HIGH altitude pulmonary edema (HAPE) is well known as a hypoxia-induced, non-cardiogenic type of pulmonary edema which occurs in healthy persons, especially in young individuals after rapid exposure to high altitudes, and it may also occur in high-altitude dwellers who return from sojourns at low altitude. HAPE develops in healthy individuals at altitudes > 2500-3000 m within 1-5 days after arrival.¹ Hypoxia and exertion have been considered as the two main factors contributing to the development of HAPE. The mechanisms that trigger the development of HAPE are not completely elucidated.

In China, mountains cover over one-fourth of the earth’s surface and are popular tourist destinations. Following the open of railway and air travel in Qinghai and Tibet, increasing numbers of people travel to high altitude areas for various reasons, such as mining, tourism, trekking and deployment. Sometimes the troops conduct military training on high plateau or the military person guards the borders of a country at high altitudes. HAPE is becoming a pathological phenomenon about which healthcare providers should have greater awareness. In the present research, we aimed to analyze the clinical feature, laboratory and imaging characteristics of Chinese HAPE patients to improve the early diagnosis and prognosis of HAPE.

The present study was carried out at the Chinese People’s Liberation Army 22 Hospital located in the city of Geermu, China. The city of is located in the western region of Qinghai with an average altitude of 2800 m, and there are approximately three hundred thousand individuals lived in this city.

We retrieved the electronic medical record of patients admitted to the Hospital in the time period from January 2011 to December 2012 with HAPE as a key word, and enrolled 98 cases diagnosed with HAPE. The diagnosis was made based on the Hultgren’s criteria² and chest X-ray results. A physician who was good at the diagnosis and treatment of HAPE carried out physical examinations for patients and made the diagnosis. Subjects having pulmonary diseases, cardiovascular diseases, mental illness, drug addiction history, or other diseases perviously were excluded. Two investigators reviewed all the medical records to confirm the diagnosis and collected the clinical, laboratory and imaging data we needed.

This study was approved by the ethics committee of the Chinese PLA General Hospital (No. S2014-070-01). Participants provided their written informed consents to participate in this study and the ethics committees approved this consent procedure. The individual enrolled in this study has given written informed consent for publishing the article in detail.

All patients underwent 12-lead resting electrocardiography using a Kenz Cardico 1210 electrocardiograph (Nagoya, Japan).

Routine blood test was performed using Sysmex XE-2100 haematology analyser (Kobe, Japan). Biochemical assay of serum was carried out with Hiachi 912 analyser (Tokyo, Japan).

Both on hospital admission and after recovery, resting arterial blood gas analysis was performed to measure pH (normal ranges: 7.35-7.45), partial pressure of carbon dioxide (PaCO₂, normal ranges: 35-45 mm Hg), partial pressure of oxygen (PaO₂, normal ranges: 80-100 mm Hg), O₂ saturation (SaO₂, normal ranges: 95%-100%) and HCO₃^- concentration (normal ranges: 22-27 mmol/L). The blood samples were drawn from the radial artery prior to nasal catheter or oral oxygen inhalation.

Posteroanterior chest radiographs were taken with patients in the erect position, without rotation and at full inspiration by using an X-ray generator (HD-150G-12, Shimazu, Kyoto, Japan) and an automatic development equipment (SAKURAVX400, Konishiroku, Tokyo, Japan). The radiographs were taken at a 2.0 m anode to film distance and at 135 KV and 300 mA.

Computed tomography scan of the brain was performed by using a scanner (PROSPEED FI, General Electric Company, Boston, United States). The fixed tube voltage was 120 KV, the pitch was 1.374 and the thickness of the slide was 10 mm. Image scan was performed under condition of 160 mA. Two radiologists evaluated these computed tomograms of the brain independently. The radiologists did not know the results of the other clinical studies.

Statistical analysis was performed with SPSS Statistics (IBM, USA). Data of normal distribution were expressed as the means of the group (±SD) and were analyzed by t-test for paired data. Data with non-normal distribution were summarized as medians (quartiles) and were analyzed by nonparametric tests. A difference with P<0.05 was considered statistically significant.

Forty-eight cases developed HAPE at the altitude ranging from 2800 m to 3000 m, 20 cases from 3200 m to 4000 m, 27 cases from 4100 to 5000 m, and 3 cases from 5100 m to 5600 m. Ninty-five (96.9%) patients were male. The mean onset age was 35.4±12.4 years. HAPE occurred at 24 to 120 hours from the arriving at the high attitude area. Ninty-five patients were the Han nationality. The other three patients were Hui nationality, Yi nationality and Tujia nationality.

Fifty-three (54.0%) patients developed HAPE induced by catching cold, twenty-three (23.5%) patients caused by hard work, and twenty-two (22.5%) individuals denied obvious causes. The average temperature of the HAPE patients on admission was 36.5°C±0.5°C. Thirteen patients developed fever. The average of the heart rates was 99.9±19.9 beats/min. Fifty-three patients developed tachycardia, and two patients developed bradycardia.

