Jean-Louis Teboul

Understanding the Haldane effect.

Physiological background CO2 is the terminal product of cell metabolism and can be generated by both aerobic and anaerobic biochemical processes. As a result of this cellular CO2 production, the venous CO2 content (CvCO2) is higher than the arterial CO2 content (CaCO2), promoting oxygen release from hemoglobin in the capillaries (Bohr effect). CO2 is transported in the blood in three forms: dissolved in plasma (5–10 %), as bicarbonate (80 %), and bound to terminal NH2 groups of certain proteins including hemoglobin (10–15 %). As it binds to the globin part of hemoglobin, CO2 does not compete with oxygen on the heme units. However, more CO2 binds to hemoglobin at lower oxygen saturation (SO2), a phenomenon known as the Haldane effect [1]. This makes sense, since the unloading of oxygen in the peripheral capillaries enhances the loading of CO2 produced by the cells, thereby increasing the CO2 carrying ability of the venous blood. In the lung capillaries, the opposite phenomenon occurs as oxygenation enhances the unloading of CO2 from hemoglobin and thus facilitates the pulmonary excretion of CO2. The relationship between CCO2 and PCO2 is affected by SO2 and acidosis. Low local SO2 increases the CO2 content for a given PCO2 (Fig. 1a) since more CO2 is bound to hemoglobin as a result of the Haldane effect. Metabolic acidosis shifts the CCO2/PCO2 relationship so that PCO2 is higher for a given CCO2 (Fig. 1b). Finally, for the highest range of CCO2, the relationship becomes flatter so that a further increase in CCO2 causes a more pronounced increase in PCO2. According to the Fick equation, there is an inverse hyperbolic relationship between cardiac output and mixed venous CCO2 (CmvCO2)-to-arterial CCO2 difference (Cmv-aCO2), for a given total CO2 production (VCO2). Accordingly, a low cardiac output results in a reduced peripheral washout of the CO2 produced by the tissues (CO2 stagnation). This in turn causes increases in Cmv-aCO2 and mixed venous-to-arterial PCO2 difference (Pmv-aCO2). During tissue hypoxia, VCO2 decreases [2] as a result of the reduced aerobic CO2 production despite CO2 generation from anaerobic pathways [3]. This VCO2 decrease shifts the relationship between cardiac output and CmvaCO2 so that Cmv-aCO2 increases less for a low cardiac output [3]. Nevertheless, both CO2 stagnation (low blood flow) and Haldane effect (low SO2) increase CvCO2, so that the flat part of the curve is reached, implying a marked increase in PvCO2. This is further amplified in the presence of metabolic acidosis (Fig. 1b). Therefore, in hypodynamic shock, Pmv-aCO2 markedly increases despite the decreased VCO2 [2]. However, in hypoxic conditions not due to low cardiac output, the venous blood flow rapidly washes out CO2 from the tissues so that both CmvaCO2 (despite the Haldane effect) and Pmv-aCO2 remain normal, stressing the unreliability of using these variables to detect tissue hypoxia [4, 5]. This fundamental issue was illustrated in an isolated limb model [6], where ischemic hypoxia resulted in increased limb venous-to-arterial PCO2 (Pv-aCO2) whereas hypoxemic hypoxia with maintained limb blood flow did not increase limb Pv-aCO2 [6]. These results confirm that Pv-aCO2 is an indicator of hypoperfusion rather than of tissue hypoxia. *Correspondence: jean‐louis.teboul@aphp.fr 1 Service de Réanimation Médicale, Hôpital de Bicêtre, Hôpitaux

Evolving concepts of hemodynamic monitoring for critically ill patients

The last decades have been characterized by a continuous evolution of hemodynamic monitoring techniques from intermittent toward continuous and real-time measurements and from an invasive towards a less invasive approach. The latter approach uses ultrasounds and pulse contour analysis techniques that have been developed over the last 15 years. During the same period, the concept of prediction of fluid responsiveness has also been developed and dynamic indices such as pulse pressure variation, stroke volume variation, and the real-time response of cardiac output to passive leg raising or to end-expiration occlusion, can be easily obtained and displayed with the minimally invasive techniques. In this article, we review the main hemodynamic monitoring devices currently available with their respective advantages and drawbacks. We also present the current viewpoint on how to choose a hemodynamic monitoring device in the most severely ill patients and especially in patients with circulatory shock.

