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Sleeping with elevated upper body does not attenuate acute mountain sickness - pragmatic randomized clinical trial
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Sleeping with elevated upper body does not attenuate acute mountain sickness - pragmatic randomized clinical trial Ulrich Limper M.D. , Vera Fiala , Jens Tank M.D. , Eva-Maria Elmenhorst M.D. , Gereon Schaelte M.D. , Ya-Yu Monica Hew Ph.D. , Peter Gauger , Peter Martus Ph.D. , Jens Jordan M.D. PII: DOI: Reference:
S0002-9343(20)30123-6 https://doi.org/10.1016/j.amjmed.2020.01.024 AJM 15598
To appear in:
The American Journal of Medicine
Please cite this article as: Ulrich Limper M.D. , Vera Fiala , Jens Tank M.D. , Eva-Maria Elmenhorst M.D. , Gereon Schaelte M.D. , Ya-Yu Monica Hew Ph.D. , Peter Gauger , Peter Martus Ph.D. , Jens Jordan M.D. , Sleeping with elevated upper body does not attenuate acute mountain sickness - pragmatic randomized clinical trial, The American Journal of Medicine (2020), doi: https://doi.org/10.1016/j.amjmed.2020.01.024
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Sleeping with elevated upper body does not attenuate acute mountain sickness - pragmatic randomized clinical trial
Ulrich Limper, M.D. 1,2, Vera Fiala 4, Jens Tank, M.D. 1, Eva-Maria Elmenhorst, M.D. 1, 3
, Gereon Schaelte, M.D. 4, Ya-Yu Monica Hew, Ph.D. 1, Peter Gauger 1, Peter
Martus, Ph.D. 5, Jens Jordan, M.D.1, 6, *
1
German Aerospace Center (DLR), Institute of Aerospace Medicine, Cologne,
Germany 2
Department of Anesthesiology and Intensive Care Medicine, Merheim Medical
Center, Hospitals of Cologne, University of Witten/Herdecke, Cologne, Germany 3
Institute for Occupational, Social and Environmental Medicine, Medical Faculty,
University Hospital RWTH Aachen, Aachen, Germany 4
Department of Anaesthesiology, Medical Faculty, University Hospital RWTH
Aachen, Aachen, Germany 5
Institute of Medical Biometry, University of Tuebingen, Tuebingen, Germany
6
Chair of Aerospace Medicine, Medical Faculty, University of Cologne, Cologne,
Germany
Running title: Elevated head position and acute mountain sickness
*
Corresponding author:
Jens Jordan, MD German Aerospace Center (DLR) Institute of Aerospace Medicine Linder Hoehe D-51147 Cologne Phone: +49 (0)2203 601 3115 Fax: +49 (0)2203 695211 [email protected] http://www.dlr.de/me/en/
Word count title: 16 Word count abstract: 239 Word count Clinical Significance: 64 Word count main text (incl. references): 1389 References: 8 Tables: 1 Figures: 2
CRediT Author Statement: Dr. Ulrich Limper: Conceptualization, Methodology, Formal analysis, Investigation, Writing - Original Draft, Writing - Review & Editing, Funding acquisition Mrs. Vera Fiala: Formal analysis, Investigation, Writing - Review & Editing, Project administration, Prof. Jens Tank: Investigation, Project administration, Provision of study materials Dr. Eva-Maria Elmenhorst: Methodology, Supervision, Writing - Review & Editing Dr. Gereon Schaelte: Methodology, Writing - Review & Editing, Supervision Dr. Ya-Yu Monica Hew: Investigation, Project administration Mr. Peter Gauger: Provision and design of study materials (wedges), Visualization, Investigation Prof. Peter Martus: Formal analysis, Methodology; Programming Prof. Jens Jordan: Supervision, Writing - Review & Editing, Funding acquisition, Methodology
Author Financial Disclosure: This study was supported by the programmatic funding of the German Aerospace Center (DLR) and by a grant from the German Society for Mountain- and Expedition Medicine (BExMed). Dr. Ulrich Limper reports grants from German Society for Mountain and Expedition Medicine (BExMed), during the conduct of the study. Mrs. Vera Fiala has nothing to disclose. Prof. Jens Tank has nothing to disclose.
Dr. Eva-Maria Elmenhorst has nothing to disclose. Dr. Gereon Schaelte has nothing to disclose. Dr. Ya-Yu Monica Hew has nothing to disclose. Mr. Peter Gauger has nothing to disclose. Prof. Peter Martus has nothing to disclose. Prof. Jens Jordan has nothing to disclose.
Transparency declaration: The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Data Availability Statement The authors declare that the data supporting the findings of this study are available within the article. Anonymized data will be shared from the corresponding author upon reasonable request from any qualified investigator.
