The link between cerebral oxygenation and abnormal respiratory drive


This review summarizes the interaction between the regulatory system of respiration and cerebral vasculature. Some clinical reports provide evidence for the association between these two physiological regulatory systems. Physiologically, arterial carbon dioxide concentration is mainly regulated by two feedback control systems: respiration and cerebral blood flow. In other words, both of these systems are sensitive to the same mediator, i.e., carbon dioxide, at a set point. In addition, respiratory dysfunction alters various physiological factors that affect the cerebral vasculature. Therefore, it is physiologically plausible that these systems are closely linked. The regulation of arterial carbon dioxide concentration affected by respiration and cerebral blood flow may be a key factor for a rise in the risk of brain disease in the patients with respiratory dysfunction. Review : Mechanisms of Respiratory Modulation of Cardiovascular Control Interaction between the respiratory system and cerebral blood flow regulation Shigehiko Ogoh 27 OCT 2019

Paula has invisible [until measured] respiratory dysfunction. It is chronic and affects brain function only during major respiratory challenges. The type of respiratory dysfunction that Paula has involves abnormal modulation of respiratory drive.

What exactly is respiratory drive? Well, that is complicated !

 Definition of Respiratory Drive

The term “respiratory drive” is frequently used, but is rarely precisely defined. It is important to stress that the activity of the respiratory centers cannot be measured directly, and therefore the physiological consequences are used to quantify respiratory drive. Most authors define respiratory drive as the intensity of the output of the respiratory centers [3], using the amplitude of a physiological signal as a measure for intensity. Alternatively, we consider the respiratory centers to act as oscillatory neuronal networks that generate rhythmic, wave-like signals. The intensity of such a signal depends on several components, including the amplitude and frequency of the signal. Accordingly, we propose a more precise but clinically useful definition of respiratory drive: the time integral of the neuronal network output of the respiratory centers, derived from estimates of breathing effort. As such, a high respiratory drive may mean that the output of the respiratory centers has a higher amplitude, a higher frequency, or both.

The respiratory drive directly determines breathing effort when neuromuscular transmission and respiratory muscle function are intact. We define breathing effort as the mechanical output of the respiratory muscles, including both the magnitude and the frequency of respiratory muscle contraction [1].

What Determines the Respiratory Drive?

Neuroanatomy and Physiology of the Respiratory Control Centers

. The respiratory centers are located in the medulla and the pons and consist of groups of interneurons that receive information from sources sensitive to chemical, mechanical, behavioral, and emotional stimuli. Important central chemoreceptors are located near the ventral parafacial nucleus (pFV) and are sensitive to direct changes in pH of the cerebrospinal fluid. Peripheral chemoreceptors in the carotid bodies are the primary site sensitive to changes in PaO2, and moderately sensitive to changes in pH and PaCO2…………. The respiratory centers integrate this information and generate a neural signal. The amplitude of this signal determines the mechanical output of the respiratory muscles (and thus tidal volume). The frequency and timing of the neural pattern relates to the breathing frequency and the duration of the different phases of the breathing cycle. Three phases can be distinguished in the human breathing cycle: inspiration, post-inspiration, and expiration (Fig. 2). Each phase is predominately controlled by a specific respiratory center (Fig. 1) [2]. ……

……..Clinical Signs and Breathing Frequency:

Clinical signs, such as dyspnea and activation of accessory respiratory muscles, strongly support the presence of high respiratory drive, but do not allow for quantification. Although respiratory drive comprises a frequency component, respiratory rate alone is a rather insensitive parameter for the assessment of respiratory drive; respiratory rate varies within and between subjects, depends on respiratory mechanics, and can be influenced by several factors independent of the status of respiratory drive, such as opioids [30] or the level of pressure support ventilation. We therefore need to evaluate more sensitive parameters of respiratory drive.

