Usefulness of venous-to-arterial partial pressure of CO₂ difference to assess oxygen supply to demand adequacy: effects of dobutamine

Introduction

Shock is defined as an imbalance between oxygen delivery (DO₂) and O₂ demand. O₂ derived parameters have been historically used as reflections of the state of organ perfusion and as targets for resuscitation (1). While such parameters, including the mixed venous oxygen saturation (SVO₂) and lactic acid levels, have great clinical information, studies have shown that they fail to fully describe the clinical picture and can be deficient when assisting the clinician in deciding on the next therapeutic step (2-6). In the following review, we will address the clinical utility of integrating venous-to-arterial partial pressure of CO₂ (PCO₂) difference (ΔPCO₂) in patients in septic shock receiving dobutamine.

Why O₂ based parameters draw an incomplete picture during shock

For patients in shock, a reduced SVO₂ often reflects an exaggerated O₂ extraction, secondary to low DO₂. When DO₂ drops below a critical threshold, anaerobic metabolism is triggered and lactic acidosis ensues. While a reduced SVO₂ reflects low O₂ availability to the tissues, a normal SVO₂ does not exclude persistent tissue hypoperfusion. This observation is explained by a heterogeneous microcirculation, capillary shunting or mitochondrial dysfunction, where SVO₂ is normal or even elevated, despite hypoxia at the cellular level, and as is often seen in patients with sepsis (7). Similarly, lactic acid, while increased when tissues are under perfused and anaerobic metabolism sets in, can also be increased in other conditions, such as liver dysfunction or inflammatory induced aerobic glycolysis (8).

Our current emphasis to monitor tissue perfusion by focusing on systemic blood flow, and the usual indicators of global tissue hypoxia (such as SVO₂ and blood lactate levels) can be misleading, especially when used alone. The ΔPCO₂ can assist the clinician in making adequate diagnostic and therapeutic decisions.

The Fick principle as it applies to CO₂

Historically, investigators described a rise in partial pressure of venous CO₂ in patients in cardiac arrest or in various types of shock. This has triggered an interest in studying the ΔPCO₂ in these clinical scenarios.

The Fick principle allows the determination of the cardiac output (CO) based on arterial and mixed venous O₂ contents and O₂ metabolism, in patients in a steady state. According to the classical equation, CO equals O₂ uptake (VO₂) divided by the arteriovenous O₂ content difference.

CO = VO₂/(CaO₂ − CvO₂) [1]

Where CaO₂, arterial oxygen content; CvO₂, venous oxygen content.

This same principle of conservation of mass applies to CO₂. CO₂ is transported in the blood mostly as bicarbonate with a small percentage dissolved in plasma and another fraction bound to hemoglobin (Hb). PCO₂ can substitute for the CO₂ content over the physiologic range of PCO₂, given the quasi linear relation over that range (9). This relationship can be affected by oxygenation of Hb (Haldane effect); low O₂ saturation favors CO₂ binding to Hb, increasing CO₂ content for the same PCO₂ level. Similarly, the acid base status affects carbaminohemoglobin so that metabolic acidosis increases PCO₂ for the same level of CO₂ content (10).

While the Fick equation relies on mixed venous values obtained from a pulmonary artery catheter (and reflecting total venous blood returning to the heart), central venous values obtained from a central venous catheter correlate with the mixed venous and are more readily available at the bedside (11,12). Based on these studied assumptions, we can reach the following equation:

CO = K ×VCO₂/(PcvCO₂ − PaCO₂) [2]

Where (PcvCO₂ − PaCO₂) = ΔPCO₂ with PcvCO₂ being the central venous PCO₂, PaCO₂ being the arterial PCO₂, VCO₂ the CO₂ production by the cells, K is the pseudo-linear coefficient supposed to be constant in physiological states.

While using the Fick equation as it applies to CO₂, ΔPCO₂ depends on CO₂ production (aerobic and anaerobic metabolism) and the CO (13).

As CO₂ is produced in the peripheral tissues during metabolism, the venous CO₂ content and venous PCO₂ are higher than their arterial values. Under normal physiological conditions, ΔPCO₂ ranges between 2 and 6 mmHg (14).

CO₂ metabolism and physiology

The relationship between metabolism and ΔPCO₂ is complex. When patients develop shock and a low CO state, DO₂ drops. Initially aerobic metabolism is maintained, VO₂ remains constant as O₂ extraction increases in a compensatory fashion. This is reflected by a drop in SVO₂. Interestingly, ΔPCO₂ is found to widen in this clinical scenario of hypoperfusion, and not because of metabolic changes. This is rather due to the low flow state causing CO₂ stagnation (i.e., reduction in CO₂ washout) (10). Vallet et al. nicely demonstrated that it is the blood flow, rather than partial pressure of oxygen (PaO₂) which affects the ΔPCO₂ (by comparing ischemic hypoxia, where blood flow is reduced below a critical DO₂ threshold vs. hypoxic hypoxia where PaO₂ was reduced) (15). When DO₂, drops below a critical level and anaerobic metabolism is triggered, anaerobic CO₂ production is initiated, causing ΔPCO₂ to widen further. Despite the contributions from aerobic and anaerobic metabolism, the impact of CO is much larger on ΔPCO₂, given the curvilinear relationship between ΔPCO₂ and CO.

