathic pain rats, which measures the avoidance for certain temperatures and monitoring the location of the rat with an infrared camera while excluding external environmental influences such as light and sound., Results: Compared to sham rats, the spared nerve injury (SNI) rats demonstrated a higher preference for the comfortable plate (27 °C) when the other three plates were set at 5 °C, 14 °C, 17 °C and 19 °C. We were unable to detect heat hyperalgesia and allodynia with the RAMP., Comparison With Existing Method: The paw withdrawal method displays similar results during cold hypersensitivity measurements as observed with the RAMP. The SNI group did display heat hypersensitivity during the paw withdrawal test., Conclusions: The results indicate that the RAMP is able to quantify cold hyperalgesia and allodynia in neuropathic pain rats while resolves some of the problems of conventional temperature sensitivity measuring paradigms in rodents., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: Cold-induced vasodilatation (CIVD) is a cyclic regulation of blood flow during prolonged cooling of protruding body parts. It is generally considered to be a protective mechanism against local cold injuries and cold intolerance after peripheral nerve injury. The aim of this study was to determine the role of the sympathetic system in initiating a CIVD response., Methods: Eight rats were operated according to the spared nerve injury (SNI) model, eight underwent a complete sciatic lesion (CSL) and six underwent a sham operation. Prior to operation, 3, 6 and 9 weeks postoperatively, both hind limbs were cooled and the skin temperature was recorded to evaluate the presence of CIVD reactions. Cold intolerance was determined using the cold plate test and mechanical hypersensitivity measured using the Von Frey test., Results: No significant difference in CIVD was found comparing the lateral operated hind limb for time (preoperatively and 3, 6 and 9 weeks postoperatively; p = 0.397) and for group (SNI, CSL and Sham; p = 0.695). SNI and CSL rats developed cold intolerance and mechanical hypersensitivity., Conclusion: Our data show that the underlying mechanisms that initiate a CIVD reaction are not affected by damage to a peripheral nerve that includes the sympathetic fibres. We conclude that the sympathetic system does not play a major role in the initiation of CIVD in the hind limb of a rat., Clinical Relevance: No substantial changes in the CIVD reaction after peripheral nerve injury imply that the origin of cold intolerance after a traumatic nerve injury is initiated by local factors and has a more neurological cause. This is an important finding for future developing treatments for this common problem, as treatment focussing on vaso-regulation may not help diminish symptoms of cold-intolerant patients., (Copyright © 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Purpose: Peripheral nerve injury of the upper extremity frequently causes changes in the thermoregulatory system of the hands and fingers and leads to reports of cold intolerance. In this study, we aimed to measure the influence of median or ulnar nerve injury on cold-induced vasodilatation (CIVD) during prolonged cooling at low temperatures., Methods: We tested 12 patients with a median (n = 6) or ulnar (n = 6) injury 4 to 76 months after nerve repair. The palmar sides of both hands were cooled continuously using a cold plate at 5°C. We measured the skin temperature of the fingers using videothermography and plotted graphs of the temperature changes of the nailbed. The presence of a CIVD reaction was defined as a minimum increase in temperature of 2.5°C starting at the distal phalanx. Furthermore, we measured self-reported symptoms of cold intolerance using the Cold Intolerance Severity Scale questionnaire., Results: A CIVD reaction was absent in the affected digits of 4 patients (follow-up, 6-37 mo), whereas the CIVD reaction in the uninjured hand was present. The CIVD was present in 6 patients after 50 months' follow-up (range, 24-76 mo). Two patients had no CIVD reaction in the injured or uninjured fingers. All patients with a CIVD response had at least diminished protective sensation. Presence of the CIVD reaction did not exclude self-reported symptoms of cold intolerance., Conclusions: After peripheral nerve injury, it is possible to recover the CIVD reaction. This might be an indication of nerve recovery. However, a positive CIVD reaction does not exclude subjective symptoms of posttraumatic cold intolerance., Type of Study/level of Evidence: Diagnostic III., (Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: It is often assumed that cold intolerance is associated with abnormalities in the skin temperature due to changes in the blood flow of the hands. In this study, we determined whether patients with and without cold intolerance after a hand fracture or healthy controls have a diminished rewarming after a cold stimulus., Methods: The severity of cold intolerance was evaluated using the Cold Intolerance Symptom Severity (CISS) questionnaire. To determine whether abnormal rewarming plays a major role in the underlying pathophysiology of cold intolerance, a cold-stress test was applied at a mean of 30 months (with a range of 11 mo) after the patients recovered from a hand fracture. A control group also underwent identical cold-stress testing for comparison. Temperature during the rewarming phase was measured using videothermography., Results: Thirteen control subjects and 18 patients participated. Control