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A 56-Year-Old, Otherwise Healthy Woman Presenting With Light-headedness and Progressive Shortness of Breath FREE TO VIEW

J. Alberto Neder, MD; Daniel M. Hirai, PhD; Joshua H. Jones, BSc; Joel T. Zelt, BSc; Danilo C. Berton, MD; Denis E. O’Donnell, MD
Author and Funding Information

aLaboratory of Clinical Exercise Physiology and Respiratory Investigation Unit, Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen’s University, Kingston, Ontario, Canada

bRespiratory Division, Department of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

CORRESPONDENCE TO: J. Alberto Neder, MD, Division of Respiratory and Critical Care Medicine, Queen’s University and Kingston General Hospital, Richardson House, 102 Stuart St, Kingston, ON, K7L 2V6, Canada


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(1):e23-e27. doi:10.1016/j.chest.2016.02.672
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A 56-year-old white woman was referred to the pulmonary clinic for evaluation of unexplained shortness of breath. She enjoyed good health until 3 months prior to this visit when she reported experiencing recurrent episodes of shortness of breath and oppressive retrosternal chest discomfort with radiation to the neck. Episodes lasting 5 to 10 min often occurred at rest and were inconsistently related to physical activity. These symptoms became progressively worse and were often associated with light-headedness and presyncope. Her past medical history was uneventful apart from a prior diagnosis of breast cysts and suspected prolactinoma. Her symptoms escalated to such a level that she was forced to seek urgent medical attention at our institutional ED on two separate occasions in the preceding weeks. These visits precipitated a number of investigations and, eventually, a referral to the pulmonary clinic.

Figures in this Article

An afebrile female presented with a heart rate of 88 beats/min; BP, 108/62 mm Hg; respiratory rate, 15 breaths/min; and oxygen saturation, 97% on room air. Although not in apparent respiratory distress, the patient reported significant breathing difficulty described as an “uncomfortable urge to breathe.” Laryngeal/tracheal auscultation did not reveal stridor or evidence of jugular distension. Cardiovascular examination produced unremarkable results, and breath sounds were normal. The remainder of the physical examination also yielded unremarkable results.

Her hemoglobin level was 12.0 g/dL; WBC count, 5,400/μL; and creatinine level, 0.6 mg/dL. Two previous troponin measurements produced normal results at < 0.01 μg/L. A chest radiograph showed a normal cardiac and mediastinal silhouette with clear bilateral lung fields. A high-resolution CT scan was negative for interstitial lung disease. Ventilation/perfusion scintigraphy excluded pulmonary embolism. Resting ECG showed a normal sinus rhythm. A trans-thoracic echocardiogram showed normal left ventricular function with an ejection fraction of 68% and normal pulmonary artery pressures. A dobutamine stress echocardiogram showed no evidence of inducible ischemia up to 101% of the target heart rate.

All pulmonary function tests produced results within normal limits. To investigate the origins of her breathlessness, an incremental cardiopulmonary exercise test (CPET) on a cycle ergometer with “arterialized” (ear lobe) blood gas assessment and dyspnea rating (0 to 10 category-ratio Borg scale) was undertaken (Fig 1).

Figure 1
Figure Jump LinkFigure 1 Key cardiopulmonary exercise testing data. A and B, Note preexercise bursts of increased ventilation and increasing dyspnea scores (A), which were out of proportion to metabolic demand (B). C, Changes in ventilation were associated with erratic variations in breathing pattern. D, End-tidal and arterialized Pco2 (Partco2) decreased in parallel. Start of exercise was associated with a decrease in dyspnea (A) and sudden recoupling of ventilation to metabolism (B), which led to a progressive increase in Pco2 (D). The patient increased ventilation near the end of exercise in order to compensate for ongoing metabolic acidosis (“respiratory compensation point”). Rec = recovery.Grahic Jump Location

What is the diagnosis?

