The following is my dissertation project from medical school, which I have decided to share for interest! I never attempted to get this published (because I was so happy to be done with it!) but I think the findings are interesting with potential for further research.
4th Year Project, MBChB
Student: Anna Wells Supervisor: Dr Faisel Khan Date: May 2015
Executive Summary
Introduction
Winter climbing is a popular activity worldwide, which is becoming progressively recognised as a mainstream sport. The winter climber often spends many hours in sub-zero temperatures, exposed and inactive, whilst holding their partner’s ropes. During these episodes, the hands typically become very cold. Raynaud’s phenomenon (RP) is a vascular disorder characterised by intermittent reversible vasospasm of the digital arteries. It is known that the secondary form of RP may develop in response to environmental factors including repeated vibrations, cold exposure, and certain chemicals. The objective of this study is to determine the prevalence of Raynaud’s-like symptoms (RS) amongst active winter climbers, identify any risk factors and investigate changes in digital skin blood flux at rest and during post-occlusive reactive hyperaemia using Laser Speckle Contrast Imaging (LSCI). If this study identifies winter climbing as a risk factor for the development of RS then we will have identified a population who may benefit from preventative measures or treatments.
Methods
This study was composed of two parts. Part 1 aimed to establish the prevalence of RS amongst winter climbers and identify any associated factors. This was done via an online questionnaire, which acquired data including: duration and frequency of involvement in winter climbing; experience of “hot-aches”; hand protection (spare gloves, glove liners, getting wet hands); and experience of Raynaud’s phenomenon. Responses from 153 climbers were analysed using SPSS (Pearson chi squared test and odds ratio.) Part 2 involved assessment of vascular function in the upper limb peripheries of 10 climbers and 10 age-sex matched controls using LSCI. Skin perfusion was recorded at baseline levels, during five minutes of vascular occlusion, and for five minutes of recovery, at eight regions of interest (RIOs) on the dorsal aspect of the left hand. Numerical arbitrary units were derived from perfusion maps and analysed using Excel and SPSS (Mann Whitney test and unpaired two-tailed student’s t-test.)
Results
Part 1 found that the prevalence of RS amongst climbers was 38.6%, of whom 30.5% reported attacks as being “frequent”. 90.2% of participants reported having experienced hot-aches, and Raynaud’s-like symptoms were more prevalent amongst climbers who frequently experienced hot-aches. Part 2 identified changes in blood flux which were seen consistently across all 8 ROIs. Basal blood flux was lower in climbers (-17.7%) compared with control subjects. During post-occlusive reactive hyperaemia, there was a decreased peak flux in climbers (-14.5%), with a prolonged time to reach this peak (+5 seconds). A prolonged recovery time (+21 seconds) was seen in climbers, with statistical significance (+34 seconds, P<0.05) in the tip of the ring finger.
Discussion
A major finding of this study was the high prevalence of Raynaud’s-like symptoms amongst winter climbers compared to the general population (1-20%). This is particularly remarkable given that the population prevalence of RP is reported to be higher in females, yet the winter climbing population is predominantly male. Laboratory studies of blood flow in the digits of winter climbers demonstrate reduced vasodilator ability, showing changes consistent with patterns observed in secondary RP. A number of underlying mechanisms may be responsible including an increase in the potent vasoconstrictor Endothelin-1, or a defect in the vasodilator role of nitric oxide. Repeated episodes of reperfusion may lead to oxidative stress and endothelial injury, and cold-induced peripheral neuropathy may be associated with a deficiency of the vasoconstrictor Calcitonin gene-related peptide (CGRP). Further research is required to investigate the pathophysiology underling this apparent manifestation of RP in winter climbers, and to identify effective preventative measures.
Introduction
Winter climbing is a popular activity amongst climbers around the world, and one that is becoming progressively recognised as a mainstream sport. With the recent formation of a British Ice Climbing Team1 and inclusion as a demonstration sport at the 2014 Sochi Winter Olympics,2 it is anticipated that participation will increase. Winter climbing is usually undertaken in pairs: the “belayer” holds the ropes while their partner ascends the above terrain using ice axes and crampons. This process is time-consuming and the belayer may be sitting in an exposed position in sub-zero temperatures for many hours, during which time the hands typically become cold, resulting in peripheral vasoconstriction. The ascending climber eventually establishes a new safety point, so the partner can ascend to meet him. As the belayer begins to climb, reactive hyperaemia like changes occur within the hands. This reperfusion is often associated with a painful sensation known to climbers as “hot-aches”.
