Mechanisms of Disease – From the Masters #1 Obesity Hypoventilation Syndrome

Questions regarding the pathophysiology and hospital-based management of obesity hypoventilation syndrome addressed by Drs. Roberta Goldring, Kenneth Berger and Beno Oppenheimer at New York University School of Medicine.

Case Vignette

A 55-year-old woman with diabetes, hypertension, obesity (BMI 45 kg/m2), and obesity hypoventilation/obstructive sleep apnea (OHS/OSA) presented to an Emergency Department with labored breathing and somnolence of 2 days duration. Arterial blood, sampled while she breathed 50% oxygen via face mask at a rate of 22 breaths per minute, revealed a pH 7.26; PCO2 80 mmHg; PO2 150 mmHg; [HCO3] 35mEq/l; BEecf 8.3 mEq/l . She was intubated for hypercapnic respiratory failure and admitted to the intensive care unit. 


What is the pathophysiology underlying this patient’s awake hypercapnia?

Drs. Goldring, Berger and Oppenheimer:

In healthy individuals, the arterial blood gas tensions and pH remain constant within a remarkably narrow range over a spectrum of activities. This stability is maintained by the precise adjustment of alveolar ventilation to metabolic rate. Reduction in alveolar ventilation (i.e., hypoventilation) produces an immediate increase in arterial partial pressure of carbon dioxide (PaCO2), with a corresponding reduction in arterial partial pressure of oxygen (PaO2). For clinical purposes, monitoring of PaCO2 is the parameter used to monitor alveolar ventilation; values higher than 45 mm Hg at sea level have been used to define presence of alveolar hypoventilation

In Obesity Hypoventilation Syndrome, the initial manifestation of alveolar hypoventilation typically occurs during sleep before the development of chronic hypercapnia during wakefulness. Sleep-related hypoventilation events range from transient events (i.e. obstructive apnea / hypopnea) to longer sustained events (i.e. sustained obstructive hypoventilation or central hypoventilation). We propose the following steps for the generation of chronic hypercapnia in patients with ventilatory sleep disorders in the absence of intrinsic cardiopulmonary disease.

  • An inciting acute ventilatory event during sleep, such as an apnea or hypopnea event, causes a transient increase in PaCO2. Patients with an adequate and immediate post-event ventilatory response sufficient to maintain the average PaCO2 at 40 mmHg during the sleeping period show no net change in total tissue CO2 stores and therefore remain eucapnic both during sleep and wake.
  • In contrast, patients with inadequate post-event unloading of CO2, due either to blunting of the post-event ventilatory response or to limitation of the interapnea breathing duration (relative to duration of apnea), demonstrate a progressive rise in PaCO2 over subsequent events with compensatory renal bicarbonate retention.
  • Although this increase in total body CO2 stores represents an acute hypercapnia at the onset of wakefulness, the maintenance of chronic hypercapnia is dependent on an individual’s inability to unload the increase in both PCO2 and bicarbonate during the waking period.
  • The ability to accomplish unloading during wakefulness is determined not only by the magnitude of the load but also by the ventilatory response to CO2 and by renal handling of bicarbonate. Of importance, persistence of an elevated bicarbonate concentration would attenuate the change in pH at the medullary chemoreceptor the any given increment in PCO2 (in accord with the Henderson-Hasselbalch relationship).
  • Thus, persistence of an elevated bicarbonate level not only defines the state of chronic hypercapnia but also provides a mechanism for the development and perpetuation of this state by blunting the ventilatory response to progressive increments in PaCO2.


Questions for the next installment

  1. Might this patient have benefitted from a trial of breathing ambient air or a lower concentration of supplemental oxygen before a decision was made to intubate her?
  1. Do opiates and tranquilizers exacerbate chronic daytime hypercapnia in OHS-OSA? And for acute-on-chronic hypercapnia, when should we consider a trial of naloxone or flumazenil? 
  1. Loop diuretics are often used both chronically and acutely in these patients. Does the metabolic alkalosis promoted by these agents exacerbate hypercapnia? 
  1. What is the role of acetazolamide in correcting the acid-base derangement of chronic and acute-on-chronic hypercapnia in OHS-OSA?


Drs. Goldring, Berger, and Oppenheimer comprise the André Cournand Pulmonary Physiology Laboratory at Bellevue Hospital.  Their interests center on study of normal physiology and pathophysiologic derangements in numerous diseases as a basis to guide clinical diagnosis and determine optimal management.

4 thoughts on “Mechanisms of Disease – From the Masters #1 Obesity Hypoventilation Syndrome

  1. I am interested to see how this progresses. In regard to the case vignette, which has not yet been addressed, the patient is very near her baseline ventilatory status, and is breathing well below her reserve. This is highly likely to be a case of “won’t breathe”, or a ventilatory drive problem, rather than a “can’t breathe”, or excessive workload problem. The latter would be represented by a higher respiratory rate, closer to the ceiling of ventilatory reserve.

    I would not have intubated this patient. She has adequate ventilation, and she appears to have reserve. I would have worked to identify the underlying causes of her clinical deterioration while observing her respiratory status. At the most, I would have applied BIPAP. Usurping control of her ventilation with mechanical ventilation will confer net harm and potentially serve as a distraction from identification of the underlying causes of her clinical deterioration. See:


  2. We see a large number of patients with OHS at Cook County Hospital. And although NIV is now used more frequently, the problems of giving obese patients or patients with chronic respiratory disease too much oxygen has not gone away.

    Most times NIV is set to augment ventilation while these patients are awake when the nurse, therapist, and physicain are around the patient making lots of noise and action. They set the NIV with a low CPAP and a high pressure support. Ventilation looks good on the ventilator. They walk away, the patient falls asleep and hypovention kicks in with exacerbated periodicity because of PSV.

    When we come in, we start CPAP at 12 while the patient is asleep and titrate it over few minutes to eliminate apnea. These can be detected by looking at the NIV screen and feeling by hand the movement of chest and abdomen. Once these are eliminated, we increase PSV if needed to give the patient a good tidal volume. Many times high CPAP alone is effective in resolving OSA, improving ventilation, and correcting hypoxia, probability by increasing FRC. We also reduce FIO2 less 30%.

    Liked by 1 person

    1. I am interested in the experience described for CCH above. I TOTALLY agree that physician involvement in titration of NIPPV is absolutely essential. I strongly believe that if oxygenation and ventilation goals are set based on “numbers” without regard to patient work of breathing, that things can go awry in a hurry. I’m totally on board here.

      I will ask an innocent question, acknowledging my relative ignorance here. When about 15 years ago I reviewed informally the evidence for the oft invoked “hypoxic drive”, I was unimpressed. My impression was that, while it does exist in the minority of patients in extreme conditions (that is, patients on the verge of ventilatory failure where all drives are contributing essentially to ventilation), that in the majority of patients, hypoxic drive is clinically negligible. I am happy to entertain references to sources that suggest that it has more than a minor impact on ventilation.



      1. By the way, this sort of “back-and-forth” dialogue about vexing clinical problems that require a rational application if evidence with a keen eye on absolute effects and empirical results, is the essence of a good blog. Controversy foments learning.


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