Medicine / Special Report

Vol. 5, NO. 1 / April 2020

The Physiology and Biophysics of Respiratory Therapy

J. Scott Turner

Letters to the Editors

In response to “The Physiology and Biophysics of Respiratory Therapy

Severe COVID-19 infection can impair blood oxygenation and cause respiratory distress, with fulminating and potentially fatal pneumonia as one possible outcome. This acute respiratory distress syndrome can be brought on by frank injury to the lung as well as respiratory infection. The goal of respiratory therapy is to sustain blood oxygenation until the crisis passes. Treatment is in stages, which can include corticosteroids to reduce inflammation, and supplemental oxygen through a nasal cannula. If neither of these treatments relieves the distress, a physician will turn to artificial ventilation of the patient’s lungs, either through a mask sealed around the nose and mouth, or through a tube inserted into the patient’s trachea.1

Artificial ventilation is a drastic and dangerous intervention in a patient’s care, and carries its own suite of risks. These include ventilator-associated lung injury and ventilator-associated pneumonia. Both can inflict serious damage to the lung, which may result in permanent respiratory disability. For a significant proportion of patients, complications are fatal.2

For these reasons, alternative therapies are needed. Some of these involve skilled nursing care. Periodic repositioning of the patient, for example, from supine to prone, or onto the side, can redistribute liquid within the lung. This can help sustain blood oxygenation by allowing for compromised portions of the lung to drain and reopen for gas exchange. These maneuvers can significantly reduce time spent on a ventilator and reduce the likelihood of both lung injury and pneumonia. Other alternatives are exotic: rather than ventilate a patient with air, which is a mixture of oxygen and nitrogen, a mix of helium and oxygen, called heliox, might be used. Oxygen can diffuse through helium faster than through nitrogen, which can speed oxygen delivery to the alveoli, the tiny pockets deep within the lung where gas exchange with the blood occurs. Nitric oxide is sometimes used to dilate the lung’s small vessels, improving blood flow and blood oxygenation. Each alternative carries its own risks and disadvantages. Helium is expensive and rare, so its use in an epidemic surge of patients would not be practical. Nitric oxide can have significant side effects, including compromising blood pressure, risky in a clinical situation where cardiac issues may be contributing to the distress.3

One possibly more practical alternative is high-frequency ventilation (HFV), which ventilates the lungs with very rapid and very shallow breaths.4 Normal ventilation frequency is about ten breaths per minute. HFV delivers breaths at a rate of hundreds to thousands of breaths per minute, either in the form of minute jets of air introduced through the breathing tube, or through pressure oscillations imposed by a magnetic piston similar to that in a low-frequency loudspeaker. HFV is a promising alternative because it can reduce the incidence and severity of lung injury and pneumonia associated with current methods of artificial ventilation.5 Its most common application has been in neonatal intensive care, where respiratory distress and lung injury is a special problem for premature infants.

The effectiveness of HFV compared to standard artificial ventilation has been a subject of ongoing debate, in large part because clinical trials comparing the two have provided mixed results. Results of clinical studies carried out in emergency situations always carry a large burden of uncertainty, however. Because patient care in such situations always trumps the design of a clinical study, this can shade the reliability of statistical comparisons. Artificial ventilation also lends itself well to rapid decision-making in emergency room environments because it is based on simple principles of lung function. HFV, in contrast, turns on seemingly arcane and counterintuitive aspects of lung function. Physicians are understandably reluctant to base critical care decisions on such uncertainty.

That HFV works at all as a respiratory therapy reveals interesting details about both the biology and physics of the lung. Consider, for example, why increased breathing rate during exercise increases the rate of respiratory gas exchange. It is not the breathing rate per se that drives gas exchange. What limits the lung’s ability to move oxygen from the atmosphere into the blood is gas mixing in the small passageways that bridge the alveoli and the larger airways of the trachea and bronchi. Faster breathing promotes increased gas exchange by increasing the mixing rate in this zone. HFV enhances respiratory gas exchange because it, too, promotes mixing in the lung’s mixed-regime zone, albeit through a radically different mechanism, one that depends more upon the acoustic and mechanical resonance of the lung and chest. These are poorly understood, even among physicists and engineers. Nevertheless, HFV sometimes finds use in the emergency room because it sustains blood oxygenation, even if it is not fully understood why.

HFV may also provide a more direct clinical benefit by ameliorating ventilator-associated lung injury. Ventilator-associated lung injury arises from the common method of artificial ventilation, positive-pressure ventilation (PPV), so called because the ventilator inflates the lung by imposing positive pressure on it. Normally, the lungs inflate by a suction pressure imposed by the expansion of the chest cavity, so-called negative-pressure ventilation (NPV).

Both PPV and NPV impose mechanical strains on the lungs, which are borne by the matrix of connective tissue that holds the lungs—and all other organs—together. The connective tissue is not simply scaffolding: it comprises an exquisitely sensitive system for monitoring mechanical strains, and it remodels itself to accommodate anomalous strains. Bones, tendons, and muscles all are shaped by this action, and lungs are too.6 Ventilator-associated lung injury follows from the anomalous patterns of mechanical strain imposed on the lung by PPV, which are perceived by the lung’s connective tissue matrix as an injury. The subsequent remodeling of the lung, if it is extensive enough, can compromise function when the patient returns to unassisted breathing and the normal regime of NPV. Among the deleterious consequences can be stiffening of the lung, producing emphysema, or blockage of small airways within the lung, producing chronic obstructive pulmonary disease. Because the lung perceives PPV as an injury, it can also induce an inflammatory response. Inflammation of any kind is mediated by the local release of cytokines—small molecules produced by immune cells, such as macrophages. When piled upon the inflammation that accompanies a coronavirus infection, PPV-associated cytokine release can increase the likelihood of cytokine storms, which can be the fatal event in a coronavirus-associated pneumonia.7

