Sjoerd P. Niehof

Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1

BackgroundIn complex regional pain syndrome type 1 (CRPS1) pro-inflammatory mediators and vascular changes play an important role in the sustained development and outcome of the disease. The aim of this study was to determine the involvement of vasoactive substances endothelin-1 (ET-1) and nitric oxide (NO) during early chronic CRPS1.MethodsIncluded were 29 patients with CRPS 1 who were diagnosed during the acute stage of their disease and observed during follow-up visits. Disease activity and impairment were determined and artificial suction blisters were made on the CRPS1 and the contralateral extremities for measurements of IL-6, TNF-α, ET-1 and nitrate/nitrite (NOx).ResultsThe levels of IL-6, TNF-α and ET-1 in blister fluid in the CRPS1 extremity versus the contralateral extremity were significantly increased and correlated with each other, whereas NOx levels were decreased.ConclusionThe NOx/ET-1 ratio appears to be disturbed in the intermediate stage of CRPS, resulting in vasoconstriction and consequently in a diminished tissue blood distribution.

Computer-assisted skin videothermography is a highly sensitive quality tool in the diagnosis and monitoring of complex regional pain syndrome type I

The use of thermography in the diagnosis and evaluation of complex regional pain syndrome type 1 (CRPS1) is based on the presence of temperature asymmetries between the involved area of the extremity and the corresponding area of the uninvolved extremity. The interpretation of thermographic images is, however, subjective and not validated for routine use. The objective of the present study was to develop a sensitive, specific and reproducible arithmetical model as the result of computer-assisted infrared thermography in patients with early stage CRPS1 in one hand. Eighteen patients with CRPS1 on one hand and 13 healthy volunteers were included in the study. The severity of the disease was determined by means of pain questionnaires [visual analogue scale (VAS) pain and McGill Pain Questionnaire], measurements of mobility (active range of motion) and oedema volume. Asymmetry between the involved and the uninvolved extremities was calculated by means of the asymmetry factor, the ratio and the average temperature differences. The discrimination power of the three methods was determined by the receiver-operating curve (ROC). The regression between the determined temperature distributions of both extremities was plotted. Subsequently the correlation of the data was calculated. In normal healthy individuals the asymmetry factor was 0.91 (0.01) (SD), whereas in CRPS1 patients this factor was 0.45 (0.07) (SD). The performance of the arithmetic model based on the ROC curve was excellent. The area under the curve was 0.97, the P value was <0.001, the sensitivity 92% and specificity 94%. Furthermore, the temperature asymmetry factor was correlated with the duration of the disease and VAS pain. In conclusion, in resting condition, videothermography is a reliable additive diagnostic tool of early stage CRPS1. This objective tool could be used for monitoring purposes during experimental therapeutic intervention.

Tumor necrosis factor-α and interleukin-6 are not correlated with the characteristics of Complex Regional Pain Syndrome type 1 in 66 patients

It was previously shown in a group of 9 patients with complex regional pain syndrome type 1 (CRPS1) that levels of the proinflammatory cytokines tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) are higher in blister fluid from the involved side. We hypothesize that local inflammation is responsible for the characteristics of CRPS1. The aim of this study was to confirm the previous observation in a large group of CRPS1 patients, repeating the measurement of TNF‐α and IL‐6 in blister fluid. Furthermore, we sought to determine whether these cytokines are responsible for the characteristics of CRPS1 and characterize the relationship between cytokine levels and duration of the disease. Sixty‐six patients with CRPS1 participated. Skin blisters were artificially induced for measurement of cytokines in both extremities. The following disease characteristics were assessed: pain and differences in temperature, volume, and mobility between the extremities. TNF‐α and IL‐6 levels were significantly higher in blister fluid from the involved side. However, cytokine levels did not correlate with the characteristics or duration of the disease. Our findings confirm the presence of local inflammation in a population of 66 patients in the first 2 years of CRPS1. Proinflammatory cytokines seem to be only partly involved in the pathophysiology of CRPS1, as indicated by the lack of coherence between TNF‐α and IL‐6 levels and the signs and symptoms of inflammation and disease duration. Other inflammatory mediators and mechanisms, such as central sensitization, are probably involved in the early stages of CRPS1.

