Abstracts of Current Literature

European Respiratory Journal

Travel to High Altitude with Pre-existing Lung Disease

As increasing numbers of individuals are venturing to higher altitudes, it is inevitable that some will have chronic illnesses, including pre-existing lung disease. The pathophysiology of high-altitude illness has been well studied in healthy subjects, but very little is known about the effects on those with chronic illness. This review was compiled to examine the risks of high altitude on individuals with various types of lung disease and to make recommendations for or against high-altitude travel, as well as to define any appropriate prophylactic measures. The authors admit that only “tentative conclusions” can be made in their article since there is limited literature on most of these subjects.

The article begins with a nice review of the environmental changes at high altitude and explains how these changes affect normal subjects as well as those with specific lung pathology. The review considered different forms of chronic lung disease including obstructive pulmonary diseases (chronic obstructive pulmonary disease, asthma, cystic fibrosis), pulmonary vascular disorders (pulmonary hypertension, thromboembolic disease), ventilatory disorders (obesity hypoventilation, obstructive sleep apnea, bilateral carotid resection), pleural disorders (bullous lung disease, recent pneumothorax), and neuromuscular diseases (muscular dystrophies, diaphragmatic paralysis, kyphoscoliosis, amyotrophic lateral sclerosis, and Guillain-Barré syndrome). Specific references and mechanisms of pathophysiology are outlined in the article—generalized recommendations are mentioned here.

Obstructive lung disease is the first process considered by these authors. Multiple cited studies have shown that those individuals living at high altitude with an obstructive pulmonary disease do have increased mortality and a higher incidence of cor pulmonale. Those with chronic obstructive pulmonary disease are recommended to have screening done prior to ascent to altitude for the use of supplemental oxygen as a way to prevent hypoxemia. However, since most of the previous studies were completed regarding the use of supplemental oxygen on commercial airliners, no recommendations can be made for ascent to altitude greater than 3048 meters. These patients are advised to carry all baseline medications and should carry rescue medications such as inhalers and corticosteroids. Those with coexisting pulmonary hypertension should avoid ascent, and if high altitude travel is necessary, should use prophylactic nifedipine. Those with a history of spontaneous pneumothorax should avoid high-altitude travel for 2 weeks after resolution of pneumothorax.

Much of the past literature concerning asthmatics has suggested that asthmatics may have some symptomatic improvement at high altitude, possibly secondary to decreased allergen load. However, inhalation of cold air may trigger an asthma exacerbation in some, and should be prevented by covering the mouth in very cold environments. Other recommendations include ascent to only 5000 meters, with avoidance of higher altitudes or remote areas by those with more severe disease. All asthmatics should carry rescue medications with them at all times. Those with cystic fibrosis should use supplemental oxygen if it is deemed necessary and should always continue any medications or respiratory therapies at altitude that are used at sea level.

Since those patients with pre-existing pulmonary hypertension are already at increased risk for development of high-altitude pulmonary edema (HAPE) (based on several cited case studies), these patients are cautioned against ascent to high altitude. If patients must ascend to greater than 2000 meters, they should know the signs and symptoms of HAPE and should use supplemental oxygen. Those not previously on nifedipine should take it for prophylaxis while at altitude. Those with thromboembolic disease without pulmonary hypertension may ascend to altitude but must continue their anti-coagulation regimen. In addition, those with a known coagulopathy should not be on oral contraceptives, and all should avoid immobility and dehydration to prevent additional thromboembolic phenomena.

Those with ventilatory disorders such as obesity, hypoventilation, and obstructive sleep apnea may benefit from prophylaxis with low-dose acetazolamide (125–250 mg orally, twice each day) and supplemental oxygen. Any patient on continuous positive airway pressure (CPAP) therapy must consider CPAP at current or higher than normal settings to limit nocturnal desaturations. Those with a history of bilateral carotid surgery may have dysfunctioning or absent carotid bodies and may have difficulty regulating the hypoxic ventilatory response. Therefore, these individuals should avoid high altitude when possible and should use supplemental oxygen if high-altitude travel is necessary. Finally, those with neuromuscular disorders may develop profound desaturation events at high altitude and thus require supplemental oxygen and possibly bilevel positive airway pressure when travel at high altitude is unavoidable.

