Sickle Cell Disease Complications Following Air Travel: A Review of the Current Literature

Every year, the number of people using commercial aircraft is estimated at two billion, and more than 300 million people take long-haul flights. Sickle cell patients may be at risk during the air journey because significant hypobaric hypoxia may occur at cruising altitude. This literature review reports complications related to air travel such as painful crises, serious spleen complications (spleen infarcts) requiring a splenectomy, or even sudden death. Prevention of these complications includes environmental protection (maintaining pressure inside the aircraft cabin in a hypobaric condition) and individual prophylaxis (general recommendations for all travelers and specific measures for sickle-cell patients). In order to assess complications associated with air travel in sickle-cell patients, an assessment of their ability to fly is necessary. In addition, the flight fitness assessment identifies patients who will need additional oxygen during flight. When prescribed by the passenger’s physician, additional oxygen is provided by most airlines. Knowing these elements makes it possible to anticipate problems and provide appropriate responses to patients.

which are not always easy to answer. Although most people travel quietly on airplanes and the recommendations for sickle cell patients are sometimes ignored, certain features need to be recalled. Air transport can expose sickle cell patients to an increased risk of disease-related complications. Several factors, such as prolonged hypoxia, dehydration, temperature changes, and stress, can contribute to SCD's complications on air travel. The purpose of this article is to address the cardiorespiratory effects of flight, the risk of SCD's complications during air travel, and procedures to be followed to assess the fitness to fly in sickle cell patients.

Epidemiology of Air Travel Complications of Sickle Cell Disease
Air travel can exacerbate passengers' underlying diseases, and new conditions may manifest during flight. 15 The actual impact of the problem is difficult to assess because airlines are not obliged to report medical incidents on their airplanes. In addition, there is no standardized national or international register to provide reliable data or to read medical events in flight 14,16 clearly. There are very few case series studies or even systematic studies related to medical problems in the sickle cell population. 17 Most of the publications explicitly focused on the air travel-related complications of SCD before the 2000s, and the majority were splenic complications. However, compared to healthy travelers, the sickle cell population is at significant risk of health complications when traveling by air. An American study conducted by Claster et al 18 reported that the average VOC per patient was 10.8% in sickle cell patients and 13.5% in composite heterozygous subjects (HbSC or HbS beta-thalassemia) on an air trip. This study identified the risk of altitude-induced hypoxemia causing painful VOC in adult sickle cell patients.