Central Venous-to-Arterial Carbon Dioxide Partial Pressure Difference

Assessing the adequacy of oxygen delivery and oxygen requirements is one of the key steps of haemodynamic resuscitation. For this purpose, clinical examination, lactate and central or mixed venous oxygen saturation (SvO2 and ScvO2, respectively) all have their limitations. Many of these limitations may be overcome by use of the carbon dioxide (CO2)-derived variables. The veno-arterial difference in CO2 tension (“ΔPCO2” or “PCO2 gap”) is not a straightforward indicator of anaerobic metabolism since it is influenced by the oxygen consumption. By contrast, it reliably indicates whether cardiac output is sufficient to carry the CO2 to the lungs in view of its clearance: it reflects the adequacy of cardiac output with the metabolic condition. The ratio of the PCO2 gap with the arteriovenous difference of oxygen content (PCO2 gap/C(A − V)O2) is a reliable marker of the adequacy between oxygen supply and requirements. Conversely to SvO2 and ScvO2, it remains interpretable if the oxygen extraction is impaired in septic shock patients. Compared to lactate, it has the main advantage to change without delay and to provide a real-time monitoring of tissue metabolism.

Is there still a place for the Swan–Ganz catheter? No

There is no doubt that the pulmonary artery catheter (PAC) provided intensivists with a lot of hemodynamic information more than 20 years ago, at a time when there was nothing else to help them to assess the hemodynamic status, to make the diagnosis of mechanisms of shock states, and to select the appropriate treatment and to monitor its effects. There is also no doubt that the use of the PAC in intensive care units (ICU) has dramatically declined worldwide over the past 25 years [1]. This is partly because the PAC is perceived by ICU physicians as an invasive and cumbersome procedure, which needs much knowledge and expertise in terms of measurements and interpretation of data to be adequately used. In addition, it is likely that intensivists have been discouraged to use the PAC after the publication of randomized controlled trials (RCT) showing no clinical benefit [2, 3]. The decline of the PAC can also be partly explained by its competition with less invasive hemodynamic monitoring and ultrasonographic methods that have developed in recent years [4]. Finally, emergence of novel techniques able to monitor real-time CO and dynamic indices of fluid responsiveness [5] have also contributed to the reduced interest of intensivists in the PAC. In this article, we present the reasons for not using the PAC in the ICU in 2018. These reasons can be summarized in simple words: there is no clinical situation where the hemodynamic information provided by the PAC is superior to that obtained less invasively and moreover, in most situations where assessment of cardiac function or volume status is required, the PAC performs far worse than other more modern technologies (Table 1). In the 1980s, one of the main reasons to insert a PAC was to estimate cardiac output (CO) through the thermodilution method. This was a revolutionary innovation at that time, but today many non-invasive, minimally invasive, or less invasive hemodynamic monitors are perfectly valuable for that purpose. The inconvenience of the PAC is that it cannot provide continuous real-time CO monitoring, even when a modified catheter equipped with thermal filament is used. Another reason to insert a PAC in the past century was to assess the left and right heart function through the analysis of the relationships between the CO and the pulmonary artery occlusion pressure (PAOP) and the right atrial pressure (RAP), respectively. However, such an analysis most often required repeated measurements of CO and filling pressures after therapeutic challenges to be reliably interpreted. The complexity of the CO-cardiac filling pressure relationships and the potential errors of measurements of PAOP and RAP often made the assessment of cardiac function unreliable. Today, there is no need for any RCT to confirm that echocardiography performs far better than PAC for the purpose of assessing the cardiac function. The technological advances in echocardiography (Doppler-derived indices, speckle tracking, real-time 3-D imaging, etc.) have made the use of PAC for the cardiac evaluation purpose a technique of the Middle Ages. An additional piece of information that made the PAC attractive in the past was the measurement of pulmonary artery pressure (PAP), which was used to assess the severity of specific diseases affecting the pulmonary vasculature (e.g., pulmonary embolism, acute pulmonary hypertension) and their response to therapies. Echocardiography can provide an estimation of the PAP (using *Correspondence: jean‐louis.teboul@aphp.fr 4 Service de Réanimation Médicale, Hôpital de Bicêtre, Hôpitaux Universitaires Paris‐Sud, 78, rue du Général Leclerc, 94 270 Le Kremlin‐Bicêtre, France Full author information is available at the end of the article

