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Year : 2020  |  Volume : 6  |  Issue : 2  |  Page : 70-75

A pilot study to assess the effectiveness of local application of salbutamol and nitroglycerine for improvement of hand dexterity and comfort in extreme cold climate at high altitude

1 Department of Physiology, All India Institiute of Medical sciences, Rishikesh, India
2 Department of Dermatology, Base Hospital Delhi Cantt & Army College of Medical Sciences, New Delhi, India
3 Department of Physiology, Army College of Medical Sciences, New Delhi, India
4 Department of Physiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
5 Vice Chancellor Sikkim Manipal University, Ex Director General Medical Services Army, Gangtok, Sikkim, India

Date of Submission07-Mar-2019
Date of Decision20-Apr-2020
Date of Acceptance19-Nov-2020
Date of Web Publication28-Dec-2020

Correspondence Address:
Gautam Kumar Singh
Base Hospital Delhi Cantt & Army College of Medical Sciences, New Delhi 110010
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijdd.ijdd_13_19

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Background: Reduced manual dexterity and hand comfort affect all people exposed to extreme cold. Ointment nitroglycerine 0.2% (NTG) and ointment salbutamol 0.5% (Sal) applied topically to the extremities could result in increased local blood flow and temperature, improving hand comfort and dexterity in extreme cold. Aim and Objectives: This study was designed to elucidate if the application of NTG or Sal would improve manual dexterity and hand comfort in extreme cold conditions. Materials and Methods: A double-blind, randomized controlled trial was conducted at 3500 m altitude in 105 individuals divided into three equal-sized groups. Group A received NTG, Group B placebo (white soft paraffin), and Group C Sal, for application to the extremities twice daily, for 2 weeks. Hand skin temperatures (Tsk), Pegboard scores, and a Graphic Rating Scale (GRS) for pain were compared before and after the intervention. Adverse effects and user acceptability criteria were recorded. Results: Participants of all three groups showed significant improvement in Tsk, Pegboard scores, and GRS scores postintervention, however none of the parameters were different between groups. The acceptability questionnaire scores were best in the placebo group. Conclusion: Neither NTG nor Sal was superior to placebo for improvement in hand comfort or dexterity, in extreme cold at high altitude.

Keywords: Extreme cold, hand comfort, hand dexterity, high altitude, nitroglycerine, salbutamol

How to cite this article:
Singh S, Singh GK, Kotwal A, Mohan L, Grewal R. A pilot study to assess the effectiveness of local application of salbutamol and nitroglycerine for improvement of hand dexterity and comfort in extreme cold climate at high altitude. Indian J Drugs Dermatol 2020;6:70-5

How to cite this URL:
Singh S, Singh GK, Kotwal A, Mohan L, Grewal R. A pilot study to assess the effectiveness of local application of salbutamol and nitroglycerine for improvement of hand dexterity and comfort in extreme cold climate at high altitude. Indian J Drugs Dermatol [serial online] 2020 [cited 2023 Jan 28];6:70-5. Available from: https://www.ijdd.in/text.asp?2020/6/2/70/305121

  Introduction Top

Skin, the largest interface between man and environment, is the sentinel site of the onslaught of environmental stressors. Approximately 140 million people worldwide are permanent residents at altitudes of over 2500 m, another 40 million sojournings annually at high altitude (HA) for work, sporting, or recreation. In India, all of Ladakh, parts of Northwest Kashmir, Sikkim, and Arunachal are inhospitable HA areas.[1] Hypoxia, high levels of ultraviolet radiation, and sub-zero temperatures for the greater part of the year, compounded by windchill, are all risk factors for varied human morbidity.[2] A large part of northern India, too, suffers cold wave conditions during extreme winters.

Cold injuries, including hypothermia, chilblains (pernio), and frostbite are the cause of the largest proportion of morbidity in lowlanders at HA.[3] The prevention of cold injuries requires good whole-body heat balance which may be achieved by adequate metabolic heat production and minimal heat loss to a cold environment. Uncovering the hands for dexterous work results in cooling, discomfort, loss of dexterity, and subsequently cold injury. Hand temperature, hence dexterity and comfort, is maintained best by ensuring maintenance of core body and arm/forearm temperature and prevention of heat loss.[4],[5],[6] While the former may be achieved by adequate nutrition, exercise, and protective clothing, heat loss cannot be prevented when working with bare hands. Thus, a warm body may have cold hands. While the vasoconstrictor response to cold protects core body temperature, repeated cold exposure enhances cold-induced vasodilation (CIVD), an intermittent cyclical vasodilation lasting a few seconds, increasing blood flow to exposed skin, thereby reducing discomfort and the risk of cold injuries. It is believed that the hypobaric hypoxia of HA attenuates CIVD response increasing the risk of cold injuries, but acclimatization over weeks may restore the response.[7],[8]