Effects of Altitude on Cardiopulmonary Function
Above sea level, the oxygen percentage is 21% in the air, and the barometric pressure (BP) varies around 760 mm Hg. In the troposphere, this pressure is inversely proportional to altitude, i.e., as altitude increases, BP gradually decreases. However, the percentage of oxygen does not vary up to 18,000 meters. This decrease in BP is similarly associated with the decrease in the partial inspiratory oxygen pressure (PiO 2 ) and the partial arterial oxygen pressure (PaO 2 ) ( Figure 1). 19 Normal flights reach cruising altitude between 25 000 and 45 000 feet (between 7000 and 14 000 m). In the aircraft cabin, the pressure during flight keeps the BP inside the aircraft higher than outside, even if the cruising altitude is high. To keep PiO 2 and PaO 2 safe during commercial aircraft flights in the cabins are pressurized. 20 According to International Civil Aviation Organization (ICAO) regulations, cabin pressure in commercial aircraft must not exceed that measured at 8000 feet, but in practice, it is typically between 5000 and 7500 feet. 11 At these cabin altitudes, the PiO 2 in commercial aircraft cabins (122 and 108 mm Hg) is significantly lower than the sea level (149 mm Hg). During flights, this decrease in PiO 2 , in turn, leads to a decrease in PaO 2 and a decrease in oxygen saturation of hemoglobin (SaO 2 ). 13,[20][21][22] Decreased PaO 2 during air travel led to stimulation of chemoreceptors and increased minute ventilation as a reflex. Although the individual variability should be considered, the increase in minute ventilation following high altitude hypoxia is a key consequence of the increase in tidal volume and not the increase in respiratory rate. Generally, this increase in minute ventilation is well tolerated by healthy travelers as they are characterized by a large ventilation reserve. 23 The hypoxic ventilatory response occurs as a compensatory response to this hypobaric hypoxia in the airplane's cabin. Also, it causes  other physiological responses (increase in cardiac output, increase in heart rate, and vasoconstriction of pulmonary arterioles and small arteries). 20,25 It has been shown to lead to a fall of SaO 2 to approximately 90%, which healthy travelers well tolerate. This decrease in SaO 2 not only varies with altitude but is also influenced by age, PaO 2 basal values, and minute ventilation. 19,25 Passengers with medical conditions associated with hypoxia, such as cardiac and respiratory conditions or severe anemia, may not tolerate reduction of BP without additional oxygen support. 11,[26][27][28][29] Pathogenesis of Complications of Sickle Cell Disease in Air Transport As mentioned above, during flights, hypobaric hypoxia in the aircraft cabin can cause a severe decrease in PaO 2 and physiological decompensation in some sickle cell patients. In addition, this situation is aggravated in sickle cell patients with a hemoglobin (Hb) level below 8.5 g/dL, reflecting a decrease in the Hb concentration of the red blood cells and a decrease in the amount of oxygen transported. Sickle cell patients were shown to have a large increase in ventilatory response due to an increase in alveolar dead space, which in turn would be caused by lower Hb concentrations, thus decreasing the amount of oxygen being managed in the pulmonary capillaries. 30 Furthermore, hypoxemia may lead to vascular occlusions by stimulating red blood cell sickling, inflammation, oxidative stress, vascular adhesion, and blood coagulation. Studies by Rayman 31 and Diggs 32 have shown that red blood cells containing hemoglobin S (HbS) can undergo sickling and block blood flow at altitudes below 10 000 feet (3048 m). However, most sickle cell patients are unlikely to develop red blood cells at altitudes below 21 000 feet (6400 m).
In addition to hypoxia, the role of dehydration should be emphasized as one of the factors involved in the occurrence of SCD complications during air travel. Ambient air in the cabin at cruising altitudes is about 10%-20% humidity, which is low compared to buildings (ranging from 40%-50%). According to some research, the low humidity of the aircraft cabin does not lead to dehydration. However, it leads to fluid loss of around 150 mL on an 8-hour flight, without any change in plasma osmolality and which would be easily compensated by normal homeostatic mechanisms. 11 In addition, this low humidity can cause dry mucous membranes of the lips and tongue, leading to a feeling of thirst and may also cause problems for contact lens wearers due to dry eyes in a healthy subject traveling by air. 33 In a sickle cell patient, however, this fluid loss would be greater than normal and could lead to dehydration, which would contribute to the installation of vascular occlusions. These vascular occlusions are responsible for tissue ischemias and pain in the body.
Based on the above, it is concluded that the most important factors in determining the fitness of sickle cell patients to fly are: (i) the functional severity of the disease; (ii) the hemoglobin level; (iii) the extent of any deficiency in the exchange of gas; (iv) basic PaO 2 at ground altitude; and (v) the availability of oxygen in reserve to provide supplementation when necessary. 34 Systematic assessment of these factors can help the physician determine which sickle cell patients will fly safely, which may need additional oxygen in flight, or which will not.

Risk Assessment of Sickle Cell Disease Complications in Air Travel
The sickle cell produces abnormal hemoglobin, which induces fragility in red blood cells, which lyse easily (anemia), the rigidity of the red blood cells which adhere to the walls of the vessels and cause in certain situations (cold, stress, infection, dehydration) their closure (vaso-occlusive crises), which causes pain often severe in bones, chest, and abdomen. In general, anyone with a hemoglobin level of less than 8.5 g/dL deserves special attention because, at such low levels, passengers may experience dizziness and even loss of consciousness during flight (often due to physical efforts such as going to toilets). 11 Sickle cell air travelers are exposed to considerable medical risks such as hypovolemia and VOC. 35 Although the literature speaks very little about the risks that sickle cell patients face when traveling by air, the few published case reports and case series studies report complications of SCD ranging from painful VOC 18,36 to severe splenic complications requiring splenectomy, [37][38][39][40] and even sudden death from a pulmonary embolism on the flight. 41,42 During flights, VOC may occur in up to 8.7% of sickle cell patients. 43 In addition, it is established that long-haul flight is one of the risk factors for venous thromboembolism. 44 Spleen infarction in sickle cell patients (and even those with a sickle cell trait generally asymptomatic) occurs during exposure to low partial oxygen pressure at high altitudes, including air travel. 17,37,42,45,46