Clinical evidence

Multiple studies observed the clinical value of ΔPCO₂ in patients in septic shock. As previously described through the Fick equation, ΔPCO₂, in the right clinical context of a steady state, reflects the CO and its adequacy to wash out CO₂ relative to the patient’s metabolic state (16). This correlates with observational studies showing how ΔPCO₂ reflects tissue perfusion parameters. Patients with high ΔPCO₂ on admission have high lactate levels (17). Lactate clearance is much improved in patients whose ΔPCO₂ normalized (it was reduced to <6 mmHg), reflecting improved organ perfusion (18). An elevated ΔPCO₂ (above 6 mmHg) identifies patients who are inadequately resuscitated, despite central venous oxygen saturation (ScvO₂) >70% (19). Reflecting the state of organ perfusion, an exaggerated ΔPCO₂ also carries a prognostic weight and signals an increased mortality (13,17). Patients with a high ΔPCO₂ at the time of presentation have worse outcomes, perhaps because of low organ perfusion. Similarly, patients whose gap is not reduced at 6 h have a higher risk of progressing to multiorgan failure.

The role of ΔPCO₂ in titrating inotropes

The observation that the venous-to-arterial difference in PCO₂ can be used clinically to reflect changes in CO has been evaluated in treating patients with septic and cardiogenic shock.

Mecher et al. studied 37 patients with severe sepsis, before and after fluid resuscitation (16). They found that an initial high ΔPCO₂ reflected a low CO. Upon completion of fluid resuscitation, ΔPCO₂ was reduced to <6 mmHg, as the CO was found to have increased. This opens the door for ΔPCO₂ to be used as a resuscitation target.

Other studies looked at the impact of inotropic agents, specifically dobutamine. Inotropes play an integral role in resuscitating patients with shock. While most patients with cardiogenic shock are likely to benefit from inotropic support, patients with vasodilatory shock will behave differently. In septic shock every effort is made to improve DO₂. This includes optimizing the stroke volume by increasing the intravascular volume, improving O₂ content and delivery by transfusing blood, adjusting the mean arterial pressure (MAP) to enhance the perfusion pressure. Patients who continue to exhibit signs of hypoperfusion despite adequate MAP and hemoglobin concentration could suffer from reduced cardiac function and benefit from increasing cardiac contractility and organ perfusion through the use of inotropes (20).

These investigators looked at patients with no evidence for anaerobic metabolism or global tissue hypoxia. They explicitly included patients who had signs of hypoperfusion (based on oliguria, mottled skin and ScvO₂ <70%), but whose MAP was >65 mmHg, Hb was >8 g/dL, who were no longer fluid responsive and whose lactate levels were normal. These were patients who exhibited signs of low perfusion, despite optimal intravascular volume, blood O₂ carrying capacity and MAP, and would potentially benefit from inotropy at this clinical stage. Two such studies have been conducted: Mallat et al. studied 22 patients in septic shock while Teboul et al. studied 10 patients with congestive heart failure (21,22). These studies investigated the impact of an incremental increase of dobutamine by 5, from 0 to 15 µg/kg/min.

Both investigators found that increasing the rate of dobutamine infusion was accompanied by an increase in cardiac index (CI) and DO₂, as anticipated. A dichotomous response was found for dobutamine doses between 0 and 10 and 10–15 µg/kg/min.

Between 0 and 10 µg/kg/min, dobutamine increased the CI and DO₂, in a dose dependent fashion (CI increased from 3 to 4.6 L/min/m²). VCO₂ increased, but to a much lesser extent compared to CI (Figure 1). This explains the commensurate decrease in ΔPCO₂, from 8±2 to 4.2±1.6 mmHg (Figure 2), attributed to increased blood flow and improved CO₂ wash out. As anticipated, SVO₂, ScvO₂, and O₂ extraction improved as DO₂ increased to organs who were still in need for O₂. At these lower doses, dobutamine’s main impact is on the patient’s hemodynamics, improved organ perfusion and CO₂ clearance.

Figure 1 Time course of oxygen consumption and oxygen delivery during dobutamine infusion. Data are presented as mean ± SD. *, P<0.001 vs. baseline (17). A, baseline; B, dobutamine 5 µg/kg/min; C, dobutamine 10 µg/kg/min; D, dobutamine 15 µg/kg/min (22).

Figure 2 Evolution of ∆PCO₂ and oxygen delivery during dobutamine infusion. *, P< 0.001 vs. baseline (17). A, baseline; B, dobutamine 5 µg/kg/min; C, dobutamine 10 µg/kg/min; D, dobutamine 15 µg/kg/min. Data are presented as mean ± SD (22).

On the other hand, while increasing dobutamine from 10 to 15 µg/kg/min CI increased from 4.6 to 5.2 L/min/m², and VCO₂ was found to increase to similar levels. As such, ΔPCO₂ remained constant (Figure 2). The increase in CO₂ production is explained by the β adrenergic simulation effect of dobutamine. It has a direct cellular metabolic effect, increasing O₂ consumption and CO₂ production. This thermogenic effect is only seen at these higher doses of dobutamine (10–15 g/kg/min).

Conclusions

Tissue hypoperfusion during circulatory failure is associated with stagnation of CO₂ in the tissues and increased tissues venous PCO₂. The ΔPCO₂ could be considered as a marker of adequacy of venous blood flow to remove the CO₂ produced by the peripheral tissues, based on the Fick equation. This requires the patient to be in a steady state, and assumes the mixed venous values are close to the central venous values, which is the case in most patients.

In patients in cardiogenic or vasodilatory shock, without signs of global hypoxia or anaerobic metabolism, ΔPCO₂ can be used to reflect the CO. This inverse correlation is a marker of the adequacy of the venous blood efflux to remove the total CO₂ produced by the peripheral tissues. ΔPCO₂ can be used to distinguish the hemodynamic from the metabolic effect of dobutamine when this inotropic agent is selected.

ΔPCO₂ is easily obtained at the bedside and when included with other markers for tissue perfusion, can provide ample information to the clinician. This makes it an attractive marker in the ICU setting.

Acknowledgments

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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