Altitude Sickness

Acute Mountain Sickness and High-Altitude Cerebral Edema

Definitions

• Acute mountain sickness (AMS): neurologic syndrome with no physical findings occurring > 6 hours after ascent to altitudes > 2,500 m (rarely, 1,500 m)
• High-altitude cerebral edema Cerebral edema Increased intracellular or extracellular fluid in brain tissue. Cytotoxic brain edema (swelling due to increased intracellular fluid) is indicative of a disturbance in cell metabolism, and is commonly associated with hypoxic or ischemic injuries. An increase in extracellular fluid may be caused by increased brain capillary permeability (vasogenic edema), an osmotic gradient, local blockages in interstitial fluid pathways, or by obstruction of CSF flow (e.g., obstructive hydrocephalus). Increased Intracranial Pressure (ICP) (HACE): diffuse encephalopathy Encephalopathy Hyper-IgM Syndrome without focal neurological deficits Focal Neurological Deficits Brain Abscess, always preceded by AMS

Epidemiology

• Because AMS becomes HACE, the epidemiological factors are the same.
• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 40%–90% based on altitude
• Risk factors:
  • Prior history of high-altitude sickness
  • Rate of ascent
  • Exertion (lack of physical fitness is not a risk factor)
  • Neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess irradiation or surgery damaging carotid bodies
  • Age > 50 years reduces risk.

Etiology

All symptomatology Symptomatology Scarlet Fever of AMS and HACE is related to hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage. The central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification (CNS) is the most sensitive organ to hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage.

Clinical presentation

• AMS:
  • Symptoms:
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess (most common)
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia 
    • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome) 
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • Physical exam is usually unremarkable. 
• HACE:
  • Symptoms and signs:
    • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
    • Altered level of consciousness Altered Level of Consciousness Intracerebral Hemorrhage
  • Physical exam findings:
    • Papilledema Papilledema Swelling of the optic disk, usually in association with increased intracranial pressure, characterized by hyperemia, blurring of the disk margins, microhemorrhages, blind spot enlargement, and engorgement of retinal veins. Chronic papilledema may cause optic atrophy and visual loss. Idiopathic Intracranial Hypertension
    • ± retinal hemorrhage
    • No focal neurologic findings

Pathophysiology

• Exact mechanism is not well understood.
• AMS:
  • High altitude → decreased partial pressure Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange of oxygen in inspired gas (hypobaric hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage)
  • Hypobaric hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage → low arterial oxygen saturation Oxygen Saturation Basic Procedures (SaO₂ is < 90%)  
  • Low SaO₂ → increased cerebral blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure:
    • Raised intracranial pressure Intracranial Pressure Idiopathic Intracranial Hypertension 
    • Increased sympathetic activity
    • Hypoventilation
    • Fluid retention 
    • Further impaired gas exchange Gas exchange Human cells are primarily reliant on aerobic metabolism. The respiratory system is involved in pulmonary ventilation and external respiration, while the circulatory system is responsible for transport and internal respiration. Pulmonary ventilation (breathing) represents movement of air into and out of the lungs. External respiration, or gas exchange, is represented by the O2 and CO2 exchange between the lungs and the blood. Gas Exchange 
• HACE:
  • As above, but swelling Swelling Inflammation progresses, leading to vasogenic cerebral edema Cerebral edema Increased intracellular or extracellular fluid in brain tissue. Cytotoxic brain edema (swelling due to increased intracellular fluid) is indicative of a disturbance in cell metabolism, and is commonly associated with hypoxic or ischemic injuries. An increase in extracellular fluid may be caused by increased brain capillary permeability (vasogenic edema), an osmotic gradient, local blockages in interstitial fluid pathways, or by obstruction of CSF flow (e.g., obstructive hydrocephalus). Increased Intracranial Pressure (ICP)
  • Swelling Swelling Inflammation puts pressure on the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification, resulting in:
    • Papilledema Papilledema Swelling of the optic disk, usually in association with increased intracranial pressure, characterized by hyperemia, blurring of the disk margins, microhemorrhages, blind spot enlargement, and engorgement of retinal veins. Chronic papilledema may cause optic atrophy and visual loss. Idiopathic Intracranial Hypertension
    • Diffuse neurological symptoms

Diagnosis

Both AMS and HACE are diagnosed clinically by noting the characteristic symptoms in a patient who ascends to high altitude. 

