Sepideh Khoshnevis

Cryotherapy-Induced Persistent Vasoconstriction after Cutaneous Cooling: Hysteresis between Skin Temperature and Blood Perfusion

The goal of this study was to investigate the persistence of cold-induced vasoconstriction following cessation of active skin-surface cooling. This study demonstrates a hysteresis effect that develops between skin temperature and blood perfusion during the cooling and subsequent rewarming period. An Arctic Ice cryotherapy unit (CTU) was applied to the knee region of six healthy subjects for 60 min of active cooling followed by 120 min of passive rewarming. Multiple laser Doppler flowmetry perfusion probes were used to measure skin blood flow (expressed as cutaneous vascular conductance (CVC)). Skin surface cooling produced a significant reduction in CVC (P < 0.001) that persisted throughout the duration of the rewarming period. In addition, there was a hysteresis effect between CVC and skin temperature during the cooling and subsequent rewarming cycle (P < 0.01). Mixed model regression (MMR) showed a significant difference in the slopes of the CVC-skin temperature curves during cooling and rewarming (P < 0.001). Piecewise regression was used to investigate the temperature thresholds for acceleration of CVC during the cooling and rewarming periods. The two thresholds were shown to be significantly different (P = 0.003). The results show that localized cooling causes significant vasoconstriction that continues beyond the active cooling period despite skin temperatures returning toward baseline values. The significant and persistent reduction in skin perfusion may contribute to nonfreezing cold injury (NFCI) associated with cryotherapy.

Sustained cutaneous vasoconstriction during and following cyrotherapy treatment: Role of oxidative stress and Rho kinase

Cryotherapy is a therapeutic technique using ice or cold water applied to the skin to reduce bleeding, inflammation, pain, and swelling following soft tissue trauma and injury. While beneficial, there are some side effects such as pronounced vasoconstriction and tissue ischemia that are sustained for hours post-treatment. This study tested the hypothesis that this vasoconstriction is mediated by 1) the Rho-kinase pathway and/or 2) elevated oxidative stress. 9 subjects were fitted with a commercially available cryotherapy unit with a water perfused bladder on the lateral portion of the right calf. Participants were instrumented with three microdialysis probes underneath the bladder. One site received lactated ringers (control site), one received the Rho-Kinase inhibitor Fasudil, and one received Ascorbic Acid. Skin temperature (Tskin) and cutaneous vascular conductance (CVC) was measured at each site. Subjects had 1°C water perfused through the bladder for 30min, followed by passive rewarming for 90min. Tskin fell from ~34°C to ~18.0°C during active cooling across all sites and this response was similar for all sites (P>0.05 for all comparisons). During passive rewarming Tskin rose to a similar degree in all sites (P>0.05 relative to the end of cooling). %CVC was reduced during active cooling in all sites; however, the magnitude of this response was blunted in the Fasudil site relative to control (P<0.001 for all comparisons) and min 25 and 30 of cooling in the Ascorbic Acid site (P<0.05). During passive rewarming %CVC at the control and Ascorbic Acid sites did not change such that values were similar to the end of cooling (P>0.05 for each comparison). %CVC at the Fasudil site remained elevated during passive rewarming such that values were higher compared to the control and Ascorbic Acid sites throughout the 90min of passive rewarming (P<0.001 main effect of Fasudil). These findings indicate that the Rho-kinase pathway contributes to pronounced vasoconstriction during cryotherapy as well as the sustained vasoconstriction during the subsequent rewarming period post treatment.

An On-Site Thermoelectric Cooling Device for Cryotherapy and Control of Skin Blood Flow

Cryotherapy involves the surface application of low temperatures to enhance the healing of soft tissue injuries. Typical devices embody a remote source of chilled water that is pumped through a circulation bladder placed on the treatment site. In contrast, the present device uses thermoelectric refrigeration modules to bring the cooling source directly to the tissue to be treated, thereby achieving significant improvements in control of therapeutic temperature while having a reduced size and weight. A prototype system was applied to test an oscillating cooling and heating protocol for efficacy in regulating skin blood perfusion in the treatment area. Data on 12 human subjects indicate that thermoelectric coolers (TECs) delivered significant and sustainable changes in perfusion for both heating (increase by (±SE) 173.0 ± 66.0%, P < 0.005) and cooling (decrease by (±SE) 57.7 ± 4.2%, P < 0.0005), thus supporting the feasibility of a TEC-based device for cryotherapy with local temperature regulation.

Quantitative evaluation of the thermal heterogeneity on the surface of cryotherapy cooling pads

We have investigated thermal operating characteristics of 13 commercially available cryotherapy units (CTUs) and their associated cooling pads using IR imaging. Quantitative examination of the temperature profiles from pad IR images shows diverse, nonuniform temperature distribution patterns. The extent of heterogeneity of the temperature fields was quantified via standard image analysis methods, including thresholding, spatial gradient diagrams, and frequency histogram distributions. A primary conclusion of this study is that it is a misnomer to characterize the thermal performance of a CTU and cooling pad combination in terms of a single therapeutic temperature.