Clinical Significance
In this pragmatic, randomized clinical trial that included 134 adults, mountaineers at 4554 meters showed an overnight increase in the AMS-C Acute Mountain Sickness score of 0.121±0.679 when sleeping with the upper body elevated vs 0.250±0.575 when sleeping in a horizontal position, a nonsignificant difference.
Sleeping with the upper body elevated by 30° does not lead to relevant reductions in acute mountain sickness symptoms.
Abstract Purpose: Acute mountain sickness commonly occurs following ascent to high altitude and is aggravated following sleep. Cephalad fluid shifts have been implicated. We hypothesized that sleeping with the upper body elevated by 30°, reduces the risk of acute mountain sickness. Methods: In a pragmatic, randomized, observer-blinded field study at 4,554 meters altitude, we investigated 134 adults aged 18–70 years with a Lake Louise score (LLS) between 3 and 12 points at the evening of their arrival at the altitude. The individuals were exposed to sleeping on an inflatable cushion elevating the upper body by 30° or on a sham pillow in a horizontal position. The primary endpoint was the change in the Acute Mountain Sickness-Cerebral (AMS-C) score in the morning after sleeping at an altitude of 4,554 meters compared with the evening before. Sleep efficiency was the secondary endpoint. Results: Among 219 eligible mountaineers, 134 fulfilled the inclusion criteria and were randomized. The AMS-C score increased by 0.250±0.575 in the control group and by 0.121±0.679 in the intervention group (difference 0.105, 95% CI -0.098 – 0.308, p = 0.308). Oxygen saturation in the morning was 79±6 % in the intervention group and 78±6 % in the control group (p=0.863). Sleep efficiency did not differ between groups (p=0.115). Conclusions: Sleeping with the upper body elevated by 30° does not lead to relevant reductions in acute mountain sickness symptoms or hypoxemia at high altitude. Trial registration: German Clinical Trial Register DRKS00012676.
Introduction Acute mountain sickness (AMS) commonly occurs following rapid ascent to high altitude. Since more than 140 million people worldwide reside at altitudes above 2500 meters, the condition is not restricted to recreational mountaineers. AMS heralds potentially life-threatening cerebral edema. While mountaineers commonly take medications, such as acetazolamide or glucocorticoids as preventive measures 1
, trials testing such interventions have been small and of variable quality. Elevated
intracranial pressure and edema formation through hypoxemia-induced dilation of cerebral arteries
2
and intracranial venous congestion have been implicated.
Maneuvers augmenting cephalad fluid shifts including bending forward and sleeping in the supine position exacerbate symptoms
3
. Conversely, patients with head
pathologies are commonly positioned with the head of the bed elevated to attenuate cephalic pressure and edema formation
4
. Sleeping with the upper body is
recommended as AMS countermeasure 5, however, evidence from randomizedcontrolled trials is lacking. Therefore, we tested the hypothesis that sleeping with the upper body elevated by 30° reduces the risk of AMS compared to sleeping in a horizontal position.
Methods We approached adults aged 18–70 years who had planned to climb to Capanna Regina Margherita in the Italian Alps located 4,554 meters above sea level, and stay there for at least one night. We recruited through social media, email messages distributed by mountain hut operators, and staff stationed at lower altitudes. Participants had to have a Lake Louise score (LLS) between 3 and 12 points on the evening of their arrival at 4,554 meters. Since consent forms and questionnaires were available in English, Italian, German, and French, they had to
speak at least one of these languages. This trial was prospectively registered on the 04/07/2017 with the German Clinical Trials Register (DRKS00012676). Written informed consent was obtained on site, and this study was approved by the ethics committees of the North Rhine Medical Association (lfd. Nr. 2017165) and the University of Torino (Prot. n. 153128 del 29\5\17). Informed consent for publication of identifying images in an online open-access publication was obtained from the individual in figure 2. All research was performed in keeping with the Medical Association's professional code of conduct of Germany and based on the seventh version of the Declaration of Helsinki. On arrival, eligible participants were randomly assigned daily in a 1:1 ratio by drawing from a sealed slip box to sleep on an inflatable cushion elevating the upper body by 30° or to sleeping on a sham pillow in the horizontal position (Figure 2). Randomization was not performed until the participants went to bed to keep the subject blinded for the intervention as long as possible. On the evening before sleeping at high altitude and the next morning, participants were evaluated by staff blinded for the intervention. The change in the Acute Mountain Sickness-Cerebral (AMS-C) score in the morning after sleeping at 4,554 meters altitude compared with the evening before was the primary endpoint of the study. Sleep efficiency percent in the night at 4,554 meters altitude was assessed using a sleep log and compared to normal sleep at home, which is the secondary endpoint. We also compared oxygen saturation and heart rate measured by pulse oximetry in the morning after sleeping at 4,554 meters altitude to the evening before. Sample size calculation was based on previously collected LLS and AMS-C data in 11 mountaineers at the same location. A 50 percent reduction in the primary endpoint was considered relevant. The AMS-C score showed greater accuracy than the LLS and was thus selected as the primary end point. We estimated that a total of
62 mountaineers would be needed to detect a relevant difference between groups, with a two-tailed α of 0.05 and a (1-β) of 0.80, for a comparison of 2 independent proportions. According to a prospective data analysis plan, primary and secondary endpoints were analyzed by an intention-to-treat approach and by Analysis of Covariance (ANCOVA). A value for p<0.05 was considered significant. All data are expressed as mean ± standard deviation.