Although petrolatum and emollients are commonly believed to decrease the risk of cold injury, studies show that “protecting” emollients seem to cause a false sense of safety and increased risk of frostbite, probably through neglect of effective heat loss prevention measures.[9],[10]

At present, there is no topical therapy which claims or is approved for improving hand dexterity and comfort or prevention of cold injuries in sub-zero temperatures. Nitroglycerine (NTG), a vasodilator that relaxes venous as well as arterial musculature, has been used topically in Raynaud's disease, Raynaud phenomenon, systemic sclerosis, and anal fissures.[11],[12],[13] Ointment salbutamol (Sal) sulfate 0.5% has been reported to have beneficial effects in discoid lupus erythematosus due to anti-inflammatory and anti-angiogenic effects through β-2 adrenergic receptors.[14] Acting through the same receptors, it may increase blood circulation to the muscle. Scintigraphy in human volunteers has shown 30%–150% and 50%–250% increase in muscular circulation of the hand, with the application of ointment Sal sulfate 0.5%, and ointment NTG 0.2%, respectively.[15] This study was, therefore, conducted to investigate if the application of ointment Sal 0.5% and ointment NTG 0.2% results in improved skin temperature over the hand and if this is associated with improvement in manual dexterity and comfort in extreme cold climate at HA.

  Materials and Methods Top

A double-blinded, randomized, controlled trial was conducted, from January 25, 2011 to February 16, 2011, in a research laboratory associated with a multispecialty hospital at Leh (altitude 3500 m), Ladakh, India [Figure 1], consort diagram]. The minimum ambient morning (5–8 am) temperature during this period ranged from −12°C at the onset of the study to −10°C by the end of the study. Maximum daytime temperatures were also, sub-zero. Institutional ethical clearance was obtained and written informed consent was obtained as per the Declaration of Helsinki.
Figure 1: Consort diagram for the trial

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Subject selection

The employees of a telecommunication company, whose work routinely involved the performance of dextrous manual tasks outdoors, were the study population.

Inclusion and exclusion criteria

Healthy lowlanders who had been at HA (3500 m) for 1 month or longer were included in the study. Those with (a) existing cold injuries, (b) current systemic ailment, e.g., fever and acute upper respiratory infection, (c) previous episodes of cold injuries, (d) chronic systemic ailments, e.g., hypertension and diabetes mellitus were excluded from the study. Secondary exclusion criteria were occurrence of (a) acute systemic ailment, (b) troublesome adverse effects to study intervention, and (c) cold injury, during the study. Of the 237 volunteers, 205 were eligible by selection criteria, of whom, 105 were selected for the study using random number tables.


The trial administrator divided the selected individuals into three equal groups (named “A,” “B,” and “C”) by simple randomization. Participants were told their group and given cream that looked alike, in identical jars labeled with group names. The content of the jar was known only to the trial administrator. Groups A, B, and C were given NTG, white soft paraffin (placebo), and Sal, respectively.

Drug administration

Participants were advised to dry their hands and feet thoroughly after washing with warm water before applying 1 cm (using marked applicator) of the ointment on the dorsum of either hand and 2 cm on the dorsum of either foot, twice a day for 2 weeks. Study investigators met them twice daily, to enquire for any adverse effects and remind them to use the cream.


Pre- and postintervention tests were conducted, between 5 am and 8 am, 2 weeks apart. Ambient temperatures, Graphic Rating Scale (GRS) score for pain, Pegboard test for hand dexterity [Supplementary Figure 1] [Additional file 1], and skin surface temperature (Tsk) by infrared thermography (infrared camera, HSI3000, Palmer Wahl, USA) were measured on both days. Testing was done in a partitioned open space, to exclude windchill. Participants did not apply any cream/ointment on the hands, on the day of testing. Each participant marked the GRS for pain after 2 min of exposure of the bare hands to ambient, followed by measurement of Tsk and administration of the Pegboard test, in that order, the entire process taking 15 min. Tsk was measured on the dorsal aspect of each metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint and on the pulp of each digit. The mean Tsk of all MCP joints, all PIP joints, and all digital pulps of either hand was calculated. The Tsk of the MCP and PIP joints of the index finger and thumb was also recorded separately for correlation with the Pegboard test scores. For the Pegboard test, the participant was asked to insert as many pegs as possible in 30 s, first with one hand, then the other. This was done thrice and the mean of the three scores, with either hand, was used for analysis. Hand discomfort/pain was scored on a discrete scale from zero to ten (”0” implying no pain/distress and “10” agonizing pain/unbearable distress) on the GRS and scores recorded as whole numbers.

