Our main finding is that breathing oxygen during severe anemia reduces heart rate by an amount equivalent to the augmentation of hemoglobin concentration by approximately 3 g/dL. In addition, (1) we have extended our previous finding of a linear relationship between heart rate and acute isovolemic anemia with heart rate increasing 4 beats/min/g Hb decrease; and (2) the relationship between heart rate and hemoglobin concentration is different between men and women.
The relationship between hemoglobin and heart rate was linear. Our previous analysis of this relationship10
was confirmed with this extended data set.
Women had a larger heart rate increase in response to decreasing hemoglobin concentration than men. The predicted heart rate difference of 6 beats/min at a hemoglobin concentration of 5 g/dL is the equivalent to a hemoglobin difference of about 1.5 g/dL. While this may not seem large, it is a difference that could impact choice of transfusion thresholds and the tolerance of profound anemia between men and women. We have shown previously that the oxygen delivery decrease during profound anemia occurs later in women than in men.6
The heart rate differences probably are an important component of this greater tolerance to profound anemia.
Reversal of the heart rate response by transfusion of erythrocytes was expected. We had found previously that there were no differences in the reversal of heart rate changes between fresh autologous blood and autologous blood stored for 21 days.11
In the present analysis, there were small but statistically significant differences between the heart rate during hemodilution and the reinfusion of erythrocytes. Our experimental method provides for very good control of isovolemia during dilution and we have shown that our physiological measurements are not confounded by change in cardiac preload.6
However, return of red blood cells was not accomplished with maintenance of isovolemia: the transfusion of 2 units of erythrocytes likely expanded blood volume by approximately 7%. Therefore, the heart rate changes may have been affected not only by the increase in hemoglobin concentration, but also by this relatively modest increase in blood volume, and thus, it is not unexpected that the heart rate changes during transfusion differed slightly and statistically significantly from changes during isovolemic dilution. The differences are not clinically significant, were detected only by the use of a very sensitive statistical analysis, and were likely due to slight augmentation of blood volume, and thus, preload.
A high inspired oxygen fraction (Fi
) substantially reduced the increased heart rate produced by anemia. This finding is not consistent with the conventional wisdom that dissolved oxygen does not deliver a substantial quantity of oxygen. We noted this effect of high Fi
during earlier studies,12,13
and sought to quantify its physiological consequences here with greater accuracy, using data pooled from our several studies, and to compare the effect with that of transfusion. Ideally, we would have data for supplemental oxygen and transfusion in the same subjects; we do not. However, the amount of data available to us retrospectively was substantial, and analysis of the complete data set has produced valuable results. Our estimate that the heart rate changes from supplemental oxygen are equivalent to an increase of 3 g/dL of hemoglobin are based on comparing the HR while breathing oxygen to the HR during hemodilution while breathing air. Comparing the HR while breathing air (91.4 beats/min) to that while breathing oxygen (83.0 beats/min) at the nadir hemoglobin would produce an equivalent of 2 g/dL hemoglobin (). The HR when breathing air, while within the 95% confidence estimates in , appears slightly lower than expected. HR data for 29 subjects immediately prior to the randomized air or oxygen treatment showed a significantly higher heart rate of 96.0 beats/min. A decreased HR response, or a prolonged effect of oxygen, 17
may have occurred in those subjects who received oxygen first; however our inability to demonstrate an effect of the treatment order12
argues against these possibilities.
The small amount of oxygen dissolved in plasma (0.0031 ml O2
/dL/mm Hg) at normal arterial oxygen partial pressure (PaO2
) (approximately 0.3 mL/dL) is more substantial at high Fi
. However, mathematically, a PaO2
of 450 mmHg would be required to have an amount of dissolved oxygen equivalent to the 1.34 ml of oxygen carried by one gram of hemoglobin. This suggests that even high Fi
would not contribute a sufficient amount of dissolved oxygen to lower the heart rate by more than 4 beats per minute in anemic subjects. With normoxia, even with anemia, only about 22% of the oxygen carried by hemoglobin is utilized when arterial blood at a PaO2
of 90 mmHg with an oxyhemoglobin saturation of 97% traverses to venous blood and a PvO2
of 40 mmHg with an oxyhemoglobin saturation of 75%. At normal PaO2
, approximately 56% ([90–40]/90) of dissolved oxygen is utilized. However, the volume of dissolved oxygen used is only 0.16 mL/dL, while the volume of oxygen used of that carried by hemoglobin is 4.7 mL/dL. Increasing arterial PO2
by about 94 mmHg would add an amount of utilized oxygen from plasma (94• 0.0031 = 0.29 mL/dL) that would be equivalent to the amount of oxygen utilized from that carried by one gram of hemoglobin ([1.34 • (0.97 – 0.75) = 0.29]). Thus, increasing PaO2
to over 400 mmHg (augmenting PaO2
by 300 mmHg by increasing Fi
), as was accomplished in healthy volunteers in our studies,12
should theoretically produce the same reduction in heart rate as 3 grams of hemoglobin (). This is consistent with our findings, where subjects breathing oxygen at a nadir hemoglobin of 5.6 g/dL had the same HR as was found during isovolemic hemodilution with these subjects breathing air at a hemoglobin concentration of approximately 8.9 g/dL (). The effect of dissolved oxygen and its higher usability is true as well at higher concentrations of hemoglobin, although the relative size of the impact is reduced ().