Upon completing this review, the authors were able to find data suggesting that those individuals with history of severe bullous disease did not show increased rate of spontaneous pneumothorax at high altitude. However, those individuals with a recent surgery or pneumothorax were cautioned against going to high altitude (including taking a commercial flight) for at least 14 days after complete resolution of the pneumothorax. Those at high risk for spontaneous pneumothorax should consider a computed tomographic scan of the chest as a screening tool to look for occult pneumothorax before any ascent to altitude.

This excellent review article summarizes the potential risks of travel to high altitude for those with chronic lung diseases and suggests ways to prevent altitude illness or worsening of the disease. However, it must be remembered that large outcome studies may not have been completed to fully support these recommendations.

(Eur Respir J. 2007;29:770–792) AM Luks and ER Swenson. Prepared by Karen Nolan Kuehl, MD, FACEP Carilion Emergency Medicine, Roanoke, VA, USA

Journal of the Association of Physicians of India

Utility of Scorpion Antivenin vs. Prazosin in the Management of Severe Mesobuthus tamulus (Indian Red Scorpion) Envenoming at Rural Setting

Mesobuthus tamulus is a common source of scorpion envenomation in western India. ¹ A 30–40% mortality rate has been reported in untreated cases in the Mahad region, where this study took place.^2,3 The venom of the species consists of short-chain peptides, which affect gated sodium and potassium channels. Envenomation results in an autonomic storm, and death can result from hypertension and pulmonary edema or from cardiogenic shock. ⁴ Use of antivenom for Mesothubus tamulus envenomation has been limited by availability. However, in January 2002 the antivenom became freely available in rural health centers. In this study, the authors compared patients who had received antivenom before referral to those who presented directly to their center and were treated with oral prazosin.

In this cohort, open label study, 25 patients who were treated with antivenom alone were compared against 28 patients who received only oral prazosin. Patients who received both antivenom and prazosin were excluded. The groups were similar in age and presenting symptoms. The authors do not report P-values for the differences between the groups. They were similar in time to presentation before a health-care provider; however, the antivenom group took much longer to reach the referral center than the prazosin group.

In the antivenom group, 4 patients (16%) died, while no patients in the prazosin group died (Pearson chi-squared 4.86, P = .028, my calculations). The recovery time was 1.5–4 (mean 2.26) days in the antivenom group, versus 1–2 (mean 1.25) days in the prazosin group.

This study is limited by its statistical analysis, its sample size, and its non-randomized design. The difference in time to presentation to the referral center may be a significant confounder. However, in this cohort a significantly smaller number of patients died after treatment with prazosin than after treatment with antivenom. The antivenom is more expensive than prazosin, although it can be stored at room temperature. It also confers the risk of serum sickness, since it is prepared from equine serum, and requires an attendant with epinephrine and antihistamines available. Prazosin carries the risk of hypotension, particularly with the first dose. This study suggests that prazosin may be a better initial intervention that antivenom in this population. Further research might focus on whether this represents a problem with this particular antivenom or whether antivenom has a role as an adjunct in patients treated with prazosin.

(J Assoc Physicians India. 2007;55:14–21) Prepared by Marlow Macht, MS4, MPHTM candidate Tulane University, New Orleans, LA, USA

Journal of Applied Physiology

Platelet Count and Function at High Altitude and in High-Altitude Pulmonary Edema

Platelet aggregation is a key component in hemostasis and may be induced by certain conditions, including hypoxia. Past animal studies have shown that increased pulmonary pressures lead to rupture of the epithelial and endothelial barriers in the lung, and activated platelets are adherent to exposed basement membranes. Since high-altitude pulmonary edema (HAPE) does cause increased pulmonary pressures, these scientists theorized that evidence of platelet activation should be evident in early HAPE.