Results Among the potentially eligible 219 mountaineers, 134 had LLS of 3–12 points upon arrival at 4,554 meters and underwent randomization (Figure 1). None dropped out of the study. Participant demographics, comorbidities, and
prescribed
medications are given in the table. All participants tolerated their assigned sleep positions. None reported negative effects or progressed to high altitude pulmonary or cerebral edema. Forty percent were on medications for different indications (Table). AMS-C score increased by 0.250±0.575 in the control group sleeping in the horizontal position and by 0.121±0.679 in the intervention group sleeping with the upper body elevated by 30° (difference 0.105, 95% CI -0.098–0.308, p=0.308) (Figure 2). Self-medication had no relevant influence on the primary outcome (p=0.222). Sleep efficiency was profoundly reduced at altitude compared to a normal sleep at home in both the control group (72±31 and 96±5%) and the intervention group (66±27 and 93±10%). However, sleep efficiency did not differ between groups (difference 3%, 95% CI -0.8 – 7.2%, p=0.115). Headache incidence increased over night to a similar extent in the control and in the intervention group (p=0.251). In the control group, oxygen saturation and heart rate were 78±5 % and 93±14 bpm in the evening and 78±5 % and 89±16 bpm in the morning. In the intervention group,
oxygen saturation and heart rate were 79±5 % and 90±15 bpm in the evening and 79±5 % and 88±15 bpm in the morning.
Discussion The important findings of our study are that sleeping with the upper body elevated by 30° is neither effective in reducing AMS nor in improving sleep efficiency or hypoxemia. Our pragmatic clinical trial conducted under field conditions was sufficiently powered to detect clinically meaningful improvements. Thus, the intervention cannot be generally recommended for preventive purposes. However, we cannot exclude modest improvements in symptoms or in the risk to progress to overt cerebral or pulmonary edema. Our findings are somewhat unexpected because cephalad fluid shifts have been implicated in the pathogenesis of AMS
2,3
. Additionally, elevation of the upper
body is commonly applied as an adjunctive intervention in patients with traumatic brain injury, stroke, and other conditions associated with increased intracranial pressure and cerebral edema formation. We speculate that fluid redistributions elicited through elevation of the upper body may not have been sufficient to overcome permeability changes in the cerebral microcirculation due to high altitude exposure. Similarly, clinical outcomes did not differ between patients who were randomized to a seated or supine position following acute stroke 6. Many people travel worldwide to high altitudes and are at risk for AMS. Mountaineers commonly take medications such as acetazolamide or glucocorticoids as preventive or therapeutic measure often without medical supervision 7. A recent meta-analysis concluded
1
that these interventions may be effective; however, the
data were of moderate quality for acetazolamide and of low quality for inhaled glucocorticoids. Moreover, many studies did not sufficiently report adverse effects
making clinical risk-benefit assessment difficult. Finally, individuals at risk in economically disadvantaged parts of the world may not have access to such treatments. Safe and inexpensive non-pharmacological prophylactic and therapeutic measures not requiring medical supervision are needed 8.
Acknowledgements The authors would like to thank the subjects, whose participation made this study possible. Furthermore the authors gratefully acknowledge the technical support of Wolfram Sies and the administrative support of Christine Becker to this study. The authors are grateful to Andrea Enzio for mountain guiding. The authors express their appreciation to the teams operating Capanna Gnifetti and Capanna Margherita. This work was supported by the programmatic funding of the German Aerospace Center (DLR) and by a grant from the German Society for Mountain- and Expedition Medicine (BExMed).
Clinical Significance
Mountaineers at 4554 meters showed an overnight increase in the AMS-C Acute Mountain Sickness score of 0.121±0.679 when sleeping with the upper body elevated vs 0.250±0.575 when sleeping in a horizontal position, a nonsignificant difference.
Sleeping with the upper body elevated by 30° does not lead to relevant reductions in acute mountain sickness symptoms.
