|Home | About | Journals | Submit | Contact Us | Français|
Over the past century, lacking the precision of today’s advanced technology, multiple studies provided conflicting data on the effects of oxygen therapy in normoxic cardiac patients. More importantly, no randomized, blinded and controlled studies have shown a benefit of such treatment. Yet the use of supplemental oxygen is widespread in cardiac patients. In these conditions, inadvertent hyperoxia commonly occurs because of concerns to ensure sufficient oxygenation and because hyperoxia is not perceived to be detrimental. In recent years, there has been mounting evidence demonstrating the potential adverse effects of hyperoxia on the cardiovascular system. In this report, we review data examining the effects of supplemental oxygen in normoxic patients with acute presentations of coronary artery disease (CAD). It is also the aim of this report to emphasize the point that oxygen therapy might have major adverse physiologic effects that must be considered when it is employed.
Between 1940 and 1970 the cardiovascular effects of hyperoxia were extensively investigated. These studies suggested that hyperoxia reduced coronary blood flow (CBF) (1), heart rate, cardiac output/index (1–3), and cardiac oxygen consumption (4), while evoking a rise in blood pressure, systemic vascular resistance and the augmentation index; a measure of large artery stiffness (3).
The American College of Cardiology/American Heart Association task force (ACC/AHA 2007 guidelines) has assigned Class I recommendation for oxygen use to correct arterial oxygen desaturation (SaO2 less than 90%) and Class IIa recommendation for all patients with UA/NSTEMI and uncomplicated STEMI within the first 6 hours after presentation. The rationale for oxygen use is based on two assumptions: 1) that increasing arterial oxygen tension decreases the acute ischemic injury and the eventual infarct area (5,6); and 2) the observation that some uncomplicated myocardial infarction patients have arterial hypoxemia due to fluid retention in the lungs and a ventilation-perfusion mismatch.
However, the evidence supporting these assumptions is limited. Moreover, we are not aware of any studies demonstrating that normoxic subjects undergoing PCI for acute myocardial infarction derive any benefit from supplemental oxygen and furthermore, there is no evidence supporting the common practice of oxygen therapy after successful PCI.
Maroko and colleagues demonstrated in dogs that 40% oxygen reduced electrocardiographic, histological and biochemical evidence of myocardial ischemic injury. Unfortunately, the sequence of gas mixture delivery during ventilation was not randomized and the ST segment elevation measurements were not blinded. Madias et al. (6) examined the effects of supplemental oxygen (delivered via a face mask) in patients with anterior myocardial infarction. Using precordial ST-segment mapping, these authors noted a 16% reduction in both the sum of ST elevations and the number of recording sites demonstrating ST elevation. However, the study wasn’t randomized, ST-segment measurements weren’t blinded, and the timing of precordial mapping wasn’t standardized. Moreover, the duration of oxygen inhalation varied greatly among subjects (48 to 80 mins).
Rawles and Kenmure (7) performed the first randomized, double blinded, controlled trial of oxygen therapy in the setting of uncomplicated myocardial infarction. After excluding 43 patients from the initial 200 subjects, 77 and 80 patients were enrolled in the air and oxygen groups respectively. Either oxygen or compressed air at a flow rate of 6 L/min was administered by mask throughout the first 24 hours. Only diamorphine was employed as medication. All parameters were comparable except higher Pao2 and aspartate aminotransferase levels were noted in the oxygen group. This study showed no benefit of oxygen therapy in reducing arrhythmias or mortality. On the contrary, supplemental oxygen elevated aspartate aminotransferase levels suggesting infarct expansion. Of note, the mortality rate in the oxygen group was 11.3% compared to 3.9% in the control group, although this difference wasn’t statistically significant.