Personal communications of the author suggest that there appears to be a high prevalence of Raynaud’s-like symptoms (RS) among winter climbers. Raynaud’s phenomenon (RP) is a vascular disorder characterised by intermittent reversible vasospasm of the digital arteries in response to cold or emotional stress.3 The estimated prevalence in the general population is between 1% and 20%,4 occurring more frequently in women.5 The condition may occur alone in the idiopathic form known as Primary RP, or as a secondary form in association with other conditions, most often connective tissue disorders.6 However, we know that symptoms may also occur in response to environmental stimuli as is the case in Hand Arm Vibration Syndrome (HAVS), a well-recognised form of occupational secondary RP affecting workers exposed to vibrating equipment such as pneumatic drills.7 Additionally, exposure to cold temperatures and certain chemicals (e.g. vinyl chloride monomer) have been identified as factors predisposing to RP. 8 The pathogenesis is not fully understood, but in the case of secondary RP, endothelial damage is thought to be an initiating factor contributing to impaired micro- circulation.9 10
Laser Speckle Contrast Imaging (LSCI) is a non-invasive technique which can be used to assess the cutaneous microcirculation.10 It provides an index of skin perfusion, referred to as the flux, which may be used as a surrogate measurement of skin blood flow.11 It is most commonly used to assess microvascular reactivity by challenging micro vessels under varying stimuli. Arterial occlusion provides a sufficient physiological stimulus to induce a transient increase in cutaneous flux, known as post-occlusive reactive hyperaemia (PORH).10 Several studies have identified marked differences in this PORH response in patients suffering from primary RP, secondary RP and healthy controls.12 13 14 LSCI has been recognised as a reliable tool to distinguish between these groups,15 and specific patterns of variation have been observed.
The objective of this study is to determine whether subjects who participate in winter climbing activities have impaired blood flow to the fingers, as identified by (i) A higher prevalence of Raynaud’s-like symptoms amongst winter climbers than population level and (ii) Impaired upper limb peripheral blood flow in winter climbers compared with control subjects, as measured by LSCI. If this study finds that partaking in winter climbing is a risk factor for the development of Raynaud’s-like symptoms with impaired blood flow to the upper-limb extremities, then we will have identified an at risk group of people who may benefit from preventative measures or treatments. Furthermore, knowledge of the long-term consequences of cold-exposure may encourage winter climbers to take more personal care in ensuring adequate hand protection.
KEY RESEARCH QUESTIONS:
- Is there an increased prevalence of Raynaud’s-like symptoms amongst active winter climbers?
- Are there any identifiable factors associated with Raynaud’s-like symptoms and impaired blood flow (e.g. number of years engaging in winter climbing activities / frequency of activities / smoking / hand protection / frequency of experiencing “hot-aches”?)
- Do subjects who participate in winter climbing activities have impaired blood flow in the upper limb peripheries compared to controls at baseline levels, and during reactive hyperaemia, as measured by LSCI?
Methods
The study was composed of two parts, with both sections receiving approval from the University of Dundee Research Ethics committee (Appendix 1). All participants provided informed consent.
- Part 1 aimed to establish the prevalence of Raynaud’s-like symptoms amongst winter climbers and identify any associated factors, via an online questionnaire
- Part 2 involved assessment of vascular function in the upper limb peripheries using LSCI
For the purpose of the study, the following definitions were established by the author:
Winter Climbing: Climbing activities involving a rope, ice axes and crampons, taking place outdoors between the months of October and April
Active winter climber: A climber who has engaged in climbing activities involving a rope, ice axes and crampons on at least ten occasions since January 2010
Part 1: Questionnaire
Active winter climbers were recruited via the online climbing forum “UKClimbing” and a Facebook group, and data was gathered via an online questionnaire facilitated by KwikSurveys (Appendix 2). Out of 258 surveys received, 68 were discarded due to being incomplete and a further 37 were discarded as respondents did not meet the participation criteria of being an active winter climber. The remaining 153 surveys were included in the study.