Six Years Follow-up of the Levels of TNF-α and IL-6 in Patients with Complex Regional Pain Syndrome Type 1

In an earlier study, levels of the proinflammatory cytokines TNF-α and IL-6 are higher in blisters fluid from the complex regional pain syndrome type 1 (CRPS1) side obtained at 6 and 30 months (median) after the initial event. The aim of this follow-up study is to determine the involvement of these cytokines in long lasting CRPS1. Twelve CRPS1 patients, with median disease duration of 72 months, participated. The levels of TNF-α and IL-6 were measured in blister fluid; disease activity was reevaluated by measuring pain and differences in temperature, volume, and mobility between both extremities. Differences in levels of IL-6 and TNF-α and mobility between both sides were significantly decreased. Pain and differences in temperature and volume were not significantly altered. No correlation was found between the cytokines and the disease characteristics. These results indicate that IL-6 and TNF-α are only partially responsible for the signs and symptoms of CRPS1.

Peripheral Flow Index Is a Reliable and Early Indicator of Regional Block Success

We investigated the usefulness of peripheral flow index (PFI) measurement using a standard pulse oximetry digit probe for early prediction of successful regional blocks. Sixty-six patients scheduled for limb surgery underwent either axillary or sciatic block using a nerve stimulator technique with mepivacaine 1.5%. PFI, which is the ratio of the pulsatile versus the nonpulsatile component of the pulse oximetry signal, was recorded from 10 min before block insertion until 30 min afterwards. PFI recordings of the unblocked limb were similarly recorded. Pinprick and cold sensation were assessed at 5-min intervals until 30 min after blockade. An increase in PFI by a factor of 1.55 at 10 min after axillary block placement (P = 0.006), and 12 min after sciatic block placement (P = 0.001) was required to predict a successful block. The sensitivity and specificity of PFI was 100% for predicting axillary block outcomes at this time. Positive predictive value was 95% and negative predictive value was 93%. For sciatic blocks, sensitivity and specificity were 90% and 100%, respectively. The calculated positive predictive value at time 12 min for sciatic blocks was 94% and negative predictive value was 92%. At 15 min after block placement, cold and pinprick sensations had the same calculated values for sensitivity and specificity at 71% and 100%, respectively, for axillary blocks. For sciatic blocks, cold sensation had a sensitivity of 77% and a specificity of 100%, whereas pinprick had a sensitivity of just 20% with a specificity of 100%. We conclude that PFI provides a simple, early, and objective assessment of the success and failure of nerve blocks.

Effect of tadalafil on blood flow, pain, and function in chronic cold Complex Regional Pain Syndrome: A randomized controlled trial

BackgroundThis double-blind, randomized, controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome (CRPS) in one lower extremity.MethodsTwenty-four patients received 20 mg tadalafil or placebo daily for 12 weeks. The patients also participated in a physical therapy program. The primary outcome measure was temperature difference between the CRPS side and the contralateral side, determined by measuring the skin temperature with videothermography. Secondary outcomes were: pain measured on a Visual Analogue Scale, muscle force measured with a MicroFet 2 dynamometer, and level of activity measured with an Activity Monitor (AM) and walking tests.ResultsAt the end of the study period, the temperature asymmetry was not significantly reduced in the tadalafil group compared with the placebo group, but there was a significant and clinically relevant reduction of pain in the tadalafil group. Muscle force improved in both treatment groups and the AM revealed small, non-significant improvements in time spent standing, walking, and the number of short walking periods.ConclusionTadalafil may be a promising new treatment for patients that have chronic cold CRPS due to endothelial dysfunction, and deserves further investigation.Trial RegistrationThe registration number in the Dutch Trial Register is ISRCTN60226869.

Thermographic temperature measurement compared with pinprick and cold sensation in predicting the effectiveness of regional blocks.