In this European study, 40 nonacclimatized volunteers were studied, including 30 subjects who were HAPE susceptible (ie, had suffered HAPE at least once in the past). The additional 10 subjects who had never had HAPE served as controls. Baseline measurements were completed on all subjects at the University Hospital of Zurich (at 490 m) in the evening and the following morning, and included physical examination, chest radiograph, lung function tests, blood sampling, and noninvasive hemodynamic examinations. All of the HAPE-susceptible subjects were then randomized to receive tadalafil (10 mg twice daily), dexamethasone (8 mg twice daily), or placebo while at high altitude. All subjects ascended in less than 24 hours from 490 m to 4559 m. All clinical examinations completed at baseline were then repeated the first night at altitude, as well as the following morning. A specific instrument (PFA-100) was used to test platelet adhesion and aggregation in vitro. Specific platelet markers were used to evaluate both platelet aggregation (plasma soluble P-selectin) and coagulation parameters (prothrombin fragments 1+2 and thrombin-antithrombin complex).

For all subjects, the platelet count decreased by more than 20% at high altitude compared to low altitude. Platelet aggregation was increased at high altitude as well, by more than 27% in the evening and 18% in the morning, compared to baseline studies. Eight HAPE-susceptible individuals developed HAPE again (7 had been in the placebo group and 1 had received tadalafil). However, there was no difference in the platelet count or platelet function in the individuals with HAPE compared to those who did not develop the syndrome. At altitude, platelets were activated (increased sP-selectin levels) but there was no evidence of activation of the remainder of the coagulation pathway.

The researchers were unable to confirm their hypothesis since, although there was evidence of platelet activation, there was no evidence of plasmatic coagulation. The paper's discussion does address this in the section “Where have the platelets gone?” According to these data, the authors believe that the platelets must either be consumed or sequestered, and they theorize that the pulmonary capillaries could be the sequestration sites of platelets, thus leading to increased pulmonary artery pressure and uneven lung perfusion. However, since the parameters were found to be similar in those with HAPE and without, this study showed that platelet activation was not a pathophysiological cause of HAPE.

(J Appl Physiol. 2006;114:690–694) T Lehmann, H Mairbaurl, B Pleisch, et al. Prepared by Karen Nolan Kuehl, MD, FACEP Carilion Emergency Medicine, Roanoke, VA, USA

Cornea

Corneal Thickness at High Altitude

Hypobaric hypoxia of high altitude causes physiologic changes in multiple organ systems, including the eye. Past studies have shown that hypoxic conditions in the eye, such as those induced by the presence of contact lenses, can cause corneal swelling. The involved mechanisms are thought to be oxygen tension, endothelial function, and corneal metabolic activity, although it is unclear how much each mechanism contributes. The authors designed this study to study the effect of hypoxia on corneal thickness in lowlanders ascending to high altitude.

Sixty-three healthy subjects with no history of ocular disease were recruited to complete the study. Central corneal thickness (CCT) was measured using ultrasound pachymetry. Measurements were completed at baseline (at sea level) prior to subjects being flown to La Paz (3700 m). Each subject underwent acclimatization for 4 days in La Paz before being driven to the laboratory at Chacaltaya (5200 m), where they stayed for 7 days. CCT was measured on days 1, 3, and 7 while at 5200 m, and then final measurements were completed at least 1 month after the subjects returned to sea level. Each subject was also enrolled in a double-blind randomized controlled trial testing antioxidants and sildenafil in prevention of acute mountain sickness.