The questionnaire acquired data including: duration and frequency of involvement in winter climbing; experience of “hot-aches”; hand protection (spare gloves, glove liners, getting wet hands); experience of Raynaud’s phenomenon.
A description of Raynaud’s phenomenon from NHS Choices16 was provided within the questionnaire and participants were asked to only report symptoms which occurred in a “non-climbing environment” to avoid ambiguity with acute cold skin changes.
The majority of respondents, 102 (65.4%) were in the 20-39 age group. 77 (50.3%) of respondents were very active winter climbers, climbing at least ten times per season.
75 (49.0%) of respondents had been winter climbing for at least 6 years, and 54 (35.3%) had over ten years of winter climbing experience. Only 6 (3.9%) of climbers were current smokers and 118 (77.1%) had never smoked.
Part 2: Laser Speckle Contrast Imagine (LSCI)
Part 2 involved assessment of vascular function using LSCI, carried out in the cardiovascular laboratory at Ninewells Hospital, Dundee. Participants were recruited via Part 1, and the first ten volunteers who were available to attend a scheduled lab session were included. Ten age-sex matched volunteers (8 male, 2 female) were identified as associates of the student or supervisor.
Participants were acclimatized by lying on a bed at room temperature (22-24°C) for fifteen minutes prior to examination. Cutaneous blood flux was measured using a Moor Instrument Full Field Laser Perfusion Imager (FLPI) at eight regions of interest (ROIs) on the dorsal aspect of the patient’s left hand, as shown in figure 1. ROIs 2, 3, 4, representing the distal phalanx of the index, middle and ring finger, were of particular interest as these have been identified as the regions most commonly effected by RP.17
Basal blood flux was measured for two minutes, after which time 200mmHg pressure was applied to the left brachial artery with a sphygmomanometer to produce vessel occlusion. Pressure was released after five minutes to induce a reactive hyperaemia. Blood flux was measured continuously throughout and for five minutes of recovery. Numerical arbitrary units were derived from perfusion maps to obtain the following data: baseline blood flow; peak blood flow (the hyperaemic peak reached following occlusion); time to peak (the time taken to reach the hyperaemic peak after cuff release); time to 50% decay (the time taken for the hyperaemic peak to reduce halfway towards the baseline value) and area under curve (units per second during the first two minutes of recovery). Figure 2 demonstrates a typical curve of reactive hyperaemia.
All data was stored on a password protected University of Dundee computer with restricted access. Participants were anonymised and identified by code only.
Data was analysed using SPSS and Microsoft Excel 2013. Pearson Chi squared test and odds ratio (95% confidence interval) were used to analyse questionnaire data and identify factors associated with experience of RS, along with the significance of the factor (p <0.05). Blood flow data was tested for normal distribution using the Shapiro-Wilk test (p<0.05). Time data (time to peak and recovery) was largely non-parametric and so those subject-control subsets were analysed using the Mann-Whitney test. The majority of the remaining data was normally distributed and subsets analysed using an unpaired two-tailed student’s t-test.
Results
Part 1: Questionnaire
Prevalence of Raynaud’s-like Symptoms
59 respondents (38.6%) reported experiencing Raynaud’s-like symptoms. Of these, 18 (30.5%) reported attacks as being “frequent”, and 5 (8.5%) reported frequent attacks affecting the whole finger on most fingers.
Experience of hot-aches
138 (90.2%) of participants report having experienced hot-aches, and
59 (38.6%) report experiencing them on most days they go winter climbing. Figure 3 demonstrates that Raynaud’s-like symptoms appear to be more prevalent amongst climbers who frequently experience hot-aches.
Part 2: Laser Speckle Contrast Imagine (LSCI)
Demographics were gathered from all participants and are presented in table 2.
Winter climbers were found to have a decreased baseline blood flow, a decreased post-occlusive peak flow, a longer time to peak, and a longer time to 50% decay compared with control subjects. Figures 4-7 illustrate these differences, which were seen consistently across all eight regions of interest.
The typical post-occlusive reactive hyperaemic response seen in climber and control participants is illustrated in figures 8 and 9.
