The ongoing journey in targeting hemodynamic interventions: missing miles for missing the last micron?

Abstract

With great interest we followed the original work by Bruno et al. [1] assessing sublingual microcirculatory perfusion variables in shock and the following discussion by Hilty et al. [2]. The authors critique the study for its use of unvalidated software and the absence of an effective, hemodynamic monitoring-based treatment plan. They also highlight the study's failure to address different shock types and their unique microcirculatory characteristics, crucial for appropriate treatment decisions.

In the last decades, therapy guided by either macrocirculatory or microcirculatory targets in patients with shock has not yet shown satisfactory results to demonstrate benefits in directing treatment for these patients.

In our response, we aim to explore an alternative perspective by examining acid–base homeostasis to evaluate shock progression or resuscitation success. We propose to focus on the dynamics of Base Excess (BE) as an indicator of successful resuscitation in shock scenarios. BE is a calculated parameter that determines the amount of acid or base required to restore the blood's pH to 7.40 under standardized conditions, assuming normal CO₂ levels. A negative BE, coupled with acidemia, indicates that the primary cause of the blood's acidity is metabolic in nature. This could be due to deranged physiological buffer systems, such as loss of bicarbonate through the gastrointestinal tract, reduced bicarbonate synthesis in the case of acute kidney injury (AKI) secondary to shock, or an increase in the strong ion difference, such as that seen in hyperchloremic acidosis resulting from resuscitation with isotonic saline. Although these elements can lead to acid–base disturbances during shock, we contend that a more crucial contributing factor is the accumulation of protons arising from impaired adenosine triphosphate (ATP) regeneration.

The daily turnover of ATP in the human body is remarkably high, underscoring ATP's crucial role as the primary energy carrier in biological processes. Typically, the human body contains about 0.1 mol of ATPa at any given moment, which is continuously cycled. The human body synthesizes and degrades an amount of ATP approximately equal to its own weight each day. We propose that the pronounced acidosis following cardiac arrest is a manifestation of this abrupt metabolic shift, in contrast to the effects or confounders mentioned above, which take some time to manifest.

Traditionally, shock has been characterized by a discrepancy between oxygen delivery (DO₂) and consumption (VO₂). However, we suggest to see DO₂/VO₂ as a partial aspect of some forms of shock but broadening this definition to encompass shock more generally as an imbalance between ATP consumption and regeneration, which results in proton accumulation during acute imbalances. This viewpoint is supported by studies showing that not all shock states display a VO₂/DO₂ mismatch [3]; yet often, non-survivors of shock are unable to increase VO₂ [4]. Therefore, we want to point to the last micron of the journey from macrocirculation to oxidative phosphorylation: the mitochondria.

For the complete oxidation of glucose in the presence of oxygen, the process involves several stages: glycolysis, the Krebs (or citric acid) cycle, and oxidative phosphorylation. The simplified overall chemical equation for the complete oxidation of glucose is:

C₆H₁₂O₆ + 6O₂ 6 CO₂ + 6 H₂O + Energy (stored in ATP)

The number of ATP molecules generated from one molecule of glucose can vary but is commonly cited as approximately 36 ATP molecules. When ATP undergoes hydrolysis to form ADP and inorganic phosphate (Pi), transferring the energy from the phosphate bond to its substrate, there is a net release of one proton (H⁺) to maintain charge balance [5]. The stoichiometry of complete oxidative phosphorylation is balanced only when the protons released during ATP hydrolysis are reintroduced and regenerated in the ongoing process [6].

Lactate levels and the clearance of lactate have been the focus of extensive research, particularly in the context of shock. We also wish to acknowledge the significant contributions to the field of lactate studies. However, we argue that acidemia and hyperlactatemia, while often occurring together, are not synonymous. We suggest that, although both values are influenced by various factors, BE serves as a more accurate indicator of metabolic disturbances in shock.

In glycolysis, direct ATP synthesis happens via substrate-level phosphorylation, not oxidative phosphorylation. Here, a high-energy phosphate from a substrate molecule is directly transferred to ADP to form ATP. The conversion of pyruvate to lactate is accompanied by the reduction of NAD⁺ to NADH. The reduction of pyruvate into lactate is a process that consumes protons. When pyruvate is reduced to lactate by lactate dehydrogenase, NADH donates electrons and is oxidized back to NAD⁺, and a proton (H⁺) is used up. Thus, the term “lactic acidosis” [7, 8] can be misleading: lactate production only leads to proton accumulation if the protons released during the subsequent ATP hydrolysis are not regenerated in complete oxidative phosphorylation (under conditions of oxygen shortage or dysfunctional mitochondria) or in gluconeogenesis [5, 6, 9].

