Oxygen therapy for medical patientsBMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4436 (Published 24 October 2018) Cite this as: BMJ 2018;363:k4436
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Pulmonary Vasodilatation Induced by Alveolar Hyperoxia as a Proposed Mechanism of Hyperoxic Lung Injury
By controlling vascular smooth muscle tone, alveolar partial pressure of oxygen (PAO2) can effectively control regional pulmonary blood flow. On the one hand, alveolar hypoxia induces pulmonary vasoconstriction, which is an adaptive mechanism to optimize ventilation/perfusion ratio by directing blood from poorly ventilated to ventilated alveoli. However, on the other hand, it is unclear whether alveolar hyperoxia—resulting from administration of high concentration of oxygen—causes pulmonary vasodilatation. Experimental evidence from animal studies1, 2 showed that alveolar hyperoxia can induce pulmonary vasodilator response through increased production of endothelium-derived relaxing factor. Interestingly, in the isolated perfused lung preparation, alveolar PO2 rather than mixed venous PO2 was responsible for pulmonary vasodilatation.2 Clinical studies of healthy volunteers also demonstrated that hyperoxia caused pulmonary vasodilatation and increased pulmonary perfusion.3, 4 In fact, it may be difficult to extrapolate data from experimental animals or healthy volunteers to critically ill patients who may have altered pulmonary vasomotor response to changes in alveolar PO2. However, these studies can be useful for hypothesis generation regarding the potential for pulmonary vasodilatation induced by alveolar hyperoxia to contribute to hyperoxic lung injury.
Despite its importance in modifying pulmonary vascular tone, alveolar PO2 is not the only determinant of regional perfusion of the lung. In addition to alveolar hyperoxia—which may induce pulmonary vasodilatation and increase blood flow to the aerated (baby) lung—regional perfusion of the baby lung is also increased as blood is shifted away from collapsed and consolidated lung. Two important mechanisms are responsible for redistribution of blood flow from non-aerated to aerated regions: (1) Hypoxic constriction of alveolar vessels; (2) Passive collapse of extra-alveolar vessels associated with lung collapse (due to loss of radial traction of lung parenchyma on the extra-alveolar vessels). I hypothesized that increased perfusion of the baby lung due to hyperoxia-induced vasodilatation of pulmonary arterioles may lead to stress failure of pulmonary capillaries, which may play a role in the pathogenesis of hyperoxic lung injury.
The baby lung was originally defined as the fraction of lung parenchyma that maintains normal ventilation—a definition that can be extended to include the portion of pulmonary vasculature that receives normal perfusion. Conceptually, the baby lung can be divided into two compartments separated by the alveolar-capillary membrane: alveolar compartment (alveolar epithelium) and capillary compartment (capillary endothelium). The “small” baby lung, which has to accommodate a large proportion of perfusion and ventilation, is at increased risk of capillary hyperperfusion and alveolar overventilation, which makes it vulnerable to injury not only by high-pressure-high-volume ventilation but also by increased capillary hydrostatic pressure that can disrupt the capillary endothelium. Experimental evidence suggests that stress (mechanical) failure of pulmonary capillaries, defined as ultrastructural changes of capillary endothelium (and alveolar epithelium), can develop because of high pulmonary capillary pressure.5 While alveolar overdistension is an established mechanism of ventilation-induced lung injury, stress failure resulting from capillary hyperperfusion is a proposed mechanism for “perfusion-induced lung injury” that can provide another explanation other than oxygen free radical generation for hyperoxic lung injury.