Although the tracings in figure 9 demonstrate different patterns of PORH, the area under curve (AUC) is similar in both groups, because the lower peak seen in climbers is off-set by the prolonged recovery time. In order to numerically capture the difference, AUC was expressed as a percentage of the peak, and found to be significantly different (p < 0.05) across all three regions of interest presented in table 3.
Discussion
A major finding of this study was the high prevalence of Raynaud’s-like symptoms within the winter-climbing population, with a prevalence of 38.6%. Several studies have investigated population prevalence of RP, and whilst results are variable depending on diagnostic criteria, survey technique and population characteristics, reported prevalence fluctuates between 1% and 20%.4 This finding is particularly remarkable given that the population prevalence of RP is reported to be higher in females,5 yet the winter climbing population is predominantly male. Although gender data was not acquired within the questionnaire, the laboratory component comprised 8/10 male and 2/10 female climbers, which is likely to reflect the demographics.
This study found no association between the patterns of hand protection and the occurrence of RS. This may be due to difficulties in detangling the cause and effect of habits: climbers who do not wear adequate hand protection (liners, spare gloves) may be more at risk of suffering cold damage; but climbers who experience painful cold hands may be more likely to wear liners and carry spare gloves. Experience of hot-aches was identified as a risk factor for RS. Over 90% of respondents had experienced hot-aches, and there was an increased prevalence of RS seen in climbers who experienced hot-aches more frequently.
Winter climbers were found to have a decreased basal flux and peak flux across all eight regions of interest compared to normal controls. These findings are similar to studies investigating digital microvascular perfusion in patients with primary and secondary RP which have also identified reductions in the amplitude at baseline12,13 and following five minutes of ischaemia in a PORH test.12 A longer “time to peak” and a longer “recovery time” was observed consistently across all eight regions of interest. The difference in recovery time was significant between climbers and controls in the distal phalanx of the ring finger (p<0.05), which is a region known to be commonly affected in RP.17 Whilst a number of studies have identified a prolonged “time to peak” in both primary and secondary RP,18 a study by Grattagliano14 et al found that a prolonged return to resting flux was unique to patients with systemic sclerosis, a condition characterised by small vessel vasculopathy with microvascular structural damage and dysfunction. 12
The underlying pathogenesis of RP is not fully understood, and various mechanisms have been proposed and debated within the literature. It is agreed that the key issue is an imbalance between vasoconstriction and vasodilation, with evidence suggesting abnormalities of the vessel wall, neural control and circulating mediators.19 Endothelin-1 is a potent endothelium derived vasoconstrictor which is thought to play a role in the excessive vasoconstriction associated with RP. Studies have observed higher baselines levels and an increased rise in response to a cold challenge in patients with RP compared to control groups.3 Chen et al20 found that chronic cold exposure was associated with a significant increase in Endothelin-1 production and an up-regulation of Endothelin-A receptors and so this may be of significance within the climbing population.
On the contrary, the endothelium is also responsible for producing a large number of vasodilator substances which may be under-produced in the incidence of endothelial damage. Research suggests that a deficiency of nitric oxide plays a key role.21 In patients with secondary RP, research suggests this may be mediated by an impairment of the smooth muscle response to NO7, or an intrinsic defect in in the mechanism of NO production22. This deficit may be amplified by the effects of oxidative stress, which has been implicated in the pathogenesis of RP both via a reduction in the level of bioavailable NO23 and as a contributor towards endothelial injury.3 Studies have demonstrated elevated levels of free radical markers in patients with RP3 and it has been suggested that this occurs as a consequence of the recurrent episodes of ischemia-reperfusion associated with vasospastic attacks in RP. Indeed, reperfusion injury has been associated with endothelial production of oxygen free radicals.24 In winter climbing, the hands are frequently exposed to sub-zero temperatures, resulting in a cold induced vasoconstriction which has a pronounced effect on the hands and fingers,25 and perhaps the reperfusion which follows, is sufficient to generate a similar endothelial response. This would be in keeping with our study’s finding that Raynauds-like symptoms are more prevalent in climbers who frequently experience hot-aches.