If we dissect now the processes from macrocirculation to the generation of the primary energy currency, ATP, through glycolysis or oxidative phosphorylation, we observe a multi-step cascade that involves various physiological processes.

Cardiac power output (CPO) signifies the heart's capacity to perform work and serves as an emblematic measure of the "energy" present within the macrocirculatory system. It is derived from the product of the cardiac output (CO) and the perfusion pressure (P_perf). Notably, P_perf is calculated as the difference between the mean arterial pressure (MAP) and the right atrial pressure (RAP). Therefore, the equation for CPO is CPO = CO × (MAP − RAP) [10]. P_perf, in essence, is the effective pressure pivotal in surpassing the intrinsic auto-regulatory thresholds of organs and tissues.

When CPO is reduced due to a decrease in CO—stemming from conditions such as ischemic pump failure, septic cardiomyopathy, inadequate left ventricular filling, or intrathoracic obstructions—the body may attempt to maintain P_perf. The primary strategy for increasing P_perf involves raising systemic vascular resistance (SVR). Clinically, this compensation is evident as "centralization," a state often indicated by cold extremities, delayed capillary refill, and skin mottling in patients. This can create a misleading impression where P_perf meets or exceeds conventional targets, presenting a facade of stability: when CPO is constrained and P_perf is artificially maintained, actual blood flow is likely compromised. Oxygen delivery (DO₂), a subsequent factor in microcirculation, considers that blood carrying a specific amount of oxygen (C_aO₂) at a given flow rate (CO) is responsible for oxygen transport to organs and tissues.

Although measurement of macrocirulatory parameters, capillary flow parameters or arterio-venous CO₂ difference [11] may act as indicators for reduced blood or oxygen transport to organs and tissues, these do not fully reflect the efficiency of the subsequent processes necessary for adequate ATP formation from substrates: namely, the mitochondria.

Mitochondrial function may be compromised by either their reduced numbers, resulting from limited microcirculatory flow, or by the availability of substrates (such as O₂ or Krebs cycle substrates) or their impaired functionality—in the context of the latter, we want to acknowledge the concept of cytopathic dysoxia, as introduced by Fink [12]. During shock or ischemia–reperfusion injuries in resuscitation efforts, numerous elements may contribute to an inherent defect in cellular and mitochondrial respiration. These factors include nitric oxide, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin-1 beta (IL-1β), and interferon-gamma (IFN-γ), as well as endotoxins and intracellular acidosis, which are known to affect mitochondrial activity, as observed in conditions like septic cardiomyopathy [13].

Given these insights, we advocate for a deeper examination BE dynamics, which can be readily assessed through routine blood gas analysis, as a crucial surrogate marker for guiding future resuscitation strategies. Our view is that targeting BE could be effective in enhancing CO, provided perfusion pressure P_perf is maintained at levels sufficient to surpass the autoregulatory thresholds of vital organs and to optimize microcirculatory perfusion by minimizing vasoconstriction. We specifically emphasize that attempting to normalize BE solely through buffering methods, such as using sodium bicarbonate, fails to address the underlying cause and might not only be ineffective but also potentially harmful [14].

We suggest pursuing further research into this approach in patients undergoing extracorporeal resuscitation (eCPR). Our hypothesis is that in these patients, aiming to normalize BE by targeting the highest possible extracorporeal life support (ECLS) flow rates, while minimizing the use of vasopressors to preserve microcirculation, could provide valuable insights.

The manuscript is designed for the series titled "Tissue Oxygenation: How to Measure, How Much to Target" and is conceptualized as a hypothesis. Consequently, it does not include sections on data or materials.