Diagnosis: Idiopathic (“primary”) hyperventilation

This case study highlights the challenges faced by the pulmonologist in identifying the most likely source(s) of worsening shortness of breath in a distressed patient whose symptoms remained unexplained despite extensive clinical investigations. In this context, classical textbooks suggest that, in the absence of a systemic cause of increased central neural drive (eg, chronic metabolic acidosis, hyperthyroidism), a plethora of diseases affecting the airways (asthma, vocal cord dysfunction), pulmonary vasculature (idiopathic pulmonary hypertension, chronic thromboembolic pulmonary hypertension), heart (valvar and pericardial disease, arrhythmias), and neuromuscular system (respiratory muscle weakness, mitochondrial myopathy) should be excluded before the symptoms are labeled as “medically unexplained.” If such recommendations are followed ad verbum, the resulting costs and potential for iatrogenic complications would soon escalate. The current case demonstrates that noninvasive and more integrative measurements, such as those provided by CPET, can prove helpful in reaching an early diagnosis and/or in directing appropriate complementary investigations.

Idiopathic hyperventilation (IHV) is a frequent cause of medically unexplained dyspnea characterized by sustained arterial and alveolar hypocapnia secondary to excessive alveolar ventilation relative to metabolic demand (ie, carbon dioxide production). IHV is associated with a number of symptoms: most commonly, shortness of breath. IHV is known to coexist with anxiety, depression, and perfectionist traits. Moreover, patients with IHV may report more intense dyspnea than patients with a variety of organic lung diseases. Early recognition of IHV is important not only to reduce the frequency of unnecessary investigations (which increase health-care costs and the risk of iatrogenic complications) but also to mitigate the distress caused by an uncertain diagnosis—which, in turn, increases anxiety leading to further hyperventilation and shortness of breath in a vicious cycle.

The symptoms of overwhelming “urge to breathe,” affective distress, anxiety, and paresthesia are more common in IHV than in medically explained dyspnea. On the other hand, symptoms of wheeze, cough, sputum, and palpitations are rarely reported in isolation by patients with IHV. Unfortunately, IHV may also occur in patients with underlying cardiopulmonary diseases, particularly in those with asthma. Thus, it is important to provide an objective demonstration of IHV before diagnostic labeling. As exemplified by the current study, the key findings during CPET suggesting IHV are as follows (Fig 1):

  • 1.

    Consistent and recurrent mismatch between (low or unaltered) metabolic demand and high ventilatory response

  • 2.

    An aberrant and erratic breathing pattern

  • 3.

    Dissociation between the level of physical stress and severity of dyspnea

Characteristically, these abnormalities tend to recede as subjects’ attention becomes more focused on the task as the work rate increases during CPET (or even when exercise commences, as in the present case) (Fig 1). Care should be taken to differentiate IHV from the cyclic fluctuations in ventilation and gas exchange found in periodic breathing (Cheyne-Stokes) in patients with cardiocirculatory impairment. It should also be noted that end-tidal Pco2 may underestimate arterial Pco2 if the patient adopts a shallow and fast breathing pattern (as less alveolar air is sampled per breath) and/or there are regional alveolar units with high ventilation/perfusion ratios, for example, pulmonary vascular disease. In this context “arterialized” (capillary) Pco2 is a minimally invasive option that can guide the interpretation of exercise end-tidal Pco2 (Fig 1).

Behavioral and/or psychologic activation of voluntary ventilatory motor control pathways is thought to be involved in the genesis of IHV. In addition, chronic hypocapnia, per se, downwardly shifts the Paco2 set point. This is likely to have a powerful perpetuating effect on IHV as higher ventilation is required to maintain Paco2 within the newly regulated lower operating range. The neurobiological origins of increased shortness of breath in IHV are not precisely known but may arise because of inappropriate cortical processing of respiratory-related sensory inputs and/or increased activation of limbic and paralimbic centers and sensorimotor and premotor cortical areas of the brain. Despite preserved central chemosensitivity, patients with IHV have shorter breath-holding time and have a greater chance of showing a “paradoxical” decrease in breath-holding time after hyperventilation. Thus, it is postulated that untreated, long-term IHV may have important self-perpetuating biological consequences.