In conclusion, in contrast to alveolar overventilation (volutrauma) which occurs because ventilation is diverted to the alveolar compartment of the baby lung, capillary hyperperfusion (pulmonary capillary stress failure) may represent a different type of lung injury arising from a different side of the alveolar-capillary membrane (i.e, capillary endothelium) due to passive redistribution of perfusion from non-aerated to aerated regions of the lung. Regional blood flow to the capillary compartment of the baby lung may also be increased due to active dilatation of pulmonary vessels associated with alveolar hyperoxia—a mechanism that may at least partly explain hyperoxic lung injury in ARDS during high FiO2 ventilation. However, rather than viewing volutrauma and pulmonary capillary stress failure as two separate entities, ventilation-induced and perfusion-induced lung injury may be thought of as two sides of the same coin. In this way, it would not be too long until a global lung-protective ventilation and perfusion strategy is used to protect against lung injury from alveolar overventilation and capillary hyperperfusion. Protective lung perfusion strategy would include permissive hypoxemia (conservative oxygenation strategy) to avoid pulmonary vasodilatation and lung injury induced by alveolar hyperoxia.
Day RW, Klitzner TS, Ignarro LJ (1993) Endothelium-dependent relaxation and the acute pulmonary vascular response to alveolar hyperoxia in neonatal pigs. Biol Neonate 63:389-96.
2. Yam J, Roberts RJ (1976) Modification of alveolar hyperoxia induced pulmonary vasodilatation by indomethacin. Prostaglandins 11:679-89.
3. Li Y, Tesselaar E, Borges JB, et al (2014) Hyperoxia affects the regional pulmonary ventilation/perfusion ratio: an electrical impedance tomography study. Acta Anaesthesiol Scand 58 :716-25.
4. Ley S, Puderbach M, Risse F, et al (2007) Impact of oxygen inhalation on the pulmonary circulation: assessment by magnetic resonance (MR)-perfusion and MR-flow measurements. Invest Radiol 42 :283-90.
5. West JB, Tsukimoto K, Mathieu-Costello O, et al (1991) Stress failure in pulmonary capillaries. J Appl Physiol 70: 1731–1742.
Competing interests: No competing interests
Change is afoot in emergency oxygen supplementation. Work by Siemieniuk and colleagues has challenged existing national guidelines and created impetus for review (1,2). This work adds significantly to the previously limited available evidence and supports a shift towards lower saturation targets for oxygen provision and titration.
Similar critical questions are being asked in the pre-hospital and military environments. The forward logistic supply of oxygen is burdensome and due to its flammable nature, it is not always brought forward onto the battlefield. As we review our current practice in these settings, the work of the Siemieniuk group is welcome to provide a clear evidence base for change.
Many publications forget the patient’s journey prior to hospital with its own unique challenges. We acknowledge the concerns detailed by Horner and O’Driscoll relating to balancing tighter oxygen control with the risk of hypoxia (3). This careful practice becomes even more challenging in the setting of a pre-hospital or resource-limited environment. Hypoxia prevention is paramount but the risk posed by hyperoxia and its associated morbidity should drive technological advancement to bridge the gap that teaching and training fail to achieve (4).
Future guidelines must consider the pre-hospital and military populations. The Academic Departments of Military Emergency Medicine and Military Anaesthesia and Critical Care have critically reviewed the literature pertaining to this population (5). Recommendations from our review support the findings of recent publications and highlight the need for this patient group to be considered further.
1. Siemieniuk RAC, Chu DK, Kim LH-Y, et al. Oxygen therapy for acutely ill medical patients: a clinical practice guideline. BMJ 2018;363:k4169.pmid:30355567
2. Chu DK, Kim LH, Young PJ, et al. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet 2018;391:1693-705. doi:10.1016/S0140-6736(18)30479-3 pmid:29726345
3. Horner D, O’Driscoll R. Oxygen therapy for medical patients BMJ 2018;363:k4436
4. Hale KE, Gavin C, O’Driscoll BR. Audit of oxygen use in emergency ambulances and in a hospital emergency department. Emerg Med J 2008;25:773-6.
5. Cottey L, Jefferys S, Wooley T, Smith JE. The use of supplemental oxygen in emergency patients – an evidence-based review and recommendations for clinical practice. J R Army Med Corps Published Online First: 15 December 2018. doi: 10.1136/jramc-2018-001076
Competing interests: No competing interests