HFV appears to reduce such negative outcomes by imposing a third pressure regime on the lung. In HFV, the lungs are kept inflated by imposing a small and continuous positive pressure, over which rapid small oscillations of pressure are imposed. The cells that sense anomalous pressures and remodel the lung in response—the fibroblasts and macrophages—appear to be relatively insensitive to steady pressures imposed upon the lung, compared to the changing pressure associated with PPV. Less extensive lung remodeling is the result. The response of the connective tissue network to anomalous strain also appears to be frequency-dependent, more sensitive to the slow and large pressure oscillation of PPV than to the rapid and small pressure oscillations imposed by HFV.8

HFV may also reduce the likelihood of ventilator-associated pneumonia. The invasive nature of any form of artificial ventilation elevates the risk of pneumonia, no matter the method. But pneumonia can arise in many ways, with the common root being a disruption of the lung’s water balance: the rate of liquid leakage into the lung’s air spaces compared to the rate at which it is removed. Liquid continuously leaks into the alveoli through the capillaries lining them. Liquid is continuously withdrawn by a slight negative pressure imposed by the pleural membranes enveloping the lung. Added to this is the continual tendency of the alveoli to collapse from surface tension. Water balance in the healthy lung depends upon a precarious balance of forces between blood pressure, suction pressure, and surface tension.

Pneumonia results when this balance is disrupted. This can arise from disruption at the alveoli, the pleural membranes, or both. Pneumonia associated with infection comes from excessive leakage of liquid into the alveoli arising from the increased blood vessel permeability that is a normal part of the inflammatory response. Pneumonia can also result from disruption of water removal through the pleural membranes.

Artificial ventilation appears to aggravate pneumonia in two ways. One is by exacerbating an already ongoing infection. Air pumped into the lungs by any means will inevitably introduce bacteria and irritants. Because these flows are reduced in HFV compared to PPV, this risk may be lowered, but not eliminated. Secondly, the periodic imposition of positive pressure can reduce the suction pressures normally present at the pleural membranes, tilting the lung’s water balance toward water accumulation and pneumonia.

HFV may ameliorate this through the imposition of a steady positive pressure that is overlain by HFV’s rapid and small oscillations of pressure. This steady positive pressure can tilt the lung’s water balance back toward removal, simply by helping to push excess liquid out through the lung’s lymphatic vessels.9

These are only the bare essentials for comparing the relative effectiveness of PPV versus HFV. The mechanics and physiology of HFV remain poorly understood, and many variants in method and application are being tested for effectiveness, both in animals and in the clinic. Even though the clinical picture remains unsettled, HFV shows sufficient promise as a less risky alternative to artificial ventilation to warrant serious consideration. In this sense, HFV occupies roughly the same off-use space that anti-malarial drugs do for treating COVID-19 infections: promising prospects, but much still to learn.

The present COVID-19 pandemic is already far enough along the curve that one can confidently say that HFV will not soon be replacing PPV as an alternative form of respiratory therapy. However, now may be the time for exploring HFV further, so that emergency medicine might be better equipped to deal with the next pandemic that is almost certainly in our future.


  1. Susan Weiss and Sonia Navas-Martin, “Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus,” Microbiology and Molecular Biology Reviews 69, no. 4 (2005): 635­–64, doi:10.1128/MMBR.69.4.635-664.2005. 
  2. Hoyte van der Zee et al., “Alterations in Pulmonary Fluid Balance Induced by Positive End-Expiratory Pressure,” Respiration Physiology 64 (1986): 125–33, doi:10.1016/0034-5687(86)90036-8. 
  3. Huige Li and Ulrich Förstermann, “Nitric Oxide in the Pathogenesis of Vascular Disease,” Journal of Pathology 190 (2000), 244–54, doi:10.1002/(sici)1096-9896(200002);2-8. 
  4. H. K. Chang and Alain Haif, “High Frequency Ventilation: A Review,” Respiration Physiology 57, no. 2 (1984): 135–52, doi:10.1016/0034-5687(84)90089-6. J. M. Drazen, R. D. Kamm, and A. S. Slutsky, “High-Frequency Ventilation,” Physiological Reviews 64 (1984): 505–43, doi:10.1152/physrev.1984.64.2.505. 
  5. Frank Ritacca and Thomas E. Stewart, “Clinical Review: High-Frequency Oscillatory Ventilation in Adults: A Review of the Literature and Practical Applications,” Critical Care 7 (2003): 385, doi:10.1186/cc2182. 
  6. J. Scott Turner, The Tinkerer’s Accomplice: How Design Emerges from Life Itself (Cambridge, MA: Harvard University Press, 2007). 
  7. Jennifer Tisoncik et al., “Into the Eye of the Cytokine Storm,” Microbiology and Molecular Biology Reviews 76, no. 1 (2012): 16–32, doi:10.1128/MMBR.05015-11. 
  8. Van der Zee et al., “Alterations in Pulmonary Fluid Balance.” D. Martin et al., “High-Frequency Ventilation: Lymph Flow, Lymph Protein Flux, and Lung Water,” Journal of Applied Physiology 57 (1984): 240–45, doi:10.1152/jappl.1984.57.1.240. 
  9. Ichidai Kudoh, Takehisa Soga, and Katsuo Numata, “Effect of High-Frequency Ventilation on Extravascular Lung Water Volume in Dogs,” Critical Care Medicine 15, no. 3 (1987): 240–42, doi:10.1097/00003246-198703000-00012. 

J. Scott Turner is Professor of Biology at the State University of New York College of Environmental Science and Forestry, and a Fellow of the Stellenbosch Institute for Advanced Study.

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