Ten or less participants were tested daily to prevent a large variation in ambient temperature during daily testing. An effort was, also, made to test equal number of participants from the three groups daily. Thus, although the median ambient temperatures for the three groups were different (not shown), the change in mean ambient temperature from pre- to postintervention testing Δ Ta was similar for all groups [Table 1].
Table 1: Differences in median values and ranges of different parameters before and after intervention

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Participants also answered an adverse effects questionnaire twice a day and an acceptability questionnaire at the end of the study [Supplementary Materials] [Additional file 2].

Statistical analysis

Nonparametric tests were used for analysis because the data were not distributed normally. Median values and ranges of all data were obtained by descriptive statistics. The Wilcoxon rank-sum test for paired samples was used to assess within group significance of difference, if any, in a parameter over time. The Mann–Whitney U test for independent samples was used to estimate the intergroup significance of the difference in a parameter both before and after the intervention. Correlation analysis between hand temperatures and Pegboard test scores and rank correlation of temperatures with GRS scores was used to establish the strength of association of changes in Tsk with improvement in dexterity and comfort levels.

  Results Top

Eighty-three of the 105 participants completed the study [Figure 1]. One participant from group B developed chilblains on the 3rd day of use of the cream, whereas one from group A developed a local allergic reaction of the hands. Both were examined by a dermatologist, treated, and dropped from the study.

The ambient temperatures were significantly higher at the time of postintervention testing. The Pegboard test score and mean Tsk at all measured points were significantly greater and the mean GRS score significantly lesser within groups, postintervention. However, intergroup comparison of Groups A or C versus Group B showed insignificant difference of median values of all tested parameters [Table 2]. The correlation of mean Pegboard scores with Tsk MCP and Tsk PIP joints of the index finger and thumb of either hand was significant but weak, both pre- and postintervention [Table 3]. Since the mean Tsk of the finger pulp was the lowest of all means of Tsk recorded, rank correlation of the lower of the mean Tsk pulp of either hand with GRS scores was sought and a weak but significant negative correlation was found (preintervention Spearman's Rho = −0.311, P = 0.0043, 95% confidence interval [CI] – 0.493 to −0.102, postintervention Spearman's Rho = −0.239, P = 0.0294, 95% CI – 0.433 to −0.0248). [Figure 2] shows one of the infrared images of the patient.
Table 2: Intergroup comparison of all parameters before and after intervention (Mann-Whitney U-test)

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Table 3: Pearson's correlation coefficients for correlation of Pegboard scores with hand temperatures

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Figure 2: Infrared images of the dorsum of the right hand of one of the patients. The green box indicates the point of focus of the camera (the area of maximal thermal resolution)

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Acceptability questionnaire

The proportion of participants reporting greater warmth of the hands/feet, with intervention, was not different between groups, whereas the proportion reporting improvement in the comfort of the extremities was significantly higher in Group “B” compared to Group C (77.4% vs. 35.71%, χ2 = 8.841, P = 0.003). Subjective perception of overall comfort was significantly greater, in Group B compared to both Groups A and C [Supplementary Table 1]a [Additional file 3] and [Supplementary Table 1]b [Additional file 4].

Adverse effects

Apart from the two participants, who developed chilblains and cutaneous allergic reaction to NTG cream, seven others developed mild adverse effects which did not warrant stoppage of therapy. One in Group B had mild redness and two discomfiting warmth of the hands within 3–4 h of application of the cream. In group C (Sal) two participants complained of troublesome warmth and two of a sensation of cooling of the hands within 3–4 h of application of cream.

  Discussion Top

All participants in this study, across groups, had improved finger dexterity, GRS scores, and increased Tsk, after the intervention. Between groups, however, no difference was found in any of these parameters, before or after the intervention. Both, exposure time and ambient temperature, have significant effects on finger skin temperatures and on Purdue Pegboard test scores in participants exposed to cold.[16] In this study, exposure time being the same in all participants, the improvement in Tsk and Pegboard scores, regardless of group, is in all probability attributable to the significantly greater ambient temperatures at the time of postintervention testing. In a study by Lehmuskallio, white soft paraffin (the placebo), an emollient was shown to affect hand temperatures for only the first 20 min after application.[9] The duration of action of Sal is 4–6 h and that of NTG approximately 8 h. The study parameters were measured 8–10 h after the last application of the test ointments/placebo when only long-term effects, if any, would persist. Therefore, it may be inferred that NTG and Sal have had no long-term effect on hand temperatures and dexterity, over and above that of placebo.

