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 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).
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).
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