• Pulse oximetry, vital signs, and laboratory exams are not useful markers as they are often normal.
• Clinical trials often use the 2018 Lake Louise AMS scoring system for diagnosis:
  • Score of ≥ 3 including headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess is considered diagnostic of AMS.
  • Not routinely used for diagnosis in clinics, but scoring systems such as the Lake Louise AMS may be useful for screening Screening Preoperative Care purposes

Prevention

• Gradual ascent is best.
• Spending 1 night at intermediate altitude before ascending to higher ones
• Proper hydration, but not overhydration
• Acetazolamide Acetazolamide One of the carbonic anhydrase inhibitors that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. Carbonic Anhydrase Inhibitors for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with prior history of AMS or when rapid descent necessary (e.g., rescue missions)

Management

• AMS:
  • Mild:
    • Discontinue ascent.
    • Rest.
    • Carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors inhibitors ( acetazolamide Acetazolamide One of the carbonic anhydrase inhibitors that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. Carbonic Anhydrase Inhibitors)
    • Ultimate treatment is descent.
  • Moderate:
    • Immediate descent
    • Supplemental oxygen Supplemental Oxygen Respiratory Failure 
    • Acetazolamide Acetazolamide One of the carbonic anhydrase inhibitors that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. Carbonic Anhydrase Inhibitors and/or dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics
    • Hyperbaric therapy
• HACE: 
  • Immediate descent 
  • Portable hyperbaric chamber (when descent not possible) 
  • Supplemental oxygen Supplemental Oxygen Respiratory Failure
  • Dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics

High-Altitude Pulmonary Edema

Definition

High-altitude pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema (HAPE) is a non-cardiogenic pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema (normal capillary wedge pressure) occurring 2–4 days after arrival at high altitude.

Epidemiology

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency ranges from 0.01%–15.5% based on altitude.
• Risk factors:
  • Prior history of HAPE
  • Rapid ascent
  • Respiratory tract infection
  • Cold temperatures
  • Exercise 
  • Pre-existing cardiopulmonary abnormalities leading to pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension

Pathophysiology

• Hypobaric hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage from high altitude → decreased nitric oxide Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from arginine by nitric oxide synthase. Nitric oxide is one of the endothelium-dependent relaxing factors released by the vascular endothelium and mediates vasodilation. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic gmp. Pulmonary Hypertension Drugs and increased endothelin 1 in pulmonary vasculature causing vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure
• Patchy pulmonary vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure → overperfusion and increased capillary pressure 
• Increased pulmonary capillary pressure → interstitial fluid Interstitial fluid Body Fluid Compartments leak → HAPE

Clinical presentation

• Symptoms:
  • Cough (most common, but nonspecific)
  • Hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea at rest
• Signs:
  • Tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination and tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children, especially at rest (important markers) 
  • Crackles on lung auscultation
  • Signs of HACE

Diagnosis

• Diagnosis is primarily clinical; requires:
  • 2 or more of the following symptoms:
    • Chest tightness or pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways 
    • Cough
    • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea at rest
    • Decreased exercise tolerance Tolerance Pharmacokinetics and Pharmacodynamics 
  • 2 or more of the following exam findings:
    • Central cyanosis Central Cyanosis Tricuspid Valve Atresia (TVA) 
    • Rales Rales Respiratory Syncytial Virus/wheezes
    • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
    • Tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination
• Imaging and lab testing support the diagnosis:
  • Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests: patchy/localized opacities and/or streaky interstitial edema Interstitial Edema Increased Intracranial Pressure (ICP)
  • Electrocardiogram Electrocardiogram An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG) ( ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG)): right ventricular strain and/or hypertrophy Hypertrophy General increase in bulk of a part or organ due to cell enlargement and accumulation of fluids and secretions, not due to tumor formation, nor to an increase in the number of cells (hyperplasia). Cellular Adaptation
  • Laboratory tests: hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage, respiratory alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis (unless on acetazolamide Acetazolamide One of the carbonic anhydrase inhibitors that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. Carbonic Anhydrase Inhibitors)
  • Ultrasound: findings consistent with pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema

Prevention

• Gradual ascent is best.
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with prior history of HAPE or when rapid descent necessary (e.g., rescue missions):
  • Sustained-release nifedipine Nifedipine A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)
  • Salmeterol Salmeterol Asthma Drugs
  • Tadalafil Tadalafil A carboline derivative and phosphodiesterase 5 inhibitor that is used primarily to treat erectile dysfunction; benign prostatic hyperplasia and primary pulmonary hypertension. Phosphodiesterase Inhibitors
  • Dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics

Management

• Immediate descent
• Portable hyperbaric chamber (when descent not possible)
• Rest and warm temperatures
• Oxygen therapy to > 90% saturation
• Extended-release nifedipine Nifedipine A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)