Figure 4 Calculated data for the amount of oxygen (O2) used by tissues that came from hemoglobin and dissolved sources: A) at hemoglobin (Hb) 5.5 g/dL and a room air (RA) arterial oxygen partial pressure (PaO2) = 90 mm Hg (RA, Hb 5.5), B) at hemoglobin 9.0 g/dL (more ...)
Figure 5 Calculated data for the oxygen (O2) used by tissues that came from hemoglobin and dissolved sources vs. hemoglobin concentration. Figure 5A shows the total oxygen used from hemoglobin at 1) room air (RA) arterial oxygen partial pressure (PaO2) = 90 mm (more ...)
Observing heart rate changes in response to higher Fi
in patients would be difficult. Many other factors affect HR clinically, including surgical stimulation, opioids, inhaled anesthetic agents, beta-adrenergic antagonists, and patient co-morbidities. HR also may not increase in response to anemia during general anesthesia.18
Human volunteer studies such as ours are very robust, allowing repeated-measures analysis, and control of confounding factors. Despite these issues in patients, the physiological greater usability of dissolved oxygen would still be present. We would also emphasize that our model is of acute isovolemic anemia. Adequate cardiac output and tissue blood flow are necessary for the benefits of dissolved oxygen, which would not necessarily be present in the case of blood loss with significant hypovolemia.
This larger effect of increased utilization of dissolved oxygen at high Fi
has potentially important clinical and therapeutic implications. For example, treatment of patients with symptomatic anemia with supplemental oxygen could be initiated while awaiting transfusion. In patients at risk for myocardial ischemia, short-term high Fi
has no risks, whereas rapid transfusion can precipitate circulatory overload and consequent pulmonary edema.19,20
When erythrocyte transfusion is warranted in this group, it may be possible to proceed more slowly and safely with the administration of supplemental oxygen as a temporizing measure. High Fi
is often already used for patients under general anesthesia, where anemia may occur due to surgical blood loss. Notably, the two editions of the American Society of Anesthesiologists Practice Guidelines for Blood Component Therapy did not been address this possibility.21,22
Additionally, supplemental oxygen has been shown to decrease heart rate following abdominal surgery.23
Treatment of anemia with oxygen has been shown to be effective in laboratory studies.24–26
Ventilation with 100% oxygen decreases critical hemoglobin concentration,26
myocardial ischemia, and signs of myocardial ischemia24
in swine. Although these investigators recognized the greater relative contribution of dissolved oxygen toward the total amount of oxygen utilized at the lowest concentration of hemoglobin, these studies did not directly compare oxygen administration to transfusion.
Fontana et al. produced isovolemic hemodilution to a mean hemoglobin concentration of 3.0 g/dL, in children undergoing scoliosis surgery with an Fi
of 1, without evidence of inadequate tissue oxygenation.27
Haque found no decrease in HR, but a decrease in cardiac output and stroke volume in patients with left ventricular failure given oxygen.28
The effect of oxygen on cardiac output was considered an adverse effect, apparently based on the misconception that dissolved oxygen could not contribute a clinically significant amount, despite the observed increases in mixed-venous PO2
. Estimates of the efficacy of supplemental oxygen are still based on the effect on total oxygen content, not “usable” oxygen.
The substantial effect of increasing PaO2
on the heart rate response to anemia raises the possibility that this could be an important factor in clinical trials concerned with anemia and transfusion, in as much as a substantial increase in HR is associated with adverse cardiac outcomes in those with or at risk for cardiovascular disease,7,8
and that risk is mitigated by lessening the HR increase by use of beta-adrenergic antagonists.29
Investigators should acknowledge this effect of breathing high oxygen concentrations in their study design and data analysis.
The receptor or transduction mechanism for increasing heart rate in response to anemia is not known. Our data describe the relationship, but do not address the mechanism. We found previously that this reflex/response could not be eliminated with beta-adrenergic blockade, using substantial doses of esmolol in conscious humans,15
yet under general anesthesia, heart rate may not increase with anemia18
. The importance of the carotid and aortic bodies in the physiological responses, including heart rate, to anemia has produced inconsistent results in laboratory studies.30–32
However, aortic chemoreceptor activation is not sufficient to explain the heart rate responses to anemia in humans, as humans lack active aortic chemoreceptors.33
Combining the data from several studies of similar volunteers allowed us to produce a substantial dataset, avoiding the necessity of performing repetitive studies that are physiologically challenging and invasive. We have extended our previous finding of a consistent linear increase in heart rate during anemia in unmedicated healthy volunteers and that return of subjects’ autologous erythrocytes reverses the HR response to anemia. Most importantly, we have shown that a high FiO2 reverses the HR response to anemia. This is consistent with greater usability of dissolved oxygen. The benefit of high PaO2 has potential clinical implications and its effect should also be considered in transfusion trial design and data analysis.
What we already know about this topic
Anemia is an independent predictor of increased morbidity in surgical patients and compensatory tachycardia that occurs during anemia may contribute to increased risk, particularly, in patients with cardiovascular disease
What this study tells us that is new
Healthy subjects breathing oxygen during severe anemia demonstrated decreases in heart rate by an amount equivalent to that of increasing hemoglobin concentration by approximately 3 g/dL
Supplemental oxygen could be a temporizing measure before transfusion of erythrocytes is initiated