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Oxygen–Flow–Pressure Targets for Resuscitation in Critical Hemodynamic Therapy

He, Huaiwu; Long, Yun; Zhou, Xiang; Wang, Xiaoting; Zhang, Hongmin; Chai, Wenzhao; Cui, Na; Wang, Hao; Liu, Dawei

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doi: 10.1097/SHK.0000000000000929
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Investigations into hemodynamics in critically ill patients have increased dramatically in the last 10 years. Literally, hemodynamics is defined as “blood flow, motion and equilibrium under the action of external forces” and is the study of blood flow in the body circulation. Hemodynamics explains the physical laws that govern the flow of blood in the blood vessels. Some physical laws of hemodynamics have been investigated and used in clinical practice, which serves as the basic principle of hemodynamic therapy. Moreover, the content of hemodynamics has been further extended to the microcirculation, tissue oxygenation, cell oxygen utilization, cellular energy, and organ function in clinical practice. Traditionally, hemodynamic monitoring (HM) is the observation of hemodynamic parameters over time, such as vital signs, cardiac output, and perfusion-related parameters. In essence, the major aim of HM in the ICU is to recognize derangements in physiologic variables, which represent a progression toward organ failure. The introduction of functional hemodynamics further expands the connotation of HM. In addition, functional hemodynamics were defined as the assessment of the dynamic interactions of hemodynamic variables in response to a defined perturbation, which is always related to the response of cardiac output to fluid challenge (1). However, HM is sometimes easy to mistake as hemodynamic therapy. HM is one of many of hemodynamic therapies. Monitoring cannot improve the outcome by itself, only when the HM data are accurately obtained and correctly interpreted (2). In other words, hemodynamic therapy not only tells the physician what would occur but also tells the physician what should be done.

On the contrary, it is also easy to misunderstand hemodynamic therapy as merely concrete bundles or guidelines for circulation supports. Recent studies questioned the value of hemodynamic bundles or targets in resuscitation (3, 4). A retrospective cohort study showed that clinical evidence of persistent fluid overload was common and was associated with the increased use of medical interventions and hospital mortality in septic shock patients who were treated with early goal-directed therapy (EGDT) (5). Therefore, some fixed therapeutic targets were not proper for all the critically ill patients, who are usually heterogeneous, unstable, and dynamic. How to use and interpret these targets is the core issue based on a physiologic point. One size does not fit all, but the guiding principles of hemodynamic therapy should be stressed in the treatment of critically ill patients.

To our knowledge, the definition of hemodynamic therapy in critically ill patients remains controversial. Here, we introduce the concept of “critical hemodynamic therapy” (CHT) and focus the oxygen–flow–pressure (OFP) targets for the resuscitation in critically ill patients.


CHT is a dynamic therapeutic process according to the physiological laws of hemodynamics. It permeates the whole course of the disease in the ICU. Here, we suggest that hemodynamic therapy should be a special and independent system in the process of medical treatment. The procedure of CHT involves triggering the clinical problem and determining and implementing the therapeutic intervention, which not only benefits prior trigger issues but also causes the potential injury. In addition, the therapeutic intervention includes determining the potential interventional direction according to the known clinical information, using physiologic directed targets to choose the intensity of the intervention, the response to the intervention, and the dynamic evaluation and adjustment of the directed targets at different time points. A schematic diagram demonstrated the procedure of hemodynamic intervention in CHT (Fig. 1). For the implementation of the hemodynamic therapy, we emphasize the following principles.