References 1
Nieto Estrada, V. H. et al. Interventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs. The Cochrane database of systematic reviews 6, Cd009761, doi:10.1002/14651858.CD009761.pub2 (2017). 2
Lawley, J. S. et al. Normobaric hypoxia and symptoms of acute mountain sickness: Elevated brain volume and intracranial hypertension. Ann Neurol 75, 890-898, doi:10.1002/ana.24171 (2014).
3
Wilson, M. H. & Imray, C. H. The cerebral venous system and hypoxia. J Appl Physiol (1985) 120, 244-250, doi:10.1152/japplphysiol.00327.2015 (2016).
4
Kenning, J. A., Toutant, S. M. & Saunders, R. L. Upright patient positioning in the management of intracranial hypertension. Surgical neurology 15, 148-152 (1981). 5
Küpper, T., Gieseler, U., Angelini, C., Hillebrandt, D. & Milledge, J. RECOMMENDATION OF THE UIAA MEDICAL COMMISSION VOL: 2 Emergency Field Management of Acute Mountain Sickness, High Altitude Pulmonary Edema, and High Altitude Cerebral Edema. www.theuiaa.org/medical_advice.html (2012).
6
Anderson, C. S. et al. Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke. The New England journal of medicine 376, 24372447, doi:10.1056/NEJMoa1615715 (2017).
7
Donegani, E. et al. Drug Use and Misuse in the Mountains: A UIAA MedCom Consensus Guide for Medical Professionals. High altitude medicine & biology 17, 157-184, doi:10.1089/ham.2016.0080 (2016). 8
Simancas-Racines, D. et al. Interventions for treating acute high altitude illness. The Cochrane database of systematic reviews 6, Cd009567, doi:10.1002/14651858.CD009567.pub2 (2018).
Figure legends
Figure 1. Participant flow.
Figure 2. Influences of sleeping position on overnight changes in acute mountain sickness severity, hypoxemia and sleep efficiency. In the intervention group, subjects slept with their upper body elevated on an inflatable wedge (box E). Two different sizes of wedges were used depending on the subject’s height (small wedge, 80 cm length of the +30° subject support area and 40 cm height; large wedge, 100 cm length of the +30° subject support area and 50 cm height). In the control group, subjects slept on an 8 cm high, inflatable sham pillow allowing a horizontal body position (box E). Sleeping position had no significant effect on the
evolution of acute mountain sickness severity overnight at 4554 meters (boxes A and B). The intervention failed, compared to the control, to improve hypoxemia overnight (box C). Subjects of both groups presented considerably disturbed sleep at altitude compared to their home environment but without any significant influence of the study intervention (box D). Center lines of box-plots show the medians; box limits indicate the 25th and 75th percentiles; crosses represent sample means; data points are plotted as open circles.
Table legends Baseline Characteristics and self-medication (cointerventions) Horizontal position
Elevated position
(n=72)
(n=62)
Age, mean (SD), yr
40.5 (11.5)
41.7 (11.6)
Male gender (n), %
74 (53)
61 (38)
Height, mean (SD), cm
175 (7)
174 (9)
Weight, mean (SD), kg
72.4 (12.2)
69.5 (10.6)
BMI (SD), kg*m-2
23.4 (2.7)
23.0 (2.5)
AMS History (n), %
34 (24)
23 (14)
Smoking (n), %
10 (7)
11 (6)
a
Regular medication (n), %
11 (8)
15 (9)
b
Chronic medical conditions (n), %
11 (8)
15 (9)
40.0 (28)
41.0 (25)
33.3 (23)
32.8 (20)
Nausea (n), %
1.4 (1)
1.6 (1)
AMS (n), %
8.7 (6)
9.8 (6)
Other (n), %
2.9 (2)
3.3 (2)
ASS (n), %
13.0 (9)
9.8 (6)
Ibuprofen (n), %
7.2 (5)
16.4 (10)
Paracetamol (n), %
8.7 (6)
6.6 (4)
Any other NSAR (n), %
7.2 (5)
4.9 (3)
Acetazolamid (n), %
4.3 (3)
1.6 (1)
Dexamethason (n), %
1.4 (1)
0
Subject Characteristics
Cointerventions Medication within 24 h before study inclusion (n), % Treatment Intentions Headache (n), %
Pharmacological Treatments
Table.
a
Regular medications include antihypertensive medication as ACE inhibitors and
calcium channel blockers, thyroid hormones, anti-asthmatic medication such as β2 mimetics, glucocorticoids and leukotriene receptor antagonists, oral contraceptives, low-dose aspirin, new oral anticoagulants and antidepressants. b
Chronic medical conditions include arterial hypertension, thyroid dysfunction, asthma, chronic
kidney failure, venous thrombosis, depression, iron deficiency and hypercholesterinemia.