Inspiratory Effort :

Respiratory drive may also be inferred from inspiratory effort measured with esophageal and gastric pressure sensors. The derivative of Pdi (dPdi/dt) reflects respiratory drive only if both the neural transmission and diaphragm muscle function are intact. As such, high dPdi/dt values reflect high respiratory drive. In healthy subjects, dPdi/dt values of 5 cmH2O/s are observed during quiet breathing [4]. dPdi/dt is often normalized to the maximum Pdi, but maximum inspiratory maneuvers are rarely feasible in ventilated ICU patients. A limitation of using Pdi-derived parameters is that Pdi is specific to the diaphragm and therefore does not include accessory inspiratory muscles, which are often recruited when respiratory drive is high. Calculating the pressure developed by all inspiratory muscles (Pmus) may overcome this. Pmus is defined as the difference between Pes (i.e., surrogate of pleural pressure) and the estimated pressure gradient over the chest wall. Other measurements of inspiratory effort are the work of breathing (WOB), and the PTP, which have been shown to correlate closely with P0.1 [4142]. However, all the above measurements require esophageal manometry, a technique that demands expertise in positioning of the esophageal catheter and interpretation of waveforms, making it less suitable for daily clinical practice. Another major limitation is the risk of underestimating respiratory drive in patients with respiratory muscle weakness; despite a high neural drive, inspiratory effort might be low.

A noninvasive estimate of inspiratory effort can be derived with diaphragm ultrasound. Diaphragm thickening during inspiration (i.e., thickening fraction) has shown fair correlation with the diaphragmatic PTP [43]. However, diaphragm ultrasound does not account for recruitment of accessory inspiratory and expiratory muscles, and the determinants of diaphragm thickening fraction require further investigation. Nonetheless, diaphragm ultrasound is readily available at the bedside, relatively low cost and noninvasive, and may therefore be a potential promising technique for the evaluation of respiratory drive.

Strategies to Modulate Respiratory Drive

Targeting physiological levels of respiratory drive or breathing effort may limit the impact of inadequate respiratory drive on the lungs, diaphragm, dyspnea sensation, and patient outcome. However, optimal targets and upper safe limits for respiratory drive and inspiratory effort may vary among patients, depending on factors such as the severity and type of lung injury (e.g., inhomogeneity of lung injury), the patient’s maximum diaphragm strength, and the presence and degree of systemic inflammation [319]. Physiology of the Respiratory Drive in ICU Patients: Implications for Diagnosis and Treatment Annemijn H. JonkmanHeder J. de Vries &  Leo M. A. Heunks  Critical Care volume 24, Article number: 104 (2020) 

Paula always has some sensation of dyspnea…but not with fast breathing, she has it with depressed breathing….even when well. She thinks this is normal. [It is not].

Paula always uses accessory muscles to exhale. She thinks this is normal [It is not].

When she was short of breath with depressed breathing she felt very very distressed yet did not recognize that the sensation was dyspnea and so could not tell anyone. She had no clue what she was experiencing .

A routine check of her vital signs, including respiratory rate at rest, would have shocked her doctor, because she was most likely experiencing some degree of respiratory failure and the doctor would not be familiar with a respiratory rate that was so impossibly low at 3 breaths per minute.

In order to understand patients like Paula, researchers need to investigate respiratory drive and respiratory rate abnormalities more carefully; there is a lot they do not know or even suspect. While it is true that respiratory rate alone is not enough to evaluate respiratory drive abnormalities, it is a great way to begin this investigation. Abnormal respiratory rates at rest suggest the need for more investigation, especially if eemood, mental status, and locomotor activity change for the worse as well.

And remember, cerebral oxygenation and respiration are linked- which is why respiratory failure most likely comes with mental slowing and mental confusion- which most likely is reversible with supportive medical care.

Mental slowing and confusion with too slow or too fast respiratory rate at rest suggests the need for an evaluation of minute ventilation and perhaps serial arterial blood gas tests at the very least.

Yet doctors do not know to do this. While it seems obvious that breathing, breathing difficulties and the function of the mind and the brain are closely interrelated, doctors never investigate respiratory drive, which is largely involuntary and unconscious.

Why? Because it has never been part of medical practice to do so. It is, however, part of basic first aid.

You would think that checking vital signs at rest would be a given, but it’s not…..doctors do not check respiratory rate, heart rate, blood pressure and body temperature as a rule.



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