  • 1. CHT is the problem-oriented aim, and the clinical problem is not confined to tissue perfusion. CHT always focuses on the restoration of tissue perfusion and circulation, but it also involves the other systems of critically ill patients with normal tissue perfusion, such as the negative fluid balance in the acute respiratory distress syndrome (ARDS), the weaning of ventilation in cardiac dysfunction, and nutrition (6, 7).
  • 2. The concepts of the therapeutic target and therapeutic endpoint should be clarified in CHT. Both the therapeutic target and the therapeutic endpoint are presented as physiologic parameters according to the clinical situation. For example, if hypotension is the clinically triggered issue, the correction of blood pressure would be the endpoint of this medical intervention. However, the blood pressure would be one of many targets to improve lactate clearance when the patients have high lactate levels, and lactate clearance would be considered as the endpoint of the medical intervention. It is important to choose a proper target for titrating the intensity of one specific medical intervention to avoid the potential conflict injury. For example, it would be a disaster for patients when lactate is chosen as a target for fluid infusion without the evaluation of cardiac filling pressure, blood pressure, and global flow. In other words, fluid infusion could not directly improve lactate clearance in a physiologic perspective. We defined the therapeutic endpoint to be related to a strategy or a serial combination of interventional targets for a clinical problem and the therapeutic target as directly related to one specific medical intervention. The therapeutic target should not be only fixed at an absolute value before the endpoint is reached, and the achievement of targets depends on the preset endpoint according to the pathophysiologic principles. Some suggestions for how to choose and achieve and use the therapeutic targets and endpoints are summarized in Table 1.
  • 3. The physiologic reference range and individualized status should be combined to determine a therapeutic target, and the dynamic evaluation of the body response is necessary when the preset target has been achieved. It is important to target a physiologically normal range to rule out some corresponding potentially oriented problems in clinical practice. For example, it is easy to exclude the global flow oriented to the clinical problem if both ScvO2 and P(v-a)CO2 are normal. However, when the direction of therapeutic treatment is difficult to determine in a complicated clinical situation, a preintervention to test the potential of the body response is preferable, such as using the fluid challenge test to assess the fluid responsiveness. Sometimes, it is difficult to determine a properly directed target to avoid over-resuscitation or under-resuscitation in critically ill patients. The dynamic evaluation of the body response is necessary when the preset target has been achieved. In addition, the intensivists should make a determination for further medical intervention based on a personalized and precise principle. Hernandez et al. (8, 9) found a serial and dynamic perfusion in multimodal monitoring strategies could lead to a physiologically oriented medical intervention.
Table 1
Table 1:
Difference between the concept of the therapeutic target and endpoint

Fig. 1
Fig. 1:
A schematic diagram of a hemodynamic medical interventional procedure of CHT.


The optimization of oxygen delivery, blood flow, and perfusion pressure to restore tissue perfusion are the main components during resuscitation in clinical practice. When patients have persistent tissue hypoxia after simple and early resuscitation (fluid/vasopressor), advanced assessment/monitoring for systemic hemodynamic targets might be useful and necessary. Here, we summarized OFP therapeutic targets to correct persistent tissue hypoxia based on a pathophysiologic perspective. The evaluation of OFP targets might be not typical clinical behavior for all cases of resuscitation in the real world. Nevertheless, OFP targets would be more important in patients with persistent tissue perfusion and a poor response to early resuscitation. These targets also provide an understanding of the predominant driving forces of tissue hypoperfusion/hypoxia and corresponding target-oriented interventions for optimizing macrocirculation parameters. The interpretation of these targets is necessary for adequate resuscitation and the correction of tissue hypoxia. The OFP targets were reviewed from sepsis guidelines and hemodynamic consensus in adult critically ill patients.

Oxygen delivery targets (assess whether DO2 demands the need of VO2)

The concept of oxygen transport is a milestone of shock resuscitation, and the determination of the dependence of DO2/VO2 has become a challenge in resuscitation (10, 11). The method to identify whether VO2 depends on DO2 was named the DO2 challenge test, which was used to assess the safety and effectiveness of DO2 challenge. In the past 20 years, researchers have searched for simple and sensitive indicators to reflect the balance of DO2/VO2 in clinical practice. In healthy populations, the mean value of ScvO2 is 77% (66%–84%), and the mean value of SvO2 is 78% (73%–85%). However, ScvO2 would be greater than SvO2 due to greater O2ER in the splanchnic circulation, intraabdominal organs, and limbs in critical patients (12). As there is good agreement between ScvO2 and SvO2, ScvO2 has been commonly used to substitute for SvO2. From the EGDT introduced by Rivers et al. (13), ScvO2 has been accepted as an indicator to reflect the dependence of DO2/VO2, and a cutoff of 70% for ScvO2 has become a target of resuscitation. However, recent clinical trials questioned ScvO2 at least 70% as a target of early resuscitation, and a high ScvO2 was also related to a poor outcome (3, 4, 14–16). The study also found both a high ScvO2 and a low ScvO2 were related to a poor outcome in septic shock patients who had a severe lactic acidosis after resuscitation (17).

