Interventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs.

BACKGROUND: High altitude illness (HAI) is a term used to describe a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (8202 feet). Acute hypoxia, acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude. In this review, the first in a series of three about preventive strategies for HAI, we assess the effectiveness of six of the most recommended classes of pharmacological interventions. OBJECTIVES: To assess the clinical effectiveness and adverse events of commonly-used pharmacological interventions for preventing acute HAI. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), LILACS and trial registries in January 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text terms to search. SELECTION CRITERIA: We included randomized-controlled and cross-over trials conducted in any setting where commonly-used classes of drugs were used to prevent acute HAI. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We included 64 studies (78 references) and 4547 participants in this review, and classified 12 additional studies as ongoing. A further 12 studies await classification, as we were unable to obtain the full texts. Most of the studies were conducted in high altitude mountain areas, while the rest used low pressure (hypobaric) chambers to simulate altitude exposure. Twenty-four trials provided the intervention between three and five days prior to the ascent, and 23 trials, between one and two days beforehand. Most of the included studies reached a final altitude of between 4001 and 5000 metres above sea level. Risks of bias were unclear for several domains, and a considerable number of studies did not report adverse events of the evaluated interventions. We found 26 comparisons, 15 of them comparing commonly-used drugs versus placebo. We report results for the three most important comparisons: Acetazolamide versus placebo (28 parallel studies; 2345 participants)The risk of AMS was reduced with acetazolamide (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.56; I2 = 0%; 16 studies; 2301 participants; moderate quality of evidence). No events of HAPE were reported and only one event of HACE (RR 0.32, 95% CI 0.01 to 7.48; 6 parallel studies; 1126 participants; moderate quality of evidence). Few studies reported side effects for this comparison, and they showed an increase in the risk of paraesthesia with the intake of acetazolamide (RR 5.53, 95% CI 2.81 to 10.88, I2 = 60%; 5 studies, 789 participants; low quality of evidence). Budenoside versus placebo (2 parallel studies; 132 participants)Data on budenoside showed a reduction in the incidence of AMS compared with placebo (RR 0.37, 95% CI 0.23 to 0.61; I2 = 0%; 2 studies, 132 participants; low quality of evidence). Studies included did not report events of HAPE or HACE, and they did not find side effects (low quality of evidence). Dexamethasone versus placebo (7 parallel studies; 205 participants)For dexamethasone, the data did not show benefits at any dosage (RR 0.60, 95% CI 0.36 to 1.00; I2 = 39%; 4 trials, 176 participants; low quality of evidence). Included studies did not report events of HAPE or HACE, and we rated the evidence about adverse events as of very low quality. AUTHORS' CONCLUSIONS: Our assessment of the most commonly-used pharmacological interventions suggests that acetazolamide is an effective pharmacological agent to prevent acute HAI in dosages of 250 to 750 mg/day. This information is based on evidence of moderate quality. Acetazolamide is associated with an increased risk of paraesthesia, although there are few reports about other adverse events from the available evidence. The clinical benefits and harms of other pharmacological interventions such as ibuprofen, budenoside and dexamethasone are unclear. Large multicentre studies are needed for most of the pharmacological agents evaluated in this review, to evaluate their effectiveness and safety.

Sun protection for preventing basal cell and squamous cell skin cancers.

BACKGROUND: 'Keratinocyte cancer' is now the preferred term for the most commonly identified skin cancers basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which were previously commonly categorised as non-melanoma skin cancers (NMSC). Keratinocyte cancer (KC) represents about 95% of malignant skin tumours. Lifestyle changes have led to increased exposure to the sun, which has, in turn, led to a significant increase of new cases of KC, with a worldwide annual incidence of between 3% and 8%. The successful use of preventive measures could mean a significant reduction in the resources used by health systems, compared with the high cost of the treatment of these conditions. At present, there is no information about the quality of the evidence for the use of these sun protection strategies with an assessment of their benefits and risks. OBJECTIVES: To assess the effects of sun protection strategies (i.e. sunscreen and barrier methods) for preventing keratinocyte cancer (that is, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) of the skin) in the general population. SEARCH METHODS: We searched the following databases up to May 2016: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trial registries and the bibliographies of included studies for further references to relevant trials. SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) of preventive strategies for keratinocyte cancer, such as physical barriers and sunscreens, in the general population (children and adults), which may provide information about benefits and adverse events related to the use of solar protection measures. We did not include trials focused on educational strategies to prevent KC or preventive strategies in high-risk groups. Our prespecified primary outcomes were BCC or cSCC confirmed clinically or by histopathology at any follow-up and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for eligibility using Early Review Organizing Software (EROS). Similarly, two review authors independently used predesigned data collection forms to extract information from the original study reports about the participants, methods of randomisation, blinding, comparisons of interest, number of participants originally randomised by arm, follow-up losses, and outcomes, and they assessed the risk of bias. We resolved any disagreement by consulting a third author and contacted trial investigators of identified trials to obtain additional information. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included one RCT (factorial design) that randomised 1621 participants.This study compared the daily application of sunscreen compared with discretionary use of sunscreen, with or without beta-carotene administration, in the general population. The study was undertaken in Australia; 55.2% of participants had fair skin, and they were monitored for 4.5 years for new cases of BCC or cSCC assessed by histopathology. We found this study to be at low risk of bias for domains such as allocation, blinding, and incomplete outcome data. However, we found multiple unclear risks related to other biases, including an unclear assessment of possible interactions between the effects of the different interventions evaluated (that is, sunscreen and beta-carotene). We found no difference in terms of the number of participants developing BCC (n = 1621; risk ratio (RR) 1.03, 95% confidence interval (CI) 0.74 to 1.43) or cSCC (n = 1621; RR 0.88, 95% CI 0.50 to 1.54) when comparing daily application of sunscreen with discretionary use, even when analyses were restricted to groups without beta-carotene supplementation. This evidence was of low quality, which means that there is some certainty that future studies may alter our confidence in this evidence.We reported adverse events in a narrative way and included skin irritation or contact allergy.We identified no studies that evaluated other sun protection measures, such as the use of sun-protective clothing, sunglasses, or hats, or seeking the shade when outdoors. AUTHORS' CONCLUSIONS: In this review, we assessed the effect of solar protection in preventing the occurrence of new cases of keratinocyte cancer. We only found one study that was suitable for inclusion. This was a study of sunscreens, so we were unable to assess any other forms of sun protection. The study addressed our prespecified primary outcomes, but not most of our secondary outcomes. We were unable to demonstrate from the available evidence whether sunscreen was effective for the prevention of basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC).Our certainty in the evidence was low because there was a lack of histopathological confirmation of BCC or cSCC in a significant percentage of cases. Amongst other sources of bias, it was not clear whether the study authors had assessed any interaction effects between the sunscreen and beta-carotene interventions. We think that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.