Recently, duplex ultrasound (HDI 5000, ATL Ultrasound, Bothell, WA) has been employed to measure coronary blood velocity (a CBF surrogate) in the left anterior descending coronary artery of seven healthy subjects (8). Coronary diastolic blood velocity (CBV) and coronary vascular resistance (CVR) were measured breathing room air and after exposure to hyperoxia (100% O2) for 5 mins. Hyperoxia decreased CBV by 15 ± 3% (P < 0.01) and raised CVR by 20 ± 4% (P < 0.01). Similar findings were observed in three cardiac transplant patients who underwent transplant 5–14 months earlier, (CBV decreased by 16% ± 2 [P < 0.01] and CVR increased by 23% ± 3 [P < 0.01; Figures 1 and and2]),2]), indicating a direct vasoconstrictor effect of hyperoxia on the coronary circulation not mediated through autonomic reflexes. These non-invasive observations are consistent with the work of McNulty et al. (9) who examined the effects of hyperoxia on the coronary circulation using intracoronary Doppler flow wire and coronary angiography in stable patients with coronary arterial disease (coronary stenosis <50% and EF > 50%). Hyperoxia decreased CBF by 29% and raised CVR by 41% (Figure 3).
Mounting evidence supports the hypothesis that hyperoxia leads to the generation of reactive oxygen species, which in turn decreases the bioavailability of nitric oxide and results in vasoconstriction (10). McNulty and colleagues (11) demonstrated that an intravenous infusion of Vitamin C (a potent anti-oxidant) quickly restores and prevents coronary vasoconstriction during hyperoxia.
During hypoxia and ischemia a fall in the intracellular ATP concentrations mediates the opening of ATP-sensitive potassium channels, which in turn causes hyperpolarization of the vascular smooth muscle cells and vasodilation. Animal studies have shown that K+ATP channels play an important role in regulating coronary artery blood flow at rest and during hypoxia and ischemia (12). Mouren and colleagues (13) demonstrated that hyperoxic coronary vasoconstriction is mediated through the closure of K+ATP channels.
Animal studies (14) demonstrate that oxygen sensitive L-Type calcium channels are present on vascular smooth muscle cells. They contribute to the local circulatory control during hypoxia and hyperoxia.
Isolated cardiac myocyte studies demonstrate that angiotensin I is produced with hyperoxia and is subsequently converted to angiotensin II possibly on the surface of endothelial cells. Angiotensin II promotes endothelin-1 release and thereby increases vascular tone (15).
Hyperoxia induces the production of 20-HETE, an arachidonic acid metabolite. 20-HETE is a constrictor and plays an important role in myogenic regulation (16).
One could speculate that an increase in oxygen extraction in ACS might compensate for the decreased CBF seen with oxygen. Animal studies suggest that a high PO2 decreases myocardial oxygen consumption independent of heart rate, cardiac performance and metabolic requirements. High PO2 decreases capillary density, which in turn may limit oxygen diffusion and extraction (17,18). Reinhart et al. (19) confirmed that in critically ill patients, high flow oxygen therapy causes a misdistribution of microcirculatory blood flow with increased functional O2 shunting and a reduction in total body oxygen consumption (total body oxygen uptake decreased by 10% due to an 18% decrease in O2 extraction). Thus high flow oxygen, despite improving oxygenation may not improve organ specific oxygen delivery.
We believe that supplemental oxygen is used excessively especially in cardiac patients to maintain oxyhemoglobin saturations close to 100%, unknowingly many of these patients are exposed to significant periods of hyperoxia. This occurs for three main reasons: 1) many medical staff (including physicians) don’t recognize that oxygen is a vasoactive substance; 2) when transcutanous blood oxyhemoglobin saturation approaches 100%, further increases in blood oxygen tension are not detected; and 3) oxygen tension isn’t adequately monitored especially in the setting of high flow oxygen therapy.
Although, the use of oxygen is clearly appropriate and advisable to treat hypoxia, we hypothesize that excessive use of supplemental oxygen in normoxic cardiac patients could potentially lead to worse outcomes in a number of patients. The current guidelines of oxygen therapy are not based on randomized, double blinded and controlled studies. We propose that such studies are imperative to delineate the precise role of oxygen therapy in these conditions. In the interim, the potential physiologic ramifications of such therapy should be considered.
Grants: This work was supported by NIH grants R01 HL070222 (Sinoway), P01 HL077670 (Sinoway), NIH/NCRR grant M01 RR010732 and C06 RR016499 and Tobacco Settlement Funds (Sinoway). There are no relationships with industry.
The authors express gratitude to Jennie Stoner for outstanding secretarial skills and Kris Gray and Jonathan Yoder for their technical assistance.