We designed this study to evaluate the usefulness of thermographic temperature measurement with an infrared camera, compared with patient response to cold and pinprick, as a means of assessing the success or failure of axillary blockades. Axillary blocks were performed on 25 patients undergoing surgery on the hand or forearm using a nerve stimulator technique with mepivacaine 1.5%. Pinprick and cold sensation were assessed on the operative site at 5-min intervals for 30 min. A thermographic image of the operative limb was recorded at similar time intervals. Thermographic images of the unblocked limb were taken before block placement and at 30 min. Temperature values at the operative site and unblocked limb were calculated from the thermographic images. Results revealed that thermography had higher combined values for sensitivity, specificity, and positive and negative predictive values than both cold and pinprick at all time intervals, with statistically significant differences at 15 min (thermography versus cold, P = 0.006; thermography versus pinprick, P = 0.026) and 30 min (thermography versus cold, P = 0.038; thermography versus pinprick, P = 0.040). For thermography as a method of block assessment, an optimal time of 15 min after mepivacaine local anesthetic injection gives the highest combined values for predicting a successful block (P = 0.004). We conclude that thermography provides an early and objective assessment of the success and failure of axillary regional blockades.

The effect of perfusion pressure on gastric tissue blood flow in an experimental gastric tube model

BACKGROUND: Anastomotic leakage and stricture formation remain an important surgical challenge after esophagectomy with gastric tube reconstruction for cancer of the esophagus. The perfusion of the anastomotic site at the proximal site of the gastric tube depends exclusively on the microcirculation, making it susceptible to hypoperfusion. We hypothesized that increasing the perfusion pressure would improve blood flow at the anastomotic site of the gastric tube. METHODS: A gastric tube was reconstructed in 9 pigs. Laser speckle imaging and thermographic imaging were used to measure blood flow and temperature, respectively, at the base, medial part, future anastomotic site, and top of the gastric tube. Measurements were repeated at every stepwise increase of mean arterial blood pressure (MAP) from 50 to 110 mm Hg. RESULTS: Besides MAP, global hemodynamics did not change throughout the experiment. The blood flow in the top of the gastric tube was significantly lower than the flow in the base and medial part of the gastric tube at all levels of MAP. Increasing MAP did not have a significant effect on blood flow at any location in the gastric tube. Distribution of temperature was similar to distribution of flow for the different locations. Increases in MAP did not change temperature values at any location of the gastric tube. CONCLUSION: Blood flow in the upper part of the gastric tube is decreased compared with more proximal sites. Gastric tissue blood flow does not increase with increased perfusion pressure. Therefore, it is not recommended to increase MAP to supranormal levels to increase anastomotic tissue blood flow and reduce postoperative complications.

Digital Rewarming Patterns After Median and Ulnar Nerve Injury

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.

Vasodilative Effect of Isosorbide Dinitrate Ointment in Complex Regional Pain Syndrome Type 1

Background In complex regional pain syndrome type 1 (CRPS1) vascular changes occur from the initial, inflammatory event onto the trophic signs during chronicity of the disease, resulting in blood flow disturbances and marked temperature changes. Pharmacotherapeutic treatment is generally inadequate. Aim To determine whether local application of the nitric oxide donor isosorbide dinitrate (ISDN) could cause vasodilation and thereby improve tissue blood distribution in the affected extremity. Methods In a pilot study, 5 female patients with CRPS1 in one hand were treated with ISDN ointment 4 times daily during 10 weeks. As a primary objective videothermography was used to monitor changes in blood distribution in both the involved and contralateral extremities. Results Patients treated with ISDN showed an increase of 4°C to 6°C in mean skin temperature of the cold CRPS1 hands, reaching values similar to that of the contralateral extremities within 2 to 4 weeks time, suggesting normalization of blood distribution. This was confirmed by an improvement in skin color. In 3 patients the Visual Analog Scale pain declined, whereas in the other 2 patients the Visual Analog Scale pain was unchanged over time. Conclusions In this pilot study, topical application of ISDN seems to be beneficial to improve symptoms for patients with cold type CRPS1, but further study is needed.