A thermogenic effect of the ointments in the first few hours after application, however, cannot be ruled out but the proportion of participants of any group reporting a subjective sensation of warmth within 3–4 h of application of the ointments was insignificantly different (50% of participants using NTG, 60.7% participants using Sal and 64.5% of the placebo group).

The finding of a significant positive correlation of Tsk of the thumb and index finger MCP/PIP joints with Pegboard scores was expected, these joints being responsible for the pincer movement required for manipulation in the Pegboard test. Manual dexterity depends on good tactile sensitivity, proprioception, muscle strength, and motor coordination, all of which are inhibited by cooling.[17],[18] The largest correlation coefficient of 0.456 obtained in this study suggests that Tsk contributes but 20.8% to Pegboard test scores. Imamura et al.[6] in a study of manual performance at −10°C have shown a correlation co-efficient of skin temperature to a “Timed” Pegboard test of 0.77. Factors such as wrist and forearm movement/muscle contraction and attention are also involved in proficiency with a Pegboard test.[19] These factors are unlikely to have played a major role in our participants because all participants were dressed in a similar extreme cold climate ensemble and had slept well. It has also been reported that exposure to −25°C at night (3–5 AM) results in a more pronounced decrease in manual dexterity coupled with greater skin temperature and diminished sensation of cold and pain, compared to similar exposure in the afternoon hours (3–5 pm) when dexterity is better despite lower skin temperature and greater sensation of cold and pain.[20] The participants of this study having been tested between 5 and 8 am, it is possible that such a desynchronization between skin temperatures and manual dexterity occurred, thereby reducing the strength of the association between the two.

Repeated intermittent exposure to cold leads to acclimatization and attenuates the subjective sensation of cold and cold-induced pain.[21] The participants of this study had been at 3500 m in peak winters for more than a month and would have acquired such acclimatization weakening the correlation of the GRS scores to skin temperatures. This finding underscores the important guideline that subjective cold/pain sensation during cold exposure should not be used as a dependable measure of the actual body and skin temperatures.[22] Testing in the early morning hours, when sensations of cold and pain may be attenuated, may also have affected the association.[20]

Acceptability questionnaire

The superior ranking of the placebo ointment compared to NTG and Sal, in the absence of objective supporting data (Tsk, Pegboard scores, and GRS scores) is consistent with the idea that subjective sensations/perceptions fail to differentiate the true physical and physiological impact of extreme cold.

Adverse effects

Coupled with the high user rating for the placebo, the occurrence of chilblains in one participant using this intervention supports the idea that the use of emollients increases the risk of cold injury, by creating a false sense of comfort.[9] Although cutaneous allergic reaction to NTG is not a serious condition, application of large quantities topically may result in systemic adverse effects. Vasodilatory headache is a recognized systemic adverse effect of topical NTG and the occurrence of severe acute mountain sickness has been reported in a lone mountaineer who used a NTG patch on the dorsum of his foot to prevent frostbite.[23]

Drawbacks of the study

This being a field trial, the subject sample size was small and the test conditions were not rigorously controlled.

  Conclusion Top

This pilot study failed to show any benefit of ointment NTG 0.2% and ointment Sal 0.5% applied topically to the hands and feet for 2 weeks, for improving hand dexterity and comfort in extreme cold conditions at HA.


The authors would like to thank all staff of the High Altitude Medical Research Centre, Leh.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Anderson ME, Moore TL, Hollis S, Jayson MI, King TA, Herrick AL. Digital vascular response to topical glyceryl trinitrate, as measured by laser Doppler imaging, in primary Raynaud's phenomenon and systemic sclerosis. Rheumatology (Oxford) 2002;41:324-8.  Back to cited text no. 12
Chung L, Shapiro L, Fiorentino D, Baron M, Shanahan J, Sule S, et al. MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: A randomized, controlled trial. Arthritis Rheum 2009;60:870-7.  Back to cited text no. 13
Jemec GB, Ullman S, Goodfield M, Bygum A, Olesen AB, Berth-Jones J, et al. A randomized controlled trial of R-salbutamol for topical treatment of discoid lupus erythematosus. Br J Dermatol 2009;161:1365-70.  Back to cited text no. 14
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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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