However, ScvO2 should not be misunderstood as a parameter of little value for the evaluation of the dependence of DO2/VO2. The poor outcomes of patients with low ScvO2 were largely reported in various conditions. ScvO2 remains the foundation for detecting the relationship of DO2/VO2 in critically ill patients, especially in cases of low ScvO2(2). The recommendations/commentary of oxygen delivery-related targets in the sepsis guidelines and hemodynamic consensus are summarized in Table 1(2, 18–23). Recently, the absolute values of the targets of oxygen delivery or a cutoff ScvO2 value of 70% in patients were not recommended in the recent guidelines. However, when the patients have persistent tissue hypoxia, the monitoring of ScvO2 is still helpful and the pursuit of a normal ScvO2 is also worthy of consideration.

More recently, the P(v-a)CO2/C(a-v)O2 ratio has been suggested as an indicator of anaerobic metabolism and a supplement for normal ScvO2(24). In tissue hypoxia, a drop in oxygen consumption (VO2) occurs together with a decrease in aerobically generated carbon dioxide (CO2), while anaerobic CO2 generation can still increase. Therefore, the global CO2 production (VCO2) decreases to a lesser extent than VO2. Consequently, a rise of the respiratory quotient (VCO2/VO2 ratio) was used as an indicator of global anaerobic metabolism. The venous-to-arterial CO2 difference/arterial-central venous O2 difference ratio [P(v-a)CO2/C(a-v)O2] serves as an alternative to the respiratory quotient in clinical practice and has shown the potential to reflect anaerobic metabolism. A high P(v-a)CO2/C(a-v)O2 ratio indicates the effective response of VO2 to an increase DO2. Several studies have demonstrated that the P(v-a)CO2/C(a-v)O2 ratio, but not ScvO2, is able to predict hyperlactatemia, lactate clearance, and an increase of VO2 response to an acute increase of DO2 in patients with ScvO2 more than 70% (25–30). Shaban et al. (31) demonstrated that the Pv-aCO2/Ca-vO2 ratio was predictive of 28-day mortality in shock patients. In addition, our study also showed a threshold of P(v-a)CO2/C(a-v)O2 ratio at least 1.6 was associated with ICU mortality and was an independent risk factor of mortality in septic shock patients with high ScvO2 (≥80%) after resuscitation (32).

However, an abnormal P(v-a)CO2/C(a-v)O2 is not only derived from tissue hypoxia, but also from mitochondrial dysfunction. If the high P(v-a)CO2/C(a-v)O2 ratio value is caused by deficits in oxygen utilization from mitochondrial dysfunction, the VO2 would not depend on DO2 anymore. Hence, when using P(v-a)CO2/C(a-v)O2 as a potential target of the DO2 in resuscitation, the dynamic evaluation of the response of P(v-a)CO2/C(a-v)O2 should be highlighted. Lastly, several factors could impact the performance of P(v-a)CO2/C(a-v)O2 to reflect cellular hypoxia, such as hemodilution, hypoxic hypoxia, arterial hyperoxia, and acute hyperventilation (33–35), and P(v-a)CO2/C(a-v)O2 should be used with caution in these cases.

Blood flow target (determines whether global blood flow demands the need of tissue perfusion)

The blood inflow delivers nutrition and O2 to the tissue, and the blood outflow removes metabolic waste products from the tissue. The blood flow is the determinant of oxygen delivery, and it is also an important component of perfusion pressure. Maintaining mainstream flow is essential for the resuscitation of microcirculatory blood flow. Flow-based intravenous management has become popular in the resuscitation of shock patients, which is also named flow responsiveness (36, 37). The flow responsiveness to fluid has been taken as the gold standard to guiding fluid intravenous during the initial resuscitation, and passive leg raising and dynamic preload variables are also recommended to evaluate the potential of the fluid response in recent guideline (21, 23). The methods to assess fluid response are similar to a preintervention diagnostic test during CHT, which is used to estimate the potential of the body for fluid infusion (38, 39). Therefore, the presence of a fluid response is necessary but insufficient for fluid infusion during resuscitation, and the trigger of fluid infusion is the clinical sign of insufficient global flow.