Sleeping with elevated upper body does not attenuate acute mountain sickness - pragmatic randomized clinical trial Ulrich Limper M.D. , Vera Fiala , Jens Tank M.D. , Eva-Maria Elmenhorst M.D. , Gereon Schaelte M.D. , Ya-Yu Monica Hew Ph.D. , Peter Gauger , Peter Martus Ph.D. , Jens Jordan M.D. PII: DOI: Reference:
S0002-9343(20)30123-6 https://doi.org/10.1016/j.amjmed.2020.01.024 AJM 15598
To appear in:
The American Journal of Medicine
Please cite this article as: Ulrich Limper M.D. , Vera Fiala , Jens Tank M.D. , Eva-Maria Elmenhorst M.D. , Gereon Schaelte M.D. , Ya-Yu Monica Hew Ph.D. , Peter Gauger , Peter Martus Ph.D. , Jens Jordan M.D. , Sleeping with elevated upper body does not attenuate acute mountain sickness - pragmatic randomized clinical trial, The American Journal of Medicine (2020), doi: https://doi.org/10.1016/j.amjmed.2020.01.024
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Sleeping with elevated upper body does not attenuate acute mountain sickness - pragmatic randomized clinical trial
Ulrich Limper, M.D. 1,2, Vera Fiala 4, Jens Tank, M.D. 1, Eva-Maria Elmenhorst, M.D. 1, 3
, Gereon Schaelte, M.D. 4, Ya-Yu Monica Hew, Ph.D. 1, Peter Gauger 1, Peter
Martus, Ph.D. 5, Jens Jordan, M.D.1, 6, *
1
German Aerospace Center (DLR), Institute of Aerospace Medicine, Cologne,
Germany 2
Department of Anesthesiology and Intensive Care Medicine, Merheim Medical
Center, Hospitals of Cologne, University of Witten/Herdecke, Cologne, Germany 3
Institute for Occupational, Social and Environmental Medicine, Medical Faculty,
University Hospital RWTH Aachen, Aachen, Germany 4
Department of Anaesthesiology, Medical Faculty, University Hospital RWTH
Aachen, Aachen, Germany 5
Institute of Medical Biometry, University of Tuebingen, Tuebingen, Germany
6
Chair of Aerospace Medicine, Medical Faculty, University of Cologne, Cologne,
Germany
Running title: Elevated head position and acute mountain sickness
*
Corresponding author:
Jens Jordan, MD German Aerospace Center (DLR) Institute of Aerospace Medicine Linder Hoehe D-51147 Cologne Phone: +49 (0)2203 601 3115 Fax: +49 (0)2203 695211 [email protected] http://www.dlr.de/me/en/
Word count title: 16 Word count abstract: 239 Word count Clinical Significance: 64 Word count main text (incl. references): 1389 References: 8 Tables: 1 Figures: 2
CRediT Author Statement: Dr. Ulrich Limper: Conceptualization, Methodology, Formal analysis, Investigation, Writing - Original Draft, Writing - Review & Editing, Funding acquisition Mrs. Vera Fiala: Formal analysis, Investigation, Writing - Review & Editing, Project administration, Prof. Jens Tank: Investigation, Project administration, Provision of study materials Dr. Eva-Maria Elmenhorst: Methodology, Supervision, Writing - Review & Editing Dr. Gereon Schaelte: Methodology, Writing - Review & Editing, Supervision Dr. Ya-Yu Monica Hew: Investigation, Project administration Mr. Peter Gauger: Provision and design of study materials (wedges), Visualization, Investigation Prof. Peter Martus: Formal analysis, Methodology; Programming Prof. Jens Jordan: Supervision, Writing - Review & Editing, Funding acquisition, Methodology
Author Financial Disclosure: This study was supported by the programmatic funding of the German Aerospace Center (DLR) and by a grant from the German Society for Mountain- and Expedition Medicine (BExMed). Dr. Ulrich Limper reports grants from German Society for Mountain and Expedition Medicine (BExMed), during the conduct of the study. Mrs. Vera Fiala has nothing to disclose. Prof. Jens Tank has nothing to disclose.
Dr. Eva-Maria Elmenhorst has nothing to disclose. Dr. Gereon Schaelte has nothing to disclose. Dr. Ya-Yu Monica Hew has nothing to disclose. Mr. Peter Gauger has nothing to disclose. Prof. Peter Martus has nothing to disclose. Prof. Jens Jordan has nothing to disclose.
Transparency declaration: The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Data Availability Statement The authors declare that the data supporting the findings of this study are available within the article. Anonymized data will be shared from the corresponding author upon reasonable request from any qualified investigator.