subjects did not report any symptoms of cold intolerance (CISS score, 0) and no loss of sensibility was measured. The mean CISS score of all patients was 27.8; 9 patients scored above the cut-off value for normal cold intolerance. No significant differences were found in the rewarming patterns between (1) the affected and non-affected hand of the postfracture patients, (2) the dominant and non-dominant hand of the control subjects, and (3) the patients and controls., Conclusions: The results of this study revealed no relation between the severity of cold intolerance and rewarming patterns after cold stress testing. This might suggest that temperature regulation of the hands in post-fracture patients might not be responsible for the symptoms of cold intolerance, based on cold-stress test response., (Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Cold induced vasoconstriction (CIVC) is a way for mammals to reduce heat loss in an effort to maintain body core temperature. As blood flow to a cooled extremity is reduced, the amount of body heat lost at the cooled location is minimised. However, when the extremity temperature gets below a certain threshold, Cold induced vasodilatation (CIVD) occurs, a phenomenon that is believed to reduce the risk of local cold injuries. Many theories explaining the mechanism of the CIVD reaction have been postulated, but no consensus has been found. One of these theories is that the CIVD reaction is controlled neurally. To study the effect of neural influence on the vascularisation and rewarming patterns a new experimental set-up was designed. This set-up is able to measure responses in both hind paws simultaneously, creating the opportunity to study the effect of nerve injury on one limb and use the contralateral limb as a control. Ten rats received a sciatic nerve transection and repair of either the left (n=5) or the right (n=5) hind limb. Measurements were performed, 1 day pre-operatively, directly post-operatively, and at days 1, 7, 14, 21, 35 and 49 post-operatively. Although results are not significant, there is a tendency for the CIVD reaction to be reduced in the nerve injured paw until the nerve is regenerated around day 35. Further investigation of neural influence on the CIVD reaction will be necessary; this set-up may prove to be useful in future experiments to elucidate the mechanism of the CIVD reaction., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The microcirculation appears to be impaired in cold chronic complex regional pain syndrome (CRPS). This double-blind, placebo-controlled, randomized trial investigated the effect of the nitric oxide (NO) donor isosorbide dinitrate (ISDN) on the peripheral blood flow in patients with chronic CRPS. Twenty-four patients received 1% ISDN in Vaseline or a placebo ointment applied to the dorsum of the affected hand four times daily for 10 weeks. The patients participated in a physical therapy program to improve activity. The primary outcome measure was blood distribution in the affected extremity, which was determined by measuring the skin temperature using videothermography. We also measured NO and endothelin-1 concentrations in blister fluid, pain using the visual analog scale, and activity limitations using an upper limb activity monitor and the Disabilities of Arm Shoulder and Hand Questionnaire. ISDN failed to produce a significant improvement in temperature asymmetry in chronic cold CRPS patients, and it did not result in the expected reduction in pain and increase in activity compared with placebo either. There may be other central or peripheral factors contributing to the disturbed vasodynamics in cold chronic CRPS that are not influenced by NO substitution. This study does not show an improvement of the regional blood distribution by ISDN in the involved extremity of patients with cold-type CRPS.

Purpose: Posttraumatic cold intolerance (CI) is a frequent and important sequel after peripheral nerve injury. In this study, it is hypothesized that altered rewarming patterns after peripheral nerve injury are related to the degree of posttraumatic CI. This hypothesis is tested by quantitatively comparing rewarming patterns of the digits in controls and in median or ulnar nerve injury patients and by investigating relationships between rewarming patterns, sensory recovery, and CI., Methods: Twelve median or ulnar nerve injury patients with a follow-up of 4 to 76 months after nerve repair and 13 control subjects had isolated cold stress testing of the hands. Video thermography was used to analyze and compare rewarming patterns of the injured and uninjured digits after cold stress testing. Temperature curves were analyzed by calculating the Q value as an indicator of heat transfer (temperature added during the first 10 minutes after start of active rewarming) and the maximum slope., Results: Test-retest reliability was 0.64 and 0.79, respectively, for the Q value and maximum slope. High Q values and maximum slopes were interpreted as the presence of active rewarming. Patients with return of active rewarming had better sensory recovery and lower Blond McIndoe Cold Intolerance Severity Scale (CISS) scores. Better sensory recovery was correlated with lower CISS scores., Conclusions: Test-retest reliability of cold stress testing was good, and we found a difference in rewarming patterns between nerve injury patients and controls. The presence of active rewarming in the nerve injury patients was related to sensory recovery and fewer complaints of posttraumatic CI.