Interestingly, growing evidence has shown that the administration of fluid to patients with shock or oliguria may not improve organ function or clinical outcomes, even when these patients are fluid responders (40–42). Apparently, the flow-based fluid infusion is challenging here. However, we would like to emphasize the importance of the therapeutic target according to the principle of CHT. It is important to determine that the clinical trigger (tissue hypoxia) results from oxygen delivery, blood flow, or perfusion pressure targets (OFP target) at a global point. For example, Lammi et al. (43) found that fluid boluses in ARDS patients who were fluid responsive did not improve either blood pressure or urine output. Nevertheless, the basal cardiac index was approximately 3.82 L/min/m2 before the fluid bolus, and other evidence of low global flow is lacking. Therefore, it is easy to infer that oliguria might be due to a low perfusion pressure target but not a global flow target. It would not be the first priority for shock patients with a high cardiac output to receive a fluid infusion to further increase the cardiac output. Therefore, the correct interpretation of the global flow target is important in CTH. The cardiac output is the standard parameter of the global flow target, which could be obtained by a pulmonary artery catheter, echocardiography, transpulmonary thermodilution, lithium dilution, arterial pulse contour analysis monitors, or bioreactance. Here, the routine measurement of cardiac output is not recommended for patients with shock during initial therapy, but it is recommended for patients with a poor response to early resuscitation (21, 23). Some simple methods to evaluate global flow would be other alternatives, such as peripheral perfusion or critical ultrasound at the bedside.

The methods for increasing global flow always involve the infusion of fluid and inotropic medicine at the bedside, which always requires the titration of the personalized flow target. Moreover, an absolute value of the cardiac output target for resuscitation is not recommended. In addition, the Pv-aCO2 gap has been suggested as an indicator of global flow, which depends on cardiac output (44). A normal Pv-aCO2 suggests that an increase of cardiac output might not be a priority target for the correction of tissue hypoxia in the therapeutic strategy. In other words, normal Pv-aCO2 indicates a high possibility of normal cardiac output, and tissue hypoperfusion would not result from a low global flow. In contrast, a high Pv-aCO2 indicates a low flow status, and the amplification of cardiac output might be a good alternative if there is evidence of tissue hypoxia (45). Currently, a cutoff of 6-mmHg Pv-aCO2 gap has been suggested as an indicator to reflect the inadequacy of cardiac output for tissue perfusion (46). Recently, Ospina-Tasco’n et al. (47) demonstrated that the Pv-aCO2 gap reflects the microcirculation in septic shock patients. Therefore, an elevated P(v-a)CO2 gap not only indicates that global flow is not sufficient for the supposed tissue hypoxia, but also reflects that microcirculatory flow is not sufficient to clear the additional CO2, even in a normal/high global flow (8). Therefore, the measurements of the Pv-aCO2 gap would be helpful to assess the underlying pattern and the adequacy of cardiac output as well as to guide therapy in patients with a central venous catheter.

Perfusion pressure target (determines whether the perfusion pressure demands the need of tissue perfusion)

Perfusion pressure is the driving pressure that pushes the blood flow into the organ. In other words, the main function of blood pressure is to deliver global flow. For example, a decrease in the distribution of global flow is partially caused by septic hypotension with a high cardiac output. There is no doubt that prolonged hypotension is associated with poor outcome and organ dysfunction. A previous study showed that the early-phase cumulative duration of hypotension is related to acute kidney injury (48). The recommendations for the target perfusion pressure in the sepsis guidelines and the hemodynamics consensus are summarized in Table 2. Table 2 shows that a cutoff of 65 mmHg mean arterial pressure (MAP) is still recommended to maintain the important organ function at the beginning of resuscitation. Importantly, the individualized target blood pressure is underlined according to the patient's pathophysiologic demand (49).

Table 2
Table 2:
Summarization the recommendations/commentary of oxygen delivery related target in sepsis guidelines and hemodynamics consensus

However, the best way to optimize the MAP target remains controversial after the initial resuscitation. The clinical evidence to guide the administration of vasopressors remains paucity in critically ill patients with septic shock (50). A study found a persistent presence of a low perfusion index (PI < 0.3) after volume resuscitation was related to the vasopressor requirement during early resuscitation in patients with severe sepsis (51).

Here, we summarize some principles to optimize the target blood pressure according to the concept of CHT. (1) Studies have shown the benefit of target MAP according to the medical history, and an MAP greater than 75 mmHg may protect against progression to acute kidney injury in patients with a history of arterial hypertension (52). (2) Potential conflicts with pathophysiologic status. The potential conflicts to pursue historical MAP should be considered during resuscitation. For example, vasoconstrictors may be used to increase MAP to acceptable values, and also may shut down microcirculation perfusion, worsening organ function (53). Furthermore, the global flow might be suppressed by the increases of pressure in cardiac dysfunction case. (3) A holistic evaluation of the response of pressure (tissue perfusion, global flow, and organ function). Different organs always require different perfusion pressure. The autoregulatory mechanism for organ flow and pressure is impaired in critically ill conditions (54, 55), and the different response of tissue perfusion and organ function should be balanced during the titration of the pressure target. For example, to some extent, using vasoconstrictors to maintain a previous MAP would be apparently helpful to renal function, but may simultaneously induce impairment to the microcirculation and cardiac function in cardiac dysfunction patients. Therefore, a holistic approach to assessing the response of perfusion pressure is preferable (Table 3).