Clinical Significance
In this pragmatic, randomized clinical trial that included 134 adults, mountaineers at 4554 meters showed an overnight increase in the AMS-C Acute Mountain Sickness score of 0.121±0.679 when sleeping with the upper body elevated vs 0.250±0.575 when sleeping in a horizontal position, a nonsignificant difference.
Sleeping with the upper body elevated by 30° does not lead to relevant reductions in acute mountain sickness symptoms.
Abstract Purpose: Acute mountain sickness commonly occurs following ascent to high altitude and is aggravated following sleep. Cephalad fluid shifts have been implicated. We hypothesized that sleeping with the upper body elevated by 30°, reduces the risk of acute mountain sickness. Methods: In a pragmatic, randomized, observer-blinded field study at 4,554 meters altitude, we investigated 134 adults aged 18–70 years with a Lake Louise score (LLS) between 3 and 12 points at the evening of their arrival at the altitude. The individuals were exposed to sleeping on an inflatable cushion elevating the upper body by 30° or on a sham pillow in a horizontal position. The primary endpoint was the change in the Acute Mountain Sickness-Cerebral (AMS-C) score in the morning after sleeping at an altitude of 4,554 meters compared with the evening before. Sleep efficiency was the secondary endpoint. Results: Among 219 eligible mountaineers, 134 fulfilled the inclusion criteria and were randomized. The AMS-C score increased by 0.250±0.575 in the control group and by 0.121±0.679 in the intervention group (difference 0.105, 95% CI -0.098 – 0.308, p = 0.308). Oxygen saturation in the morning was 79±6 % in the intervention group and 78±6 % in the control group (p=0.863). Sleep efficiency did not differ between groups (p=0.115). Conclusions: Sleeping with the upper body elevated by 30° does not lead to relevant reductions in acute mountain sickness symptoms or hypoxemia at high altitude. Trial registration: German Clinical Trial Register DRKS00012676.
Introduction Acute mountain sickness (AMS) commonly occurs following rapid ascent to high altitude. Since more than 140 million people worldwide reside at altitudes above 2500 meters, the condition is not restricted to recreational mountaineers. AMS heralds potentially life-threatening cerebral edema. While mountaineers commonly take medications, such as acetazolamide or glucocorticoids as preventive measures 1
, trials testing such interventions have been small and of variable quality. Elevated
intracranial pressure and edema formation through hypoxemia-induced dilation of cerebral arteries
2
and intracranial venous congestion have been implicated.
Maneuvers augmenting cephalad fluid shifts including bending forward and sleeping in the supine position exacerbate symptoms
3
. Conversely, patients with head
pathologies are commonly positioned with the head of the bed elevated to attenuate cephalic pressure and edema formation
4
. Sleeping with the upper body is
recommended as AMS countermeasure 5, however, evidence from randomizedcontrolled trials is lacking. Therefore, we tested the hypothesis that sleeping with the upper body elevated by 30° reduces the risk of AMS compared to sleeping in a horizontal position.
Methods We approached adults aged 18–70 years who had planned to climb to Capanna Regina Margherita in the Italian Alps located 4,554 meters above sea level, and stay there for at least one night. We recruited through social media, email messages distributed by mountain hut operators, and staff stationed at lower altitudes. Participants had to have a Lake Louise score (LLS) between 3 and 12 points on the evening of their arrival at 4,554 meters. Since consent forms and questionnaires were available in English, Italian, German, and French, they had to
speak at least one of these languages. This trial was prospectively registered on the 04/07/2017 with the German Clinical Trials Register (DRKS00012676). Written informed consent was obtained on site, and this study was approved by the ethics committees of the North Rhine Medical Association (lfd. Nr. 2017165) and the University of Torino (Prot. n. 153128 del 29\5\17). Informed consent for publication of identifying images in an online open-access publication was obtained from the individual in figure 2. All research was performed in keeping with the Medical Association's professional code of conduct of Germany and based on the seventh version of the Declaration of Helsinki. On arrival, eligible participants were randomly assigned daily in a 1:1 ratio by drawing from a sealed slip box to sleep on an inflatable cushion elevating the upper body by 30° or to sleeping on a sham pillow in the horizontal position (Figure 2). Randomization was not performed until the participants went to bed to keep the subject blinded for the intervention as long as possible. On the evening before sleeping at high altitude and the next morning, participants were evaluated by staff blinded for the intervention. The change in the Acute Mountain Sickness-Cerebral (AMS-C) score in the morning after sleeping at 4,554 meters altitude compared with the evening before was the primary endpoint of the study. Sleep efficiency percent in the night at 4,554 meters altitude was assessed using a sleep log and compared to normal sleep at home, which is the secondary endpoint. We also compared oxygen saturation and heart rate measured by pulse oximetry in the morning after sleeping at 4,554 meters altitude to the evening before. Sample size calculation was based on previously collected LLS and AMS-C data in 11 mountaineers at the same location. A 50 percent reduction in the primary endpoint was considered relevant. The AMS-C score showed greater accuracy than the LLS and was thus selected as the primary end point. We estimated that a total of
62 mountaineers would be needed to detect a relevant difference between groups, with a two-tailed α of 0.05 and a (1-β) of 0.80, for a comparison of 2 independent proportions. According to a prospective data analysis plan, primary and secondary endpoints were analyzed by an intention-to-treat approach and by Analysis of Covariance (ANCOVA). A value for p<0.05 was considered significant. All data are expressed as mean ± standard deviation.