Acute hyperventilation has been associated with chest tightness and oppression, possibly as a result of vagal reflexes and/or the effects of acute lung hyperinflation. Each 1-mm Hg decrement in Paco2 is associated with a 2% to 3% decrease in cerebral blood flow, which can be associated with neurological symptoms. Moreover, low cerebral blood flow increases local hydrogen ion concentration, which can further stimulate central chemoreceptors. This patient provided a unique opportunity to assess whether the reported neurological symptoms were related to hypocapnia-induced cerebral vasoconstriction. As shown in Figure 2, decrements in prefrontal cerebral oxygenation by a noninvasive technique (near-infrared spectroscopy) were consistently associated with hypocapnia and light-headedness. Cerebral oxygenation and symptoms subsequently improved as end-tidal Pco2 increased during exercise. In severe cases, however, these abnormalities might progress to presyncope and even transient loss of consciousness. It is currently unknown whether chronic cerebral hypoperfusion compromises the central integration of respiratory-related afferents, thereby contributing to dyspnea. Chronic (respiratory) alkalosis and cerebral ischemia may also induce sympathoexcitation, tachycardia, and high blood pressure. Because of sustained stimulation of phosphofructokinase, patients with IHV may develop significant hypophosphatemia. Respiratory alkalosis may lead to hypocalcemia, which increases neuronal excitability resulting in perioral and peripheral extremity parasthesias and, in more severe cases, carpal spasm.

Figure 2
Figure Jump LinkFigure 2 Near-infrared spectroscopic measurements of cerebral oxygenation as related to prevailing end-tidal Pco2 levels. Note progressive impairment in preexercise cerebral oxygenation (proportional to cerebral perfusion in nonhypoxemic patients) with accompanying neurological symptoms as end-tidal Pco2 decreased. Cerebral oxygenation subsequently improved (and the symptoms subsided) as end-tidal Pco2 increased during exercise.Grahic Jump Location
Clinical Course

The patient presented with medically unexplained dyspnea that had been extensively investigated in the acute care setting. Ultimately, the data from incremental cardiopulmonary exercise testing supported the diagnosis of idiopathic hyperventilation. The patient was reassured of the psychosomatic nature of her symptoms and of the absence of any significant underlying cardiopulmonary disease. Thereafter the patient participated in psychological counseling and enrolled in yoga classes that incorporated breathing and relaxation exercises. At the 3-month follow-up appointment, she reported substantial improvement in her respiratory symptoms and quality of life.

  • 1.

    Symptoms associated with IHV may mimic several life-threatening cardiopulmonary and neurological conditions, including coronary artery disease, pulmonary embolism, and cerebrovascular disease. These symptoms frequently prompt multiple investigations with substantial personal and societal burdens.

  • 2.

    Although an uncomfortable “urge to breathe,” affective distress related to breathing, anxiety, and paresthesia are more common in IHV than in medically explained dyspnea, there is substantial overlap in individual patients. Objective demonstration of primary hyperventilation is key for diagnostic confirmation and reassurance of the patient.

  • 3.

    By showing consistent mismatch between metabolic and ventilatory demands, an aberrant and erratic breathing pattern, and dissociation between physical stress and severity of dyspnea, cardiopulmonary exercise testing remains a valuable tool to diagnose IHV and can eliminate other diagnostic considerations.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: D. E. O’D. has received research funding via Queen’s University from Astra Zeneca, Boehringer Ingelheim, and GlaxoSmithKline, and has served on speakers’ bureaus, consultation panels, and advisory boards for Almirall, Astra Zeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Pfizer. None declared (J. A. N., D. M. H., J. H. J., J. T. Z., D. C. B.).

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.


Figures

Figure Jump LinkFigure 1 Key cardiopulmonary exercise testing data. A and B, Note preexercise bursts of increased ventilation and increasing dyspnea scores (A), which were out of proportion to metabolic demand (B). C, Changes in ventilation were associated with erratic variations in breathing pattern. D, End-tidal and arterialized Pco2 (Partco2) decreased in parallel. Start of exercise was associated with a decrease in dyspnea (A) and sudden recoupling of ventilation to metabolism (B), which led to a progressive increase in Pco2 (D). The patient increased ventilation near the end of exercise in order to compensate for ongoing metabolic acidosis (“respiratory compensation point”). Rec = recovery.Grahic Jump Location
Figure Jump LinkFigure 2 Near-infrared spectroscopic measurements of cerebral oxygenation as related to prevailing end-tidal Pco2 levels. Note progressive impairment in preexercise cerebral oxygenation (proportional to cerebral perfusion in nonhypoxemic patients) with accompanying neurological symptoms as end-tidal Pco2 decreased. Cerebral oxygenation subsequently improved (and the symptoms subsided) as end-tidal Pco2 increased during exercise.Grahic Jump Location

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