To our knowledge, this is the first attempt to describe the patterns of tissue perfusion disorder in patients with cardiogenic shock in terms of oxygen debt accumulation and repayment and its impact on short-term survival.
The initial two-step cluster analysis algorithm based on the total oxygen debt and its dynamic defined three clusters in our study group (Fig. 2). These, with sequential clusterization, exposed three distinguished patterns of initial oxygen debt and its repayment in our patients. The cluster analysis methods used in combination in our study have numerous successful reports that are more and more often appearing in clinical studies.23–26 Interested reader can look for principles and algorithms of cluster analysis elsewhere.27
It is also well established that accumulated oxygen debt due to a disproportion between the oxidative requirement and the level of oxygen delivery without timely repayment leads to multiple organ failure and mortality.17 Maintenance and fast restoration of oxygen delivery sufficient to facilitate adequate cellular metabolism are fundamental in sustaining organ function. The early improvement of tissue perfusion by all means, including mechanical circulatory support7,28−33 and rapid decrease or normalization of lactate levels, is critical for survival.7,34−38
Our findings support the relevance and positive impact of the early start of ECLS. The ECLS in patients included in our study was initiated during the first 8 hours after insult in 97.8% of patients who survived a six-month observation period compared to 76.4% of non-survives. However a relatively high number of cases with a start of ECLS withing 8 hours in non-survivors questions the importance of this factor as the primary determinant of the outcome. Furthermore, the distribution of patients with a start of ECLS within 8 hours in clusters was not statistically significant despite a substantial difference in mortality rates. This can be explained by the fact that our study's initial classification was based on the total oxygen debt, which is the accumulation of oxygen deficit over time and embodies both the severity of shock and time spent in the shock state.17,18
The total oxygen debt during the first 26 hours of ECLS and its repayment patterns were derived from the serial measurements of lactate concentration at the study time-points. As a quantitative metric, this variable more adequately represents the metabolic state of the patient 17 than just a lactate concentration in arterial blood. Linear regression equation, used in our study, based on the animal hemorrhagic shock model described by Dieter Rixen et al., 2001.21 However, the equivalence of metabolic acidosis and accumulated oxygen debt permits quantification of the severity of the ischemic shock process in both animals and humans.18,39 The total oxygen debt was computed as oxygen debt times the bodyweight of a patient. Total oxygen debt states the additional oxygen that must be taken into the body to restore all systems to their normal states. Considering the prognostic importance of lactate clearance and absolute lactate levels40, we used oxygen debt at the start and the end of the period as variables for the clustering procedure. So, the clustering procedure was affected by the initial value of debt and its repayment efficiency.
The distribution of patients by the etiology of cardiogenic shock was statistically significant after the initial cluster step. Observed high frequency of post-cardiotomy patients in Cluster 1 with the lowest initial oxygen debt (Fig. 3a) can be explained by continuous observation and treatment of these patients after the end of surgery till the start of ECLS. The concentration of patients with 'Out of Hospital Circulatory Arrest' in Cluster 3 with the highest accumulated oxygen debt (Fig. 3a) could be expected because of the severity of the condition and commonly longer time between insult and starting ECLS. This difference by etiological factor disappears already after 2 hours of support (Fig. 3b). Although we did not find a statically significant relationship between the etiology of cardiogenic shock and six-month survival (Fig. 1b, p = 0.069), the effect of the initial insult and reversibility of myocardial damage is self-explanatory. However, on the other hand, our data showed that timely and effective oxygen debt repayment could prevent slipping in a vicious cycle of injury, cardiac and systemic decompensation, and further injury and decompensation. The survival rate was significantly higher in patients initially assigned to Cluster 1 (with accumulated oxygen debt around 1500 mL), and it even further increased due to the migration of patients in the course of the 26 hours of ECLS observation period.