The average systolic blood pressure was 116.7±16.7 mm Hg, and the average diastolic blood pressure was 76.9±13.4 mm Hg. Sixteen patients suffered from hypertension. Moist rales were heard over the right lung in fifteen patients and were heard over the left lung in three patients. The intensity of the moist rales was more obvious over the right lung than that over the left lung in fourteen patients, and it was equal over the right or left lung in the remainders.

Ninety-one (92.9%) patients complained of chest tightness or shortness of breath. Eighty-five patients complained of cough and expectoration. Sixty-two patients produced sputum, in which 38 patients had frothy sputum (17 with white frothy sputum, 16 with pink frothy sputum and 5 with yellow frothy sputum) and 24 had thick mucus sputum (12 with yellow phlegm and 12 with white phlegm).

The results of routine blood test are shown in Table 1. White blood cell (WBC) count was higher on admission than that before discharge (P<0.01). Neutrophil count was higher, whereas the counts of lymphocyte, eosoniphil, basophil, monocyte were lower on admission than those after recovery (all P<0.05). The red blood cell (RBC) count, haemoglobin (Hb) concentration, and percent of haematocrit were higher on admission (all P<0.05). There was no significant difference in mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) (all P>0.05), but mean platelet volume (MPV) were lower on admission (P<0.01).

As illustrated in Table 2, biochemical analysis revealed serum levels of total protein, albumin, total bilirubin, indirect bilirubin, alkaline phosphatase (AKP), cholinesterase, creatinine, serum glucose, uric acid (UA) were higher on admission than those before discharge (all P<0.05). The serum levels of calcium and carbondioxide combining power (CO₂CP) were lower on admission than those before discharge (P<0.05).

Arterial blood gas results showed on admission the value of pH [7.470 (quartiles, 7.448, 7.510)] was elevated, and the values of PaO₂ (57.0±13.9 mm Hg), PaCO₂ (28.9±3.6 mm Hg), anion gap (15.2±3.1 mmol/L), SaO₂ (89.0%±8.9%) and ctO₂ (21.7±3.7 Vol%) were decreased. Bicarbonate (21.3±2.9 mmol/L) and standard bicarbonate (23.3±2.7 mmol/L) were within normal limits.

Chest roentgenograms on admission showed patchy fuzzy shadow, ground-glass opacity, high density shadow and increased lung markings. Eighty patients had bilateral edema, and the intensity of the abnormal shadows was more obvious in the right lung than that in the left lung in fourteen patients of them. Eighteen patients were with unilateral edema; the abnormal shadows of fifteen patients were distributed in the right lung, and there were only three patients whose abnormal shadows distributed in the left lung. The shape, size, and structure of bilateral hilar showed no obvious abnormality. Bilateral costophrenic angles were sharp and the diaphragm was smooth and integrated.

Forty-nine patients complained of headache and dizziness and thirteen patients developed disturbance of consciousness. CT of the brain revealed that the brain parenchyma density decreased, especially in white matter, the brain sulci became obscure and the boundary of the white and gray matter became fuzzy. A total of twenty-nine HAPE patients accompanied with high altitude cerebral edema, of whom five patients were in coma and four patients developed ataxia.

It has been reported previously that HAPE is rarely observed below altitudes of 2500-3000 m, but our results revealed that 48 (49.0%) cases developed HAPE at the altitude of 2800 m to 3000 m, indicating HAPE might commonly occur at moderate high altitude at least in Chinese people.

Our research showed that 96.9% of HAPE were male, indicating that men are more susceptible to HAPE.³ The research conducted by Sophocles indicated that premenopausal women with physiologic levels of female hormones are somehow protected from HAPE. Hypobaric hypoxia mediated mitochondrial dysfunction was reported to be due to repression of oestrogen-related receptor-α (ERRα).⁵ ERRα is the regulator of mitochondrial biogenesis and oxidative phosphorylation.⁶ We speculated that it was the different transduction of ERRα signaling pathway in male and female staying at the high altitude that made the male individuals more susceptible to HAPE, and the detailed mechanisms responsible for regulating susceptibility to HAPE is in need of further study.

Previous researches reported the majority of HAPE patients had a fever, but our research revealed that only 13.3% of the patients developed body temperature rise, indicating that HAPE is not an infectious disease.

In our cohort of HAPE patients, approximately 54.1% developed tachycardia, only 2.1% developed bradycardia. We also noticed that 16.6% of HAPE patients suffered from hypertension. As is well known that hypobaric hypoxia is the invariant stimulus for high altitude disorders. Hypoxia impairs cellular mitochondrial function, which alters normal oxidative metabolism and allows toxic metabolites to accumulate.⁷ Exposure to oxygen-depleted environment triggers onset of a range of physiological and biochemical reactions, including hypertension, tachycardia, and bradycardia.