1. Bruno RR, Wollborn J, Fengler K et al (2023) Direct assessment of microcirculation in shock: a randomized-controlled multicenter study. Intensive Care Med 49:645–655. https://doi.org/10.1007/s00134-023-07098-5

   Article PubMed PubMed Central Google Scholar

2. Hilty MP, Duranteau J, Montomoli J, Yeh TY, Ince C (2023) A microcirculation-guided trial doomed to fail. Intensive Care Med 49(12):1557–1558. https://doi.org/10.1007/s00134-023-07223-4

   Article PubMed Google Scholar

3. Ronco JJ, Fenwick JC, Wiggs BR, Phang PT, Russell JA, Tweeddale MG (1993) Oxygen consumption is independent of increases in oxygen delivery by dobutamine in septic patients who have normal or increased plasma lactate. Am Rev Respir Dis 147(1):25–31. https://doi.org/10.1164/ajrccm/147.1.25

   Article CAS PubMed Google Scholar

4. Goonasekera CDA, Carcillo JA, Deep A (2018) Oxygen delivery and oxygen consumption in pediatric fluid refractory septic shock during the first 42 h of therapy and their relationship to 28-day outcome. Front Pediatr 23(6):314. https://doi.org/10.3389/fped.2018.00314

   Article Google Scholar

5. Silverstein TP (2023) The real reason why ATP hydrolysis is spontaneous at pH > 7: It’s (mostly) the proton concentration. Biochem Mol Biol Educ. 51(5):476–485. https://doi.org/10.1002/bmb.21745

   Article CAS PubMed Google Scholar

6. Zilva JF (1978) The origin of the acidosis in hyperlactataemia. Ann Clin Biochem 15(1):40–43. https://doi.org/10.1177/000456327801500111

   Article CAS PubMed Google Scholar

7. Kraut JA, Madias NE (2014) Lactic acidosis. N Engl J Med 371(24):2309–2319. https://doi.org/10.1056/NEJMra1309483

   Article CAS PubMed Google Scholar

8. Madias NE (1986) Lactic acidosis. Kidney Int 29:752–774

   Article CAS PubMed Google Scholar

9. Torrens SL, Robergs RA, Curry SC, Nalos M (2023) The computational acid-base chemistry of hepatic ketoacidosis. Metabolites 13(7):803. https://doi.org/10.3390/metabo13070803

   Article CAS PubMed PubMed Central Google Scholar

10. Lim HS (2020) Cardiac power output revisited. Circulation 13(10):e007393. https://doi.org/10.1161/CIRCHEARTFAILURE.120.007393

    Article PubMed Google Scholar

11. McDonald CI, Brodie D, Schmidt M, Hay K, Shekar K (2021) Elevated venous to arterial carbon dioxide gap and anion gap are associated with poor outcome in cardiogenic shock requiring extracorporeal membrane oxygenation support. ASAIO J 67(3):263–269. https://doi.org/10.1097/MAT.0000000000001215

    Article CAS PubMed Google Scholar

12. Fink MP (2002) Bench-to-bedside review: cytopathic dysoxia. Crit Care 6(6):491–499. https://doi.org/10.1186/cc1824

    Article PubMed PubMed Central Google Scholar

13. Hollenberg SM, Singer M (2021) Pathophysiology of sepsis-induced cardiomyopathy. Nat Rev Cardiol 18(6):424–434. https://doi.org/10.1038/s41569-020-00492-2

    Article PubMed Google Scholar

14. Wang T, Yi L, Zhang H, Wang T, Xi J, Zeng L, He J, Zhang Z, Ma P (2021) Risk potential for organ dysfunction associated with sodium bicarbonate therapy in critically ill patients with hemodynamic worsening. Front Med (Lausanne) 7(8):665907. https://doi.org/10.3389/fmed.2021.665907

    Article Google Scholar

Download references

Authors and Affiliations

1. Internistische Intensivmedizin, Zentrum Für Innere Medizin, Klinikum Stuttgart, Kriegsbergstraße 60, 70174, Stuttgart, Germany

   Johannes Heymer & Daniel Raepple

Authors

1. Johannes HeymerView author publications

   You can also search for this author in PubMed Google Scholar

2. Daniel RaeppleView author publications

   You can also search for this author in PubMed Google Scholar

Contributions

DR developed the original hypothesis, drafted, and substantially revised the work. JH significantly contributed to both the concept and the manuscript.

Corresponding author

Correspondence to Daniel Raepple.

Conflict of interest

Johannes Heymer: None. Daniel Raepple: book royalties from Springer, Heidelberg.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

Cite this article

Heymer, J., Raepple, D. The ongoing journey in targeting hemodynamic interventions: missing miles for missing the last micron?. ICMx 12, 35 (2024). https://doi.org/10.1186/s40635-024-00621-y

Download citation

• Received: 17 January 2024

• Accepted: 04 April 2024

• Published: 09 April 2024

• DOI: https://doi.org/10.1186/s40635-024-00621-y

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable link

Sorry, a shareable link is not currently available for this article.

Copy to clipboard

Provided by the Springer Nature SharedIt content-sharing initiative