Results Among the potentially eligible 219 mountaineers, 134 had LLS of 3–12 points upon arrival at 4,554 meters and underwent randomization (Figure 1). None dropped out of the study. Participant demographics, comorbidities, and
prescribed
medications are given in the table. All participants tolerated their assigned sleep positions. None reported negative effects or progressed to high altitude pulmonary or cerebral edema. Forty percent were on medications for different indications (Table). AMS-C score increased by 0.250±0.575 in the control group sleeping in the horizontal position and by 0.121±0.679 in the intervention group sleeping with the upper body elevated by 30° (difference 0.105, 95% CI -0.098–0.308, p=0.308) (Figure 2). Self-medication had no relevant influence on the primary outcome (p=0.222). Sleep efficiency was profoundly reduced at altitude compared to a normal sleep at home in both the control group (72±31 and 96±5%) and the intervention group (66±27 and 93±10%). However, sleep efficiency did not differ between groups (difference 3%, 95% CI -0.8 – 7.2%, p=0.115). Headache incidence increased over night to a similar extent in the control and in the intervention group (p=0.251). In the control group, oxygen saturation and heart rate were 78±5 % and 93±14 bpm in the evening and 78±5 % and 89±16 bpm in the morning. In the intervention group,
oxygen saturation and heart rate were 79±5 % and 90±15 bpm in the evening and 79±5 % and 88±15 bpm in the morning.
Discussion The important findings of our study are that sleeping with the upper body elevated by 30° is neither effective in reducing AMS nor in improving sleep efficiency or hypoxemia. Our pragmatic clinical trial conducted under field conditions was sufficiently powered to detect clinically meaningful improvements. Thus, the intervention cannot be generally recommended for preventive purposes. However, we cannot exclude modest improvements in symptoms or in the risk to progress to overt cerebral or pulmonary edema. Our findings are somewhat unexpected because cephalad fluid shifts have been implicated in the pathogenesis of AMS
2,3
. Additionally, elevation of the upper
body is commonly applied as an adjunctive intervention in patients with traumatic brain injury, stroke, and other conditions associated with increased intracranial pressure and cerebral edema formation. We speculate that fluid redistributions elicited through elevation of the upper body may not have been sufficient to overcome permeability changes in the cerebral microcirculation due to high altitude exposure. Similarly, clinical outcomes did not differ between patients who were randomized to a seated or supine position following acute stroke 6. Many people travel worldwide to high altitudes and are at risk for AMS. Mountaineers commonly take medications such as acetazolamide or glucocorticoids as preventive or therapeutic measure often without medical supervision 7. A recent meta-analysis concluded
1
that these interventions may be effective; however, the
data were of moderate quality for acetazolamide and of low quality for inhaled glucocorticoids. Moreover, many studies did not sufficiently report adverse effects
making clinical risk-benefit assessment difficult. Finally, individuals at risk in economically disadvantaged parts of the world may not have access to such treatments. Safe and inexpensive non-pharmacological prophylactic and therapeutic measures not requiring medical supervision are needed 8.
Acknowledgements The authors would like to thank the subjects, whose participation made this study possible. Furthermore the authors gratefully acknowledge the technical support of Wolfram Sies and the administrative support of Christine Becker to this study. The authors are grateful to Andrea Enzio for mountain guiding. The authors express their appreciation to the teams operating Capanna Gnifetti and Capanna Margherita. This work was supported by the programmatic funding of the German Aerospace Center (DLR) and by a grant from the German Society for Mountain- and Expedition Medicine (BExMed).
Clinical Significance
Mountaineers at 4554 meters showed an overnight increase in the AMS-C Acute Mountain Sickness score of 0.121±0.679 when sleeping with the upper body elevated vs 0.250±0.575 when sleeping in a horizontal position, a nonsignificant difference.
Sleeping with the upper body elevated by 30° does not lead to relevant reductions in acute mountain sickness symptoms.
