Gaurav Sikri

In Response to Risk Determinants of Acute Mountain Sickness by Lawrence and Reid

To the Editor: We recently read with profound interest the article titled “Risk Determinants of Acute Mountain Sickness and Summit Success on a 6-Day Ascent of Mount Kilimanjaro (5895 m)” by Lawrence and Reid. Authors of the present study have reported a lower incidence of acute mountain sickness (AMS) (52.6% with Lake Louise Score Z3) during a 6-day ascent of Mount Kilimanjaro than described in earlier studies on 4and 5-day ascents. This incidence of AMS is seen in spite of the fact that 88% of the trekkers were taking acetazolamide to prevent AMS. Presentation of a detailed evaluation of the temporal profile of acetazolamide intake by the trekkers, such as the location along the ascent route when chemoprophylaxis was initiated and stopped, could have aided understanding of the reasons for the lower incidence of AMS and thus led to a wider future application of the findings of the study. Acetazolamide is known to be effective, ideally if started 1 day before ascent in a dosage of 125 mg twice daily, and it should be continued for 2 to 3 days after target altitude has been achieved. In the present study, to avoid extreme altitude exposure to subjects, trekkers did not spend much time at the summit. The descent of trekkers would have lasted for a few hours, and the expedition doctor would have taken their Lake Louise Score after their return to the base camp (4730 m). This could have added to a recall bias, especially in the background of a possible disturbed sleep during the night of day 5 as all trekkers would have woken early in the morning of day 6 before attempting the summit. As physiologists working in the field of high-altitude medicine, we were interested in knowing the details of physical activity undertaken by the participants during the trek, such as average ascent/descent rate, especially on day 6. Amount of physical activity, rate of ascent, and actual altitude reached are known to affect the incidence of AMS. Also, 1 participant was diagnosed with high altitude pulmonary edema (HAPE) at 2900 m on day 2 and was treated with dexamethasone. We were interested to learn if this patient was experiencing concomitant AMS/high altitude cerebral edema. As per Wilderness Medical Society consensus guidelines, dexamethasone is indicated for prevention of HAPE in a susceptible subject and prevention/treatment of AMS and high altitude cerebral edema. Recommendations on its use for treatment of HAPE has been graded weak with low or very low quality evidence.

Comment on “Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema”

We read with profound interest the article titled “Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema” by Hilty et al. [1]. The authors have concluded that soluble urokinase-type plasminogen activator receptor (suPAR) plasma concentration measured before hypoxic exposure may predict susceptibility of a lowlander to high altitude pulmonary edema (HAPE). Despite the fact that inflammation is associated with acute hypoxia exposure in both HAPE and acute mountain sickness (AMS), studying these two high altitude illnesses together in the same cohort in this study seems to be convoluted. AMS and HAPE are known to have pathophysiological processes involving central nervous system and cardiopulmonary systems, respectively, with hypoxia being the common triggering factor [2]. This has also been indirectly acknowledged by the authors, while suggesting that cellular based inflammation does not play a role in the central form of high altitude disease, comprising AMS and high altitude cerebral edema. Moreover, occurrence of HAPEmay not always be associated with AMS [3]. Though the role of inflammation in priming pulmonary endothelium towards hypoxia-related pulmonary edema is well established, the study of the biomarker with respect to AMS is intriguing. Acute hypoxia exposure is associated with sympathetic activation, which results in rise in heart rate (HR) [4]. However, on the contrary as per Table 1 of the study, in dexamethasone prophylaxis group of HAPE susceptible subjects (n = 10), HR was found to decrease from their sea level HR of 74/min to 68/min after hypoxia exposure. As physiologists with experience of working in high altitude physiology, we contemplate if use of dexamethasone in these individuals resulted in these changes. HAPE is a disease known to occur two or more days after exposure to altitudes above 3000m [5]. However, subjects in this study were assessed for HAPE after 24 hours of hypoxia exposure at Margherita Hut (4559m), and an insignificant difference was seen in suPAR levels of HAPE susceptible and nonsusceptible individuals. Subjects were given dexamethasone 24 hours after hypoxia exposure as part of another research project. Otherwise serial measurements of suPAR in clinical overt HAPE subjects, if any, occurring over next 4 days of observation could have helped in establishing suPAR as a possible biomarker for HAPE susceptibility.The outcome of the bigger research project, of which the present work is a part, will definitely be worth a wait, which might mark the end of the pursuit of a well-established biomarker for a potentially fatal but preventable disease like HAPE.