Physical examination revealed moist rales were heard over the right lung in 15.3% of the patients, only 3.1% of the patients were heard over the left lung. The intensity of moist rales was more obvious over the right lung than that over the left lung. The above data concurred with the results of chest roentgenographic findings.

Approximately 50% of patients had headache and dizziness, and 29 (29.6%) HAPE patients accompanied with high altitude cerebral edema, which was verified by CT of the brain. Five patients were in coma and four patients developed ataxia.

The counts of lymphocyte, eosoniphil, basophil, monocyte decreased on admission, and recovered after treatment. Cortisol was reported to increase in response to hypoxic stress of acute altitude exposure.² It might alter circulating leukocyte number and function, thus increasing WBC count and exerting differential effects on leucocyte subsets.⁸ Glucocorticoid administration causes marked, but transient lymphocytopenia, eosinopenia, monocytopenia, and neutrophilia.⁹ We thus proposed that the elevation of cortisol upon hypoxic stress of acute altitude exposure might result in the decrease of leucocyte subset counts and increase of leukocyte counts with a left shift.

RBC count, Hb concentration, MCV, and percent of haematocrit were higher on admission, while MCHC was lower. It has been reported that hypoxia increased erythropoietin levels in lowlanders and high-altitude natives exposed to high aititude, thus elevating RBC count, Hb concentration and haematocrit levels.^10-12 High altitudes increase erythrocytes, hemoglobin, platelet and leucocytes, thereby furnishing four of the most important factors in the building-up of a stronger resistance against infectious diseases.

Our research revealed that MPV was significantly lower in patients living in high altitude area. MPV is an indicator of the average size and activity of platelets. A higher MPV value indicats a larger average platelet size. Small platelets synthesize less thromboxane A2, unable to aggregate better.¹³ As a result, this decreased MPV values in HAPE patients may reflect decreased aggregability of platelet.

Total protein and albumin were elevated on admission, which agreed with the previous report that showed plasma concentrations of total protein and albumin were stimulated by high altitude.¹⁴

We found that the level of total bilirubin was higher on admission than that before discharge, which might be due to increase of indirect bilirubin. In the present research we reported that RBC was higher on admission, and it has been reported that heme oxygenase-1 (HO-1) was increased in response to hypoxia and was constitutively up-regulated in top alpinists.¹⁵ Taken together with biochemical function of HO-1 that catalyzes heme into CO and bilirubin, it was the increase of RBC count and HO-1 that resulted in the increased bilirubin production in response to decreased oxygen availability at high altitude.

We also noticed that AKP and cholinesterase were higher on admission than those before discharge. Creatinine and UA were also higher on admission than those after recovery, but there was no difference in blood urea nitrogen. UA is an oxidative stress marker. The increase of UA at high altitude contributes to an appreciable portion of plasma total antioxidant capacity, but may not be effective in preventing oxidative stress at high altitude.^16-17 Creatinine is critically important in assessing renal function because it has several interesting properties. In blood, it is a marker of glomerular filtration rate. The elevation of creatinine revealed by our research and other study indicated renal function was damaged at high altitude.¹⁸

Serum glucose was higher on admission than those after recovery. Exposure to altitude hypoxia elicits changes in glucose homeostasis with elevation of glucose which was the consequence of a transient peripheral insulin resistance.¹⁹ Increase of CK was observed in subjects diagnosed with acute mountain sickness (AMS) at high altitude compared with apparently healthy controls.²⁰ The change of CK in HAPE remained unclear, we found that it was elevated significantly on admission in HAPE patients. The serum level of calcium was lower on admission than that before discharge. Sudden exposure to high altitude resulted in fall in plasma aldosterone and parathormone with subsequent decrease of related electrolytes, especially calcium.²¹

Arterial blood gas analysis revealed hypoxemia and respiratory alkalosis on admission, which was similar with the results reported by Ge et al on patients exposed to high altitude.²² The extraordinary respiratory alkalosis has some fascinating implications, which can increase oxygen affinity of hemoglobin. It is interesting that mammals that live in high altitude area generally have an increased oxygen affinity and therefore a left-shifted oxygen dissociation curve, maintaining a reasonable level of arterial SaO₂ at high altitude. The PaO₂ falls because of the decreasing PaO₂ in the air around the climber. The PaCO₂falls because of the increasing hyperventilation.

In summary, the present study showed that HAPE developed at moderate high altitude. Men are prone to HAPE, which might attribute to the differential expression of hormones between different genders and their signal transduction pathways. The lesions of the right lung were more serious than those of the left lung of HAPE patients. Inflammatory factor may be involved in the occurrence of HAPE. Hypoxia played a vital role in the development and progression of HAPE.

The authors declare that they have no competing interests.