CCT increased significantly from 543 micrometers to 561 micrometers on Day 1 (P < .001). Thickness then increased further to 563 micrometers on the third day and to 571 micrometers on Day 7, but returned to 541 micrometers after descent. These data clearly show that CCT not only increases upon ascent to altitude but also continues to increase with time spent at altitude. In addition, neither sildenafil nor antioxidants had any effect on CCT at altitude.

The authors of this study conclude that hypoxia does cause significant corneal swelling in healthy volunteers ascending to altitude. The data did show significant variation of change in CCT in different subjects, suggesting that there is individual susceptibility to corneal hypoxia. Changes in corneal thickness could cause significant problems in mountaineers who have undergone refractive surgery. Dr. Beck Weathers, who had undergone radial keratotomy (RK), is one example of a climber who had severe vision loss while attempting Mount Everest in 1996. LASIK is less invasive than RK, but the surgical changes to the cornea could cause refractive error when corneal swelling exists.

(Cornea. 2007;26(3):308–311) DS Morris, JE Somner, KM Scott, et al. Prepared by Karen Nolan Kuehl, MD, FACEP Carilion Emergency Medicine, Roanoke, VA, USA

Shock

Platonin, A Cyanine Photosensitizing Dye, is Effective for Attenuation of Heatstroke in Rats

Heatstroke is a physiologic condition defined by an internal body temperature of greater than 40 degrees Celsius and multi-organ failure. Systemic inflammation, hypercoagulability, and tissue injury are thought to be the mechanisms leading to organ failure and, if untreated, inevitable death. Common laboratory findings in heatstroke include elevated liver tranaminases and serum creatinine, while physiologic findings include elevated intracranial pressures, decreased mean arterial pressure, and decreased partial pressure of oxygen. Platonin, also known as trithiazole pentamethine cyanine, activates macrophages and is an immunomodulator. Mentioned studies have shown this agent to reduce pyrogen expression in some fevers and to attenuate the effects of heatstroke in rats. These researchers designed a study to see if platonin is an effective prophylactic agent against heatstroke.

Anesthetized rats were divided into the following groups of 8 animals: normothermic controls (no treatment), normothermic controls (platonin 50 μg/mL/kg), isotonic sodium chloride, platonin (12.5 μg/mL/kg), platonin (25 μg/mL/kg), platonin (50 μg/mL/kg), platonin (25 μg/mL/kg) + 36°C saline, and platonin (25 μg/mL/kg) + 4°C saline directly into the jugular vein. Each rat, except the controls, was exposed to ambient temperatures of 43°C to simulate heatstroke. Constant monitoring of physiologic parameters occurred, and blood samples were analyzed at 0, 70, and 85 minutes after the initiation of heat exposure.

Rats pretreated only with isotonic saline had survival times of only 20–24 minutes. Pretreatment with platonin improved survival times to 63–185 minutes (with increased survival times found with increased dosing of platonin). Rats pretreated with a combination of platonin in addition to 4°C saline injected into the jugular vein had even more impressive survival times (mean 352 minutes). Plasma levels of creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and tumor necrosis factor were significantly attenuated in those rats pretreated with platonin. In addition, pretreatment with platonin appeared to prevent prolongation of bleeding times, indicated by higher levels of platelets and smaller values of partial thromboplastin time and prothrombin time.

This study shows that the use of platonin as a pretreatment for heatstroke-affected rats improves survival time, attenuates cellular injury and organ dysfunction, attenuates the hypercoagulable state, and attenuates physiological dysfunction and cerebral damage. A referenced study has also shown platonin to be protective when used immediately after onset of heatstroke. Currently, body cooling is the primary treatment for hyperthermia. However, this study shows an adjunctive treatment that works to attenuate the inflammatory activation, the hypercoagulable cascade, and cerebrovascular dysfunction that have been activated by the initial insult.

(Stroke. 2006;26(6):601–607) CC Tsai, MT Lin, CC Yang, et al. Prepared by Karen Nolan Kuehl, MD, FACEP Carilion Emergency Medicine, Roanoke, VA, USA