Calcitonin gene-related peptide (CGRP) is a neuropeptide with a potent vasodilatory action. Immunohistochemical studies have identified a deficiency of CGRP nerve fibres in biopsies of finger skin from patients with RP and HAVS,26,27 suggesting that a dysfunction in the neurovascular axis may play a role in the disease pathophysiology. Goldsmith et al27 also investigated levels of Protein Gene Product 9.5 (PGP), which is a constitutive protein of all nerves. They found PGP immunostaining to be significantly reduced in patients with HAVS, suggesting a generalised loss of peripheral nerves. Prolonged periods of exposure to wet conditions in cold temperatures have been associated with peripheral neuropathy29 and so this may contribute to the impaired vascular function we have identified in the hands of winter climbers.
Limitations of the study: (1) Participants may not reflect a random sample of the winter-climbing population as those who experience troublesome cold-symptoms may have had increased motivation to participate in the study. (2) The laboratory study was not blinded and many of the climbers and controls were known personally by the author. (3) The questionnaire nature of this study resulted in participants offering a self-diagnosis of RS and despite efforts to explain the symptoms and features of RP within the questionnaire, this may have led to over-reporting.
Next steps: This pilot study has demonstrated that winter climbing is likely to be a risk factor for the development of RS, both from a clinical and laboratory perspective. Clinician assessment of RS amongst the winter climbing population may provide a more accurate prevalence rate by avoiding the issue of self-reporting. Collection of data including gender, family history, and medical history may lead to the identification of further associations. Future studies with LSCI should focus on ROIs 2, 3 and 4. Power calculations indicate that a sample size of 34 (per group) would be adequate to demonstrate significant difference (p<0.05) in the baseline value, peak value and recovery time between climber and control groups, based on taking the average flux between ROIs 2, 3 and 4. Ultrasound assessment of digital arteries and capillary nail folds may demonstrate structural morphology and further explain the pathophysiology underlying these changes in digital blood flux.
Conclusion
There is an increased prevalence of Raynaud’s symptoms within the winter-climbing population. The severity of Raynaud’s symptoms appears to be directly related to the climber’s experience of “hot-aches” – the reperfusion pain following cold-induced vasoconstriction. Laboratory studies of blood flow in the digits of winter climbers demonstrate changes consistent with those seen in patients with primary and secondary Raynaud’s phenomenon including decreased basal flux, decreased peak flux during post-occlusive reactive hyperaemia, a prolonged time to reach the peak flux and delayed recovery. A number of underlying mechanisms may be responsible including, Endothelin-1, NO, oxidative stress and peripheral neuropathy associated with CGRP. As winter-climbing continues to increase in popularity it is important that participants are made aware of this risk so that they may take preventative measures to avoid prolonged cold-exposure. Further research is required to identify effective preventative measures and investigate the pathophysiology underling this apparent manifestation of RP.
References
- Council TBM. GB Ice Climbers rack up for the 2015 Ice World Cup. [cited; Available from: https://www.thebmc.co.uk/gb-ice-climbers-rack-up-for-the-2015-ice-world-cup
- UIAA. Ice Climbing at the 2014 Sochi Winter Olympics. [cited; Available from: http://www.theuiaa.org/iceclimbing-sochi2014.html
- Herrick AL. Pathogenesis of Raynaud’s phenomenon. Rheumatology. 2005 May 1, 2005;44(5):587-96.
- Voulgari PV, Alamanos Y, Papazisi D, Christou K, Papanikolaou C, Drosos AA. Prevalence of Raynaud’s phenomenon in a healthy Greek population. Ann Rheum Dis. 2000 Mar;59(3):206-10.
- Garner R, Kumari R, Lanyon P, Doherty M, Zhang W. Prevalence, risk factors and associations of primary Raynaud’s phenomenon: systematic review and meta-analysis of observational studies. BMJ Open. 2015 March 1, 2015;5(3).
- Valdovinos ST, Landry GJ. Raynaud Syndrome. Techniques in Vascular and Interventional Radiology. 2014;17(4):241-6.
- Kennedy G, Khan F, McLaren M, Belch JJ. Endothelial activation and response in patients with hand arm vibration syndrome. Eur J Clin Invest. 1999 Jul;29(7):577-81.
- Roquelaure Y, Ha C, Le Manac’h AP, Bodin J, Bodere A, Bosseau C, et al. Risk factors for Raynaud’s phenomenon in the workforce. Arthritis Care & Research. 2012;64(6):898-904.