Risk of high altitude pulmonary edema and telomere length

We read with profound interest the article entitled ‘Telomere length‐ related gene ACYP2 polymorphism is associated with the risk of HAPE in Chinese Han population’ by He et al., which reports a significant association between two single nucleotide polymorphisms (SNPs), rs12615793 and rs11896604, and a decreased risk of high altitude pulmonary edema (HAPE). A total of 568 Han Chinese lowlanders (265 HAPE patients and 303 healthy controls) from Northwest China were included in the study group. It was noted that HAPE was diagnosed on the basis of standard criteria, which included patient interviews such as cough, dyspnea and cyanosis at rest, as well as imaging examinations such as X‐ray, computed tomography or magnetic resonance imaging of the chest. All HAPE cases were found to have confirmed radiological findings suggestive of HAPE. Clinically, HAPE is diagnosed by the presence of at least two symptoms (dyspnea at rest, cough, weakness or decreased exercise performance, chest tightness or congestion) or at least two signs (rales or wheezing in at least one lung field, central cyanosis, tachypnea, tachycardia) in the setting of a recent gain in altitude. It would have been appropriate for He et al. to have also included other important parameters (e.g. heart rate and respiratory rate) required for the diagnosis of HAPE so that their results could be compared with other genetic studies carried out on HAPE. He et al. reported that none of the subjects of control group (who had same ascent rate and altitude as achieved by the HAPE cases) developed signs and symptoms of HAPE within 7 days of exposure to high altitude. The basis of choosing a ‘7‐day’ period of observation for the control group is not clear because HAPE is known to occur mostly 2–4 days after reaching an altitude of 3000 m or more. It would also have been appropriate for the timing of appearance of the symptoms of HAPE to have been included in their study. HAPE is classified into various grades, varying from mild to severe, based on clinical profile, X‐ray findings and objective criteria such as heart rate and respiratory rate. Although not within the scope of the

Acute mountain sickness amongst tourists to Lhasa

Acute mountain sickness is the commonest acute high altitude illness occurring at high altitude. Its prevalence is dependent on the ascent rate, altitude achieved, physical effort required to reach the target altitude and pharmacological intervention undertaken by the tourists visiting high altitude areas. This Letter to the Editor is an endeavour to re-emphasise the importance of all these factors affecting the prevalence of acute mountain sickness.

Acute mountain sickness and oxygen saturation.

Dear Editor: We read with profound interest the article titled “Diagnosis and prediction of the occurrence of acute mountain sickness measuring oxygen saturation—independent of absolute altitude?” by Leichtfried et al. [1]. The authors have concluded that practical use of pulse oximetry for the diagnosis and risk prediction of acute mountain sickness (AMS) in a population of trekking tourists remains debatable. Apart from the limitations brought out by the authors of this study, pulse oximetry has other inherent problems. Its use is limited by the cold induced peripheral vasoconstriction, and it is advised to warm the extremities before measuring oxygen saturation (SPO2) in a cold environment [2]. In the present study, it becomes relevant as all measurements were done at 7 am following breakfast in outdoors or after opening the windows of the room. We were interested in knowing if such warming of extremities prior to readings had been carried out in order to avoid the variation in SPO2 due to changes in ambient temperature. It is well known that the atmospheric pressures at high altitude (HA) areas located near equator are higher than other regions [3]. However, authors have studied 204 trekkers, who climbed altitudes of 2500–5500m in Nepal, India, Africa, and South America located over varying latitudes, as one cohort. The altitudes of the “incomparable” latitudes would have exposed trekkers to diverse degrees of hypobaric hypoxia [3]. It would have been nice if AMS data for each expedition was presented separately so as to enable comparison of outcome of this work with other studies. In the present work, authors have stated that the trekkers walked with small loads for 4–6 h daily at altitudes ranging from 2500 to 5500 m and the daily difference in their sleeping altitudes was not more than 300–400 m. As per a popular rule of thumb amongst trekkers, this ascent rate is considered to be conservative provided this much of ascent is followed by 2 to 3 days of rest at that altitude [3]. It would have been interesting if authors had divided the subjects into groups depending on the peak altitude achieved by the mountaineers on daily basis (ascent profile) and then studied the correlation between altitude dependent SPO2 and occurrence of AMS in each group. The concept given by the authors that correlation between SPO2 and AMS are independent of absolute altitudes, and the time course of adaptation at these altitudes is quite novel. The authors have further qualified the basis of their hypothesis by not making consistency in ascent profiles of subjects a prerequisite to this study. But this view is quite divergent from the established fact that SPO2 is a function of the arterial partial pressure of oxygen (PaO2), and this relationship is not linear. SPO2 falls significantly with respect to small changes in PaO2 at HA [2]. Hence other workers have used absolute altitudes in studies on AMS and altitude dependent SPO2 [4]. Contrary to the authors’ assumptions that time course of HA adaptation is not important, the self-limiting symptoms of AMS are known to occur 6–12 h after an of ascent of 2500 m or more and these symptoms generally subside by 2–3 days of stay [3, 5]. However, as mountaineers in this study have scaled altitude varying from 2500 to 5500 m on different days of the summits, it becomes pertinent for authors to specify the * Gaurav Sikri drgaurav35@gmail.com

Optic Nerve Sheath Diameter and Acute Mountain Sickness.