Table 3
Table 3:
Summarization the recommendations/commentary of perfusion pressure related target in sepsis guidelines and hemodynamics consensus

In summary, the OFP targets are determinants of the global circulation during the management of resuscitation, and the guiding principle of OFP targets is useful in the management of critically ill patients. Figure 2 shows a recursive and regression tree of OFP-oriented targets for persistent tissue hypoxia patients who have a poor response to the initial resuscitation.

Fig. 2
Fig. 2:
A recursive and regression tree to optimize hemodynamics based on OFP target.


The achievement of the OFP target is not the end of resuscitation. Here, the authors propose a conceptual stepwise target in the resuscitation interprets the direction of resuscitation according to pathophysiologic consideration (Fig. 3). The terminal endpoint of resuscitation is to restore cellular energy and organ function. It is well known that poor systemic circulation variables always result in poor local perfusion variables, and the correction of personalized systemic circulation remains the first choice to restore the tissue perfusion in clinical practice. However, good global variables do not guarantee good local variables. Many studies have shown that persistent abnormalities in tissue perfusion are associated with a poor outcome and multiple organ dysfunctions even if the global hemodynamic variables are normalized (56–62). Recently, the concept of a loss of hemodynamic coherence was introduced. It states that microcirculation function is not correspondingly accompanied by the improvement of macrohemodynamics (63). Moreover, there is also a disassociation between the cellar oxygen utilization dysfunction and tissue perfusion (64).

Fig. 3
Fig. 3:
A conceptual framework of the stepwise targets in the resuscitation.

Here, the incoherence phenomenon of resuscitation is stressed, and it has become a persistent challenge in clinical practice. The integration of microcirculation and cellular oxygen metabolism and global hemodynamic information would be helpful to determine the incoherence phenomenon of resuscitation. Early identification of incoherence phenomenon during the resuscitation could reduce the risk of over-resuscitation and change the therapeutic direction. First, if tissue hypoperfusion exists after the improvement of OFP targets, a loss of coherence between macrocirculation and microcirculation should be suspected. Second, if cellular oxygen utilization dysfunction exists after the restoration of tissue perfusion, the loss of coherence between tissue perfusion and cellular oxygen utilization should be suspected. When there is a incoherence phenomenon during the resuscitation, some other interventional strategies are worthy of consideration, such as, enhance the treatment of etiology, improve cellular energy metabolism (control VO2 et al.) and use vasodilators and steroids (65). Moreover, sometimes tissue perfusion is estimated in a binary (good or poor) fashion that might be insufficient in clinical practice. The critical value of tissue perfusion should not be misunderstood as the normal value from the healthy population. Without a personalized endpoint, pursuing a total normalization of tissue perfusion could also induce over-resuscitation. In other words, pursuing better physiology not necessarily is associated with better outcome. The sacrifice of peripheral perfusion is a self-protection mechanism in the critically status, so the impairment of peripheral perfusion might be acceptable to some extent. Hence, the targets of tissue perfusion might also demand the personalized physiological requirement of critically ill patients (66). In summary, a conceptual diagram showed the incoherence phenomenon of resuscitation (Fig. 4).

Fig. 4
Fig. 4:
A conceptual protocol to identify incoherence phenomenon for resuscitation.


ScvO2 more than 70% has not been recommended as a direct target in the initial resuscitation, and the direct target of MAP remains 65 mmHg. Moreover, the individual MAP target is underlined, and using flow-dependent methods to guide fluid infusion is recommended in the recent guidelines. The concept of the incoherence phenomenon has attracted attention, and the early identification of incoherence could reduce the risk of over-resuscitation and change the therapeutic direction.


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Critical hemodynamic therapy; incoherence phenomenon; P(v-a)CO2; resuscitation; ScvO2; CHT; critically hemodynamic therapy; DO2; oxygen delivery; MAP; mean arterial pressure; OFP; oxygen–flow–pressure; P(v-a)CO2; veno-arterial CO2 tension difference; SaO2; arterial oxygen saturation; ScvO2; central venous oxygen saturation; SvO2; mixed venous oxygen saturation; VO2; oxygen consumption

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