Prevention of Complications and Recommendations to Sickle Cell Patients During Air Travel
Sickling of erythrocytes and, therefore, complications of SCD may, however, be induced by mild hypoxemia. Air travel that maintains cabin pressure at approximately 6000 to 8000 feet is associated with a decrease in PaO 2 that may affect Sickle cell patients. 18 Knowing that reduced oxygen pressures can worsen SCD, these patients are advised not to travel by air without medical oxygen as it has been shown that a sickle cell crisis could be fatal on-air travel. 17,41 Oxygen therapy is recommended for sickle cell patients on board aircraft at altitudes above 2135 m (7600 feet), especially if they have splenomegaly and have a relatively higher blood viscosity. 47 Although air travel is a probable risk factor for VOC, there is no universal consensus on additional oxygen recommendations. 48 Further research is needed to determine the need for additional oxygen to prevent flight-related complications in sickle cell patients.
In addition, sickle cell patients are advised to have their anemia corrected before traveling by air. 11 Flying in pressurized aircraft is generally not a problem for sickle cell patients when the recommendations are correctly met. 35 The most important considerations are to move around the aircraft cabin as often as possible, to drink plenty of fluids, and to dress warmly. 49 Although they are often overlooked, the advice from the physician to patients is essential before any air travel. 50 The pre-travel health consultation provides an opportunity to assess the health risks of travel for an individual and provide education and advice to promote healthy travel. A key component of the pre-travel consultation is an individualized health risk assessment based on traveler demographics and details of the planned trip (including itinerary, duration, and planned activities). 51 Before traveling by air, sickle cell patients should follow the following recommendations 34 : • combat relative hypoxemia: no unpressurized airplane flight, careful treatment of asthma and airway obstruction; • correct anemia if Hb is below 8.5 g/dL; • folic acid supplementation (to compensate for secondary needs of bone marrow regeneration) and zinc supplementation (pre-pubertal); • maintain adequate hydration (amount to be adapted in case of diarrhea or a dry atmosphere); • no undue exertion, no trampling, no sudden or prolonged standing; • combat cold (warm clothes); • combat circulatory slowdown (watch for postures, tight clothes). Thus, preventive measures against complications of SCD during air travel can be summarized in two categories: • Individual prophylaxis with general recommendations is for all travelers and specific measures for sickle cell patients. The general rules are to avoid sitting long, walking short in the aisle every 2-3 hours, drinking lots of water, and avoiding alcohol consumption. • Environmental protection includes maintaining the pressure in the aircraft cabin under hypobaric conditions (altitude 1800 to 2500 m). In addition, the prevention of dehydration by providing adequate moisture via air conditioners and encouraging passengers to drink water or non-alcoholic beverages; movement and easy walking in the aisles are possible. Similarly, oxygen support may be useful in some patients with SCD. A trained travel medicine specialist should evaluate all sickle cell patients planning to travel by air. These visits are productive when they are made well in advance of the trip.

Conclusion
Air travel may be associated with higher risks (especially for long-term flights) and require detailed preparation. However, there are no absolute contraindications to air travel, except for certain situations such as severe anemia that require correction prior to flight. Therefore, a clinical and functional assessment of the fitness to fly is recommended to identify patients who require oxygen and fluid supplements and reduce the risk of health complications during flight.

What Is Already Known?
SCD is a hereditary hemoglobin disease that causes abnormal expression of hemoglobin. In sub-Saharan Africa, this disease affects approximately 12 to 15 million people. Sickle cell patients have an increased risk of complications during air travel. Prolonged hypoxia, dehydration, temperature changes, and stress contribute to the occurrence of complications in these patients.

What Does This Study Add?
Through this literature review, we highlight the existence of an increased risk of complications in sickle cell air travelers, particularly VOC. In addition, this review reviews the epidemiology and physiopathology of these complications and proposes preventive options to follow. This paper is intended not only for physicians who provide pre-travel and post-travel advice but also for sickle cell patients and their families to know the risk involved when traveling by air.