Understanding the carbon dioxide gaps

Purpose of reviewThe current review attempts to demonstrate the value of several forms of carbon dioxide (CO2) gaps in resuscitation of the critically ill patient as monitor for the adequacy of the circulation, as target for fluid resuscitation and also as predictor for outcome. Recent findingsFluid resuscitation is one of the key treatments in many intensive care patients. It remains a challenge in daily practice as both a shortage and an overload in intravascular volume are potentially harmful. Many different approaches have been developed for use as target of fluid resuscitation. CO2 gaps can be used as surrogate for the adequacy of cardiac output (CO) and as marker for tissue perfusion and are therefore a potential target for resuscitation. CO2 gaps are easily measured via point-of-care analysers. We shed light on its potential use as nowadays it is not widely used in clinical practice despite its potential. Many studies were conducted on partial CO2 pressure differences or CO2 content (cCO2) differences either alone, or in combination with other markers for outcome or resuscitation adequacy. Furthermore, some studies deal with CO2 gap to O2 gap ratios as target for goal-directed fluid therapy or as marker for outcome. SummaryCO2 gap is a sensitive marker of tissue hypoperfusion, with added value over traditional markers of tissue hypoxia in situations in which an oxygen diffusion barrier exists such as in tissue oedema and impaired microcirculation. Venous-to-arterial cCO2 or partial pressure gaps can be used to evaluate whether attempts to increase CO should be made. Considering the potential of the several forms of CO2 measurements and its ease of use via point-of-care analysers, it is recommendable to implement CO2 gaps in standard clinical practice.

Control of Confounding and Reporting of Results in Causal Inference Studies: Guidance for Authors from Editors of Respiratory, Sleep, and Critical Care Journals

Citation for published version (APA): Lederer, D. J., Bell, S. C., Branson, R. D., Chalmers, J. D., Marshall, R., Maslove, D. M., Ost, D. E., Punjabi, N. M., Schatz, M., Smyth, A. R., Stewart, P. W., Suissa, S., Adjei, A. A., Akdis, C. A., Azoulay, É., Bakker, J., Ballas, Z. K., Bardin, P. G., Barreiro, E., ... Vincent, J-L. (2019). Control of Confounding and Reporting of Results in Causal Inference Studies: Guidance for Authors from Editors of Respiratory, Sleep, and Critical Care Journals. Annals of the American Thoracic Society, 16(1), 22-28. https://doi.org/10.1513/AnnalsATS.201808564PS

Monitoring Myocardial Dysfunction as Part of Sepsis Management

Sepsis-induced cardiac dysfunction occurs early in the course of severe sepsis. The mechanisms responsible for its development are complex and intricate. The degree of severity of septic myocardial depression is variable from patient to patient. Doppler echocardiography is the best method to make the diagnosis of cardiac dysfunction (a decrease in left ventricular ejection fraction). The transpulmonary thermodilution monitor (decrease in cardiac function index, decrease in cardiac output) and the pulmonary artery catheter (decrease in cardiac output and/or decrease in mixed venous oxygen saturation) can be used either to alert clinicians of the possibility of cardiac dysfunction or to monitor the effects of inotropic therapy. Low plasma levels of B-type natriuretic peptide levels can serve to rule out severe cardiac dysfunction. In contrast, high levels of natriuretic peptides do not allow diagnosing myocardial depression with certainty and should prompt the performance of echocardiographic examination. Administration of inotropic drugs, such as β1-agonist agents, is a matter of debate and should be carefully monitored in terms of efficacy as well as tolerance.