References 1
Nieto Estrada, V. H. et al. Interventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs. The Cochrane database of systematic reviews 6, Cd009761, doi:10.1002/14651858.CD009761.pub2 (2017). 2
Lawley, J. S. et al. Normobaric hypoxia and symptoms of acute mountain sickness: Elevated brain volume and intracranial hypertension. Ann Neurol 75, 890-898, doi:10.1002/ana.24171 (2014).
3
Wilson, M. H. & Imray, C. H. The cerebral venous system and hypoxia. J Appl Physiol (1985) 120, 244-250, doi:10.1152/japplphysiol.00327.2015 (2016).
4
Kenning, J. A., Toutant, S. M. & Saunders, R. L. Upright patient positioning in the management of intracranial hypertension. Surgical neurology 15, 148-152 (1981). 5
Küpper, T., Gieseler, U., Angelini, C., Hillebrandt, D. & Milledge, J. RECOMMENDATION OF THE UIAA MEDICAL COMMISSION VOL: 2 Emergency Field Management of Acute Mountain Sickness, High Altitude Pulmonary Edema, and High Altitude Cerebral Edema. www.theuiaa.org/medical_advice.html (2012).
6
Anderson, C. S. et al. Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke. The New England journal of medicine 376, 24372447, doi:10.1056/NEJMoa1615715 (2017).
7
Donegani, E. et al. Drug Use and Misuse in the Mountains: A UIAA MedCom Consensus Guide for Medical Professionals. High altitude medicine & biology 17, 157-184, doi:10.1089/ham.2016.0080 (2016). 8
Simancas-Racines, D. et al. Interventions for treating acute high altitude illness. The Cochrane database of systematic reviews 6, Cd009567, doi:10.1002/14651858.CD009567.pub2 (2018).
Figure legends
Figure 1. Participant flow.
Figure 2. Influences of sleeping position on overnight changes in acute mountain sickness severity, hypoxemia and sleep efficiency. In the intervention group, subjects slept with their upper body elevated on an inflatable wedge (box E). Two different sizes of wedges were used depending on the subject’s height (small wedge, 80 cm length of the +30° subject support area and 40 cm height; large wedge, 100 cm length of the +30° subject support area and 50 cm height). In the control group, subjects slept on an 8 cm high, inflatable sham pillow allowing a horizontal body position (box E). Sleeping position had no significant effect on the
evolution of acute mountain sickness severity overnight at 4554 meters (boxes A and B). The intervention failed, compared to the control, to improve hypoxemia overnight (box C). Subjects of both groups presented considerably disturbed sleep at altitude compared to their home environment but without any significant influence of the study intervention (box D). Center lines of box-plots show the medians; box limits indicate the 25th and 75th percentiles; crosses represent sample means; data points are plotted as open circles.
Table legends Baseline Characteristics and self-medication (cointerventions) Horizontal position
Elevated position
(n=72)
(n=62)
Age, mean (SD), yr
40.5 (11.5)
41.7 (11.6)
Male gender (n), %
74 (53)
61 (38)
Height, mean (SD), cm
175 (7)
174 (9)
Weight, mean (SD), kg
72.4 (12.2)
69.5 (10.6)
BMI (SD), kg*m-2
23.4 (2.7)
23.0 (2.5)
AMS History (n), %
34 (24)
23 (14)
Smoking (n), %
10 (7)
11 (6)
a
Regular medication (n), %
11 (8)
15 (9)
b
Chronic medical conditions (n), %
11 (8)
15 (9)
40.0 (28)
41.0 (25)
33.3 (23)
32.8 (20)
Nausea (n), %
1.4 (1)
1.6 (1)
AMS (n), %
8.7 (6)
9.8 (6)
Other (n), %
2.9 (2)
3.3 (2)
ASS (n), %
13.0 (9)
9.8 (6)
Ibuprofen (n), %
7.2 (5)
16.4 (10)
Paracetamol (n), %
8.7 (6)
6.6 (4)
Any other NSAR (n), %
7.2 (5)
4.9 (3)
Acetazolamid (n), %
4.3 (3)
1.6 (1)
Dexamethason (n), %
1.4 (1)
0
Subject Characteristics
Cointerventions Medication within 24 h before study inclusion (n), % Treatment Intentions Headache (n), %
Pharmacological Treatments
Table.
a
Regular medications include antihypertensive medication as ACE inhibitors and
calcium channel blockers, thyroid hormones, anti-asthmatic medication such as β2 mimetics, glucocorticoids and leukotriene receptor antagonists, oral contraceptives, low-dose aspirin, new oral anticoagulants and antidepressants. b
Chronic medical conditions include arterial hypertension, thyroid dysfunction, asthma, chronic
kidney failure, venous thrombosis, depression, iron deficiency and hypercholesterinemia.