Patients in Cluster 1 and Cluster 2 had significantly higher mean arterial pressures (Fig. 6a) and required less norepinephrine infusion rates (Fig. 6b) than patients assigned to Cluster 3. The clusters in our population could be imposed on cardiogenic shock stages defined by the SCAI Consensus Statement Classification.41,42 The patients in Cluster 3 most likely had stage E ("Extremis") or refractory cardiogenic shock with relatively low mean arterial and not significant in time intervals decreasing (repayment) of oxygen debt despite ECLS and high rate of norepinephrine infusion(Fig. 6a and b). Cluster 2 pulls together patients who most likely had stage D ("Deteriorating") or a mixture of the last three SCAI shock stages. These patients readily migrated to Cluster 1 or Cluster 3 (Fig. 4). Most of our patients were assigned to Cluster 1. Presumably, these patients were in stage C ("Classic") of cardiogenic shock. These patients required a lower infusion rate of norepinephrine for maintaining mean arterial pressure around 70 mmHg (Fig. 6a, b). However, an observed significant elevation of oxygen debt after 2 hours of circulatory support (Fig. 2) suggests further deterioration, but to our belief, rising lactate with increasing total blood flow with the initiation of ECLS could be explained by washout of lactate from previously hypoperfused tissues.43 Furthermore, this cluster's patients demonstrated a steady decrease in total oxygen debt during each following time interval until the end of the observation period (Fig. 2). From this point of view, the absence of an oxygen debt rises after 2 hours of support in Cluster 3 is the sign of vasoplegia and washing out of substrates of anaerobic metabolism to the circulation before the start of ECLS. This suggestion is supported by the highest amount of oxygen debt accumulated (Fig. 2) and persisted hypotension despite the highest infusion rate of norepinephrine through the ECLS observation period (Fig. 6a, b).
Yet, the accumulation of total oxygen debt, even more than 15000 ml (Cluster 3), does not mean inevitable death. Timely and effective repayment of oxygen debt can prevent irreversible damage. Four patients migrated from Cluster 3 to Cluster 2 between eight and 14 hours of support (Fig. 4). Two of these patients migrated further to Cluster 1 between 20 and 26 hours of support and survived until the end of the six-month observation period.
We realize that the amount of 'total oxygen debt' computed using linear regression equation based on animal models of hemorrhagic shock can differ from the actual 'debt'. However, the universal character of pathophysiological mechanisms of oxygen debt accumulation and repayment and a robust linear relation of debt with lactate concentration permits us to use this value as an indicator of the severity and duration of the shock. Furthermore, the application of the oxygen debt theory to the cardiogenic shock patients sustained by ECLS combined with cluster analysis allowed us to describe better and understand the patterns of end-organ hypoperfusion recovery and mechanisms of its failure. The failure of massive oxygen debt repayment in the intensive care unit could be related to persisting abnormal microcirculatory perfusion despite normal oxygen delivery values.44 However, one of the most challenging problems in the treatment of patients in severe circulatory shock is that the burden of accumulated oxygen debt must be repaid by timely increasing oxygen delivery above baseline levels to restore metabolic function and prevent ongoing organ injury at the cellular level.17,18,20,39 Therefore, just returning oxygen delivery to normal basal levels after an accumulation of oxygen debt is insufficient to prevent subsequent organ injury. Mechanical circulatory support devices, especially with peripheral cannulation, cannot cover the required increase of oxygen delivery.
There are several ways to bypass this limitation and should be further investigated., Decreasing a metabolic rate by permissive hypothermia, used with success in trauma patients,45 could create a necessary excess (relative) oxygen delivery. Another possible way is to limit the duration of exposure to the products of anaerobic metabolism, and concomitant inflammatory respond reaction is high-volume hemofiltration, which is widely used in critically ill patients46,47 or zero-balanced ultrafiltration.48
The retrospective single-center design has inherent limitations, including missing data and ascertainment bias. The absence of information about the preserved myocardial contractility and cardiac output in patients sustained by ECLS did not allow us to estimate actual oxygen delivery required for the effective repayment of accumulated oxygen debt. Also, the patients with irreversible myocardium damage, patients who died from postoperative complications other than cardiogenic shock, or complications of ECLS were intentionally not excluded from the analysis and might have affected the reported mortality rate. Concomitant SIRS reactions, as well as resulted in multiple organ failure in patients in cardiogenic shock, are left beyond our investigation.
Application of oxygen debt theory to the cardiogenic shock patients sustained by v-a ECLS combined with cluster analysis uncovers three patterns of oxygen debt repayment. The patterns have an association with six-months mortality. Understanding the pathophysiology of oxygen debt accumulation and its repayment as a basic pathophysiological process independent from the causes of primary insult may offer new insights for a more rational, goal-directed treatment of this highly morbid condition with cardiogenic shock.