- Lambova SN, Muller-Ladner U. New lines in therapy of Raynaud’s phenomenon. Rheumatol Int. 2009 Feb;29(4):355-63.
- Roustit M, Cracowski J-L. Assessment of endothelial and neurovascular function in human skin microcirculation. Trends in Pharmacological Sciences. 2013;34(7):373-84.
- Roustit M, Cracowski JL. Non-invasive assessment of skin microvascular function in humans: an insight into methods. Microcirculation. 2012 Jan;19(1):47-64.
- Gaillard-Bigot F, Roustit M, Blaise S, Gabin M, Cracowski C, Seinturier C, et al. Abnormal amplitude and kinetics of digital postocclusive reactive hyperemia in systemic sclerosis. Microvascular Research. 2014;94(0):90-5.
- Wollersheim H, Droste H, Reyenga J, Thien T. Laser Doppler evaluation of skin vasomotor reflexes during sympathetic stimulation in normals and in patients with primary Raynaud’s phenomenon. International journal of microcirculation, clinical and experimental / sponsored by the European Society for Microcirculation. 1991;10(1):33-42.
- Grattagliano V, Iannone F, Praino E, De Zio A, Riccardi MT, Carrozzo N, et al. Digital laser doppler flowmetry may discriminate “limited” from “diffuse” systemic sclerosis. Microvasc Res. 2010 Sep;80(2):221-6.
- Murray A PJ. Raynaud’s Phenomenon: A Guide to Pathogenesis and Treatment. : Springer-Verlag New York; 2015.
- NHS. Raynaud’s phenomenon. 2012.
- Heslop J, Coggon D, Acheson ED. The prevalence of intermittent digital ischaemia (Raynaud’s phenomenon) in a general practice. The Journal of the Royal College of General Practitioners. 1983;33(247):85-9.
- Ziegler S, Gschwandtner M, Zoch C, Barth A, Minar E, Rudiger H, et al. Laser Doppler anemometry distinguishes primary Raynaud phenomenon from VWF syndrome. Microvasc Res. 2004 Nov;68(3):203-8.
- Murray AK, Moore TL, Manning JB, Taylor C, Griffiths CEM, Herrick AL. Noninvasive imaging techniques in the assessment of scleroderma spectrum disorders. Arthritis Care & Research. 2009;61(8):1103-11.
- Chen G-F, Sun Z. Effects of chronic cold exposure on the endothelin system; 2006.
- Tucker AT, Pearson RM, Cooke ED, Benjamin N. Effect of nitric-oxide-generating system on microcirculatory blood flow in skin of patients with severe Raynaud’s syndrome: a randomised trial. The Lancet. 1999;354(9191):1670-5.
- Romero LI, Zhang DN, Cooke JP, Ho HK, Avalos E, Herrera R, et al. Differential expression of nitric oxide by dermal microvascular endothelial cells from patients with scleroderma. Vasc Med. 2000;5(3):147-58.
- Forstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010 May;459(6):923-39.
- Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol. 2000 Feb;190(3):255-66.
- Castellani JW YA, Ducharme MB, Giesbrecht GG, Glickman E, Sallis RE. Prevention of Cold Injuries during Exercise. [cited; Available from: http://www.medscape.com/viewarticle/717044
- Bunker CB, Terenghi G, Springall DR, Polak JM, Dowd PM. Deficiency of calcitonin gene-related peptide in Raynaud’s phenomenon. Lancet. 1990 Dec 22-29;336(8730):1530-3.
- Goldsmith PC, Molina FA, Bunker CB, Terenghi G, Leslie TA, Fowler CJ, et al. Cutaneous nerve fibre depletion in vibration white finger. Journal of the Royal Society of Medicine. 1994;87(7):377-81.
- Takeuchi T, Futatsuka M, Imanishi H, Yamada S. Pathological changes observed in the finger biopsy of patients with vibration-induced white finger. Scand J Work Environ Health. 1986 Aug;12(4 Spec No):280-3.
- Irwin MS. Nature and mechanism of peripheral nerve damage in an experimental model of non-freezing cold injury. Ann R Coll Surg Engl. 1996 Jul;78(4):372-9.