Pronounced and sustained cutaneous vasoconstriction during and following cyrotherapy treatment: Role of neurotransmitters released from sympathetic nerves

Cryotherapy is a therapeutic technique using ice or cold water applied to the skin to manage soft tissue trauma and injury. While beneficial, there are some potentially detrimental side effects, such as pronounced vasoconstriction and tissue ischemia that are sustained for hours post-treatment. This study tested the hypothesis that this vasoconstriction is mediated by 1) activation of post-synaptic α-adrenergic receptors and/or 2) activation of post-synaptic neuropeptide Y1 (NPY Y1) receptors. 8 subjects were fitted with a commercially available cryotherapy unit with a water perfused bladder on the lateral portion of the right calf. Participants were instrumented with four intradermal microdialysis probes beneath the bladder. The following conditions were applied at the four treatment sites: 1) control (Ringer solution), 2) combined post-synaptic β-adrenergic receptors and neuropeptide (NPY) Y1 receptors blockade (P+B site), 3) combined post-synaptic α-adrenergic receptor, β-adrenergic receptor, and NPY Y1 receptor blockade (Y+P+B site), and 4) blockade of pre-synaptic release of all neurotransmitters from the sympathetic nerves (BT site). Following thermoneutral baseline data collection, 1°C water was perfused through the bladder for 30min, followed by passive rewarming for 60min. Skin temperature (Tskin) fell from ~34°C to ~18.5°C during active cooling across all sites and there was no difference between sites (P>0.05 vs. control for each site). During passive rewarming Tskin rose to a similar degree in all sites (P>0.05 relative to the end of cooling). In the first 20min of cooling %CVC was reduced at all sites however, this response was blunted in the BT and the Y+P+B sites (P>0.05 for all comparisons). By the end of cooling the degree of vasoconstriction was similar between sites with the exception that the reduction in %CVC in the Y+B+P site was less relative to the reduction in the control site. %CVC was unchanged in any of the sites during passive rewarming such that each remained similar to values obtained at the end of active cooling. These findings indicate that the initial vasoconstriction (i.e. within the 1st 20min) that occurs during cryotherapy induced local cooling is achieved via activation of post-synaptic α-adrenergic receptors; whereas nonadrenergic mechanisms predominate as the duration of cooling continues. The sustained vasoconstriction that occurs following cessation of the cooling stimulus does not appear to be related to activation of post-synaptic α-adrenergic receptors or NPY Y1 receptor.

Effects of Cold Temperature on the Skin

The response of skin to the application of surface cooling is manifested primarily as a local vasoconstriction and reduced blood flow. Major functions of skin blood flow (SBF) are to sustain the metabolic process of the skin cells and to facilitate heat transfer between the body core and the environment via the cutaneous circulation. One consequence of surface cooling is to insulate the body core from the environment by reducing the magnitude of SBF. The magnitude of vasoconstriction has a nonlinear dose response to the applied temperature so that even mild cooling can cause the loss of a significant fraction of SBF. Other thermally sensitive processes are also influenced, in particular metabolism, which decreases with falling temperature. So long as a cold state is maintained, both the blood flow and metabolism remain depressed. When the skin is rewarmed, metabolism will likewise increase proportionately. However, in the absence of an externally applied stimulation, the SBF will remain at depressed levels for many hours, presumably due to the action of locally expressed humoral vasomotive agents that block the vasodilation process. The consequences may be prolonged exposure to an ischemic state in conjunction with a high metabolic rate, which may exacerbate the potential for nonfreezing cold injury (NFCI) expressed as tissue necrosis and neuropathy. The decoupling of temperature and SBF during rewarming gives rise to a hysteresis effect that is independent of the speed of the cooling and warming processes.

Persistence of cryotherapy induced ischemia for hours after cooling ends

Orthopedic surgery and sports medicine commonly use cryotherapy to reduce inflammation, alleviate pain, lower the chance of secondary hypoxic injury, and decrease hematoma formation [1,2]. Methods of cryotherapy vary widely in their sophistication, ranging from bags of ice or freezable gel packs to liquid perfusion cryotherapy devices. These perfusion cryotherapy devices circulate near 0°C water through a flexible bladder, resulting in localized tissue cooling.Copyright

Cryosurgery Causes Profound and Persistent Ischemia

Cryotherapy has been used in the treatment of soft tissue trauma and other ailments since the time of Hippocrates. Currently it is commonly applied in conjunction with surgical procedures and by athletic trainers and physical therapists to control pain, swelling, bleeding, and inflammation. Localized cooling also results in slowing of the nerve conduction velocity and reduced muscle spasm and secondary hypoxic injury1,2. Cooling is commonly used for soft tissue injuries in combination with rest, compression and elevation to minimize inflammation.© 2012 ASME

Measurement and Analysis of Cutaneous Perfusion Depression During Cryotherapy

Localized cooling is commonly used after orthopedic surgery and in sports medicine to reduce bleeding, inflammation, metabolism, muscle spasm, pain, and swelling following musculoskeletal trauma and injury. The therapeutic application of cold therapy has a long history dating from the time of Hippocrates and has been widely documented in the literature1–3. Nonetheless, there remains to the present time considerable controversy over the appropriate protocol for application of cryotherapy. One extreme camp advocates continuous use of cryotherapy to a treatment site with no break in cooling for days or even weeks4–5, whereas other practitioners recommend a maximum application duration of 20 to 30 minutes followed by a cessation period of about 2 hours6–7. Although continuous cooling appears to be tolerated by many patients, there has been a large number of reported incidences in which continuous application of cryotherapy device led directly to extensive tissue necrosis and/or nerve injury in the treatment area, sometimes with dire medical consequences6,8.Copyright

Response of Normal Canine Prostate Tissue to Thermal Therapy

The goal of this study was to evaluate post-thermal stress cell survival in canine prostatic epithelial and stromal cells. Epithelial and stromal cells isolated from canine prostate were exposed to thermal stress using a water bath. Post-thermal stress cell viability was measured by flow cytometry and analyzed using FlowJo software. An ongoing analysis also measures Heat Shock Protein expression for the same stress protocols.Copyright