To the Editor: We read with great interest the article titled “Optic Nerve Sheath Diameter Increase on Ascent to High Altitude: Correlation With Acute Mountain Sickness,”1 which was part of a double-blind randomized placebocontrolled trial.2 The authors concluded that the use of sonography for measurement of the optic nerve sheath diameter in cases of acute mountain sickness has a limited role as a diagnostic tool. As physiologists with experience in the field of hypoxia and high altitude, we were interested in knowing the actual hike time taken by the participants to travel a moderately strenuous 4.3 km (as brought out in the earlier published work2) from 3545 to 3810 m. Physical exertion of even a short duration during the early part of ascent to 3810 m could have initiated or aggravated symptoms of acute mountain sickness, which would have influenced the self-reported symptom-based Lake Louise score on day 1 of the evaluation.3 Moreover, the participants of the study had “high” risk for developing acute mountain sickness, as they ascended more than 3500 m (from 300 m at residence to 3810 m) in 1 day.2,4 That was probably why the acute mountain sickness incidence of 55.8% (48 of 86) in the study was higher compared to other studies at moderate high altitude.5 Traditionally, acute mountain sickness is diagnosed as a Lake Louise score higher than 3 in the presence of headache, and the same criteria were used in this study. However, unfortunately, the Lake Louise score system has its own inevitable limitations. Some form of fatigue or lack of sleep is likely to be present after a long journey or a hike at high altitude. To overcome this factor, for the purpose of research and to have clinically relevant acute mountain sickness, a Lake Louise score of 5 or higher has been suggested by Bartsch et al.6 In this study, evaluation and analysis of the optic nerve sheath diameter and the Δ optic nerve sheath diameter in participants with clinically relevant acute mountain sickness (using a Lake Louise score ≥5) would have given a new perspective to the field of sonography at high altitude in diagnosing severe acute mountain sickness and high-altitude cerebral edema (a severe form of acute mountain sickness with neurologic signs such as ataxia, confusion, and an altered mental state).4

Role of dexamethasone in prevention of high altitude pulmonary edema

its role remains questionable for prevention and treatment of HAPE. However, dexamethasone is recommended for prevention of AMS/HACE in individuals who have a history of allergic reaction to acetazolamide (recommendation grade: 1A). Gradual ascent and a calcium channel blocker like nifedipine (60 mg SR) are the recommended preventive measures for HAPE. Other drugs as reported by Bhagi et al. have no or limited roles to play in prevention of HAPE. The long-acting inhaled beta agonist salmeterol can only be used as a supplement to nifedipine. Phosphodiesterase inhibitors like tadalafil (10 mg twice daily) have a preventive role only in HAPE-susceptible individuals. Although not recommended by the WMS, inhaled nitric oxide in combination with oxygen has a role to play in treatment of HAPE, but the medical infrastructure required for a nitric oxide delivery system does not warrant a mention of its role in prevention of HAPE.

ROCK2 and MYLK variants and high-altitude pulmonary edema

© 2016 Sikri and Bhattachar. This work is published by Dove Medical Press Limited, and licensed under a Creative Commons Attribution License. The full terms of the License are available at http://creativecommons.org/licenses/by/4.0/. The license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Inevitable Acclimatization and Acute Mountain Sickness

I read the article titled “Inhaled Budesonide and Oral Dexamethasone Prevent Acute Mountain Sickness” with great interest. Acute mountain sickness is a self-limiting disease after acute ascent above 2500 m, and its symptoms are most pronounced after spending one night at an altitude. These symptoms generally subside with acclimatization on their own within 2-3 days of arrival at high altitude. Interestingly, all lowlander subjects in this study were exposed to acute hypobaric hypoxia twice with varying quantum: the first time on July 4, 2013 (from 650 m to 2600 m) and the second time on July 7, 2013 (from 3200 m to 4200 m). However, their Lake Louise score was taken on July 8, 2013 after descending from 4200 m to 3900 m and having already spent 96 hours at altitudes varying from 2600 m to 4200 m (“inevitable acclimatization”). It would have been very interesting to compare the incidence and severity of acute mountain sickness of all 3 groups if the Lake Louise score was also taken on the mornings of July 5, 2013 (2600 m) and July 8, 2013 (4200 m) following each of the acute ascents. Previous exposure to high altitude, rate of ascent, and amount of physical exertion undertaken at high altitude are known risk factors for occurrence of acute mountain sickness. In the present study, authors have reported an incidence of acute mountain sickness in the placebo group as 60.46% at 3900 m after slow ascent and “inevitable

Acute mountain sickness and duration of pre-exposure to high altitude.

We recently read the article ‘Short-term high-altitude pre-exposure improves neurobehavioral ability’ by Guo et al. [1] with profound interest. In this field study with a large sample size, the authors have showed that a short-term pre-exposure (4 days) at 3700 m elicits a greater effect compared with a long-term pre-exposure (3-month) in improving human neurobehavioral parameters, including mood states and cognitive performance, and reducing acute mountain sickness (AMS) at an altitude of 4400 m. The authors evaluated mood states, cognitive performance, and AMS at 400, 3700 m (on the 4th day of the exposure), and 4400 m (on the 10th day of exposure) in participants.