Physiology Principles Underlying Goal Directed Therapies in Children

A Thesis Project has been undertaken which has the objectives to determine the impact of Goal directed therapies on postoperative outcome in children [1]. The background of this Thesis Project were the results of five retrospective observational studies realized in the pediatric surgical settings [2-6]. These studies had the objectives of determining predictors of adverse postoperative outcomes in the surgical pediatric population. The aim of this Thesis Project is to bring improvement measures in domains where predictors of postoperative adverse outcomes were identified. In order to implement these measures prospective and randomized controlled trials need to be developed. The hypothesis of the Thesis is by implementing goal directed therapies in fields were predictors of pejorative postoperative outcome have been identified, outcome in terms of postoperative morbidity and length of hospital stay will be improved.

Goal directed therapies (GDT) include goal directed fluid and hemodynamic therapy (GDFHT), transfusion goal directed protocols (TGDP) and enhanced recovery after surgery (ERAS) [7-33]. GDFHT, TGDP and ERAS share common goals. These aims are to optimize oxygen delivery (DO₂), oxygen consumption (VO₂) and oxygen extraction in different tissues of the organism. Considering the following equations, one will understand the physiology and the basis of GDT [14,22,23,34,36].

DO₂= COxCaO₂= COx(Hbx1.31xSaO₂+0.0031xPaO₂)

VO₂= CO(CaO₂-CvO₂)

CaO₂=Hbx1.31xSaO₂+0.0031xPaO₂

CvO₂= Hbx1.31xSvO₂+0.0031xPvO₂

O₂ER= CaO₂-CvO₂/CaO₂=SaO₂-SvO₂/SaO₂=VO₂/DO₂

CO= SV x HR= VTIxD²x Π /4xHR

SV= Aortic Velocity Time Integral x area of the aortic valve=VTIxD²x Π /4

PP= SVR x CO

Where CO= Cardiac output, SV= Stroke volume, HR= Heart rate, PP= Tissular perfusion pressure, SVR= Systemic vascular resistance, VTI= Aortic velocity time integral, D= Diameter of the aortic valve, CaO₂= Arterial oxygen content, CvO₂= Venous oxygen content, Hb= Hemoglobin levels, PaO₂= Arterial oxygen partial pressure, PvO₂= Venous oxygen partial pressure, SaO₂= Arterial oxygen saturation, SvO₂= Venous oxy-gen saturation, O₂ER= Oxygen extraction ratio.

The determinants of DO₂ are CO, Hb, SaO₂, PaO₂.

The determinants of VO₂ are CO, Hb, SaO₂, PaO₂, SvO₂, PvO₂.

The determinants of CO are SV and heart rate.

The determinants of SV are afterload [ventricular relaxation and compliance (diastolic function); systemic arterial blood pressure, systemic vascular resistance; pulmonary arterial pressure, pulmonary vascular resistance], preload (volemia) and heart contractility (systolic function). The determinants of tissular perfusion pressure are SVR and CO.

Optimizing DO₂, VO₂ and O₂ER means that the demand (VO₂) has to be fulfilled by the offer (DO₂) [23]. If VO₂ exceeds DO₂, the tissues have to increase oxygen extraction in order to fulfill the demand [23]. If VO₂ exceeds DO₂ and oxygen extraction does not increase, a deficit in oxygen will occur which will lead to anaerobic metabolism which will increase lactate production and decrease tissular perfusion which will lead to organ dysfunction [22,23,34-36]. In normal states, VO₂ is independent of DO₂. If DO₂ decreases to a critical state, VO₂ becomes dependent on oxygen delivery. In this situation O₂ER increases to fulfill VO₂. However O₂ER cannot increase continuously when DO₂ decreases under the critical point. In this state of DO₂ dependency, hypoxia occurs and leads to organ dysfunction and lactate levels increase due to anaerobic metabolism [22,23,34-36].

Considering the goal directed fluid and hemodynamic therapy (GDFHT) point of view [9-20]. The objectives of the GDFHT are to optimize DO₂ to the tissues and tissular VO₂. DO₂ can be optimized in GDFHT by increasing CO. CO can be increased by optimizing SV. SV can be assessed echocardiograph-ically with aortic peak velocity variation (ΔVpeak), aortic velocity time integral (VTI) and distance minute (DM) at the aortic valve [9-20]. Assessing aortic velocity time integral (VTI) and aortic peak velocity variation (ΔVpeak) will determine fluid responsiveness if fluid therapy with crystalloids and or colloids is necessary or vasopressor-inotropic therapy to increase SV and thus cardiac output [14]. As precised here above the determinants of tissular perfusion are systemic vascular resistance and cardiac output. Tissular perfusion pressure can decrease if SVR is low and or if CO is low. Optimizing SV with fluid and or ino-tropic therapy and SVR with vasopressor therapy will increase tissular perfusion pressure. In GDFHT, DO₂ can be optimized by increasing CO as explained here above. GDFHT aims to avoid DO₂ dependency states and prevent organ dysfunction [22,23,34-36].

Considering the transfusion goal directed protocols (TGDP) point of view [23-28,33,36]. Optimizing DO₂ and VO₂ will be achieved by optimizing hemoglobin levels. The ideal hemoglobin level is one that avoids situations where VO₂ is dependent on DO₂ and depends on the clinical context [22]. Since transfusion of all sorts of blood products has been related to postoperative morbidity in terms of organ dysfunction among others, it is important to transfuse the right product at the right time [2-5]. Using point of care viscoelastic methods can be helpful l to guide and transfuse correctly [24-28]. These point of care devices have been shown to reduce length of hospital stay in hemorrhagic surgeries in children [28]. Maintaining the optimal hemoglobin levels to avoid situations where VO₂ exceeds DO₂ is mandatary since anemia has been related to increased mortality in children [26].

The important issue is to avoid unnecessary blood product administration which increases morbidity [2-5] and also avoid unnecessary anemia which can increase mortality [26]. In hemorrhagic settings like surgery, point of care devices can be useful to detect coagulation disorders which can be promptly treated with the appropriate blood products. Correcting coagulation disorders will further reduce bleeding which will avoid hemoglobin level decrease and thus avoid red blood cell transfusion. The use of TGDP is beneficial in bleeding sit-uations to guide the correct use of blood products. Transfusion of red blood blood cells has been shown to reduce oxygen extraction ratio in cardiac surgical children with high extraction ratio [33]. The ideal hemoglobin level is the one that avoids to reach the oxygen delivery dependency state and depends on patients clinical con-text. The objectives of TGDP are to avoid and prevent situations where VO₂ becomes dependent on DO₂. DO₂ dependency state can lead to organ dysfunction (Table 1).

Table 1: Factors influencing determinants of DO₂ and VO₂.

Considering enhanced recovery after surgery (ERAS) point of view [23,29-36] The objectives of ERAS is to reduce the perioperative stress which can have adverse consequences on postoperative recovery [23,29,30]. ERAS englobes measures which aim to reduce perioperative stress. These measures include optimal pain therapy, minimal invasive techniques whenever possible, optimal prevention and treatment of postoperative nausea and vomiting, prevention of postoperative organ dysfunction including infections, reducing fastening periods, favoring oral intake whenever possible, favoring early mobilization, respiratory physiotherapy to prevent pulmonary dysfunction which can lead to hypoxemia and hypoxia. Increasing oxygen saturation with oxygen therapy can increase DO₂, CaO₂ and decreases oxygen extraction ratio [33,35,36]. Oxygen consumption can be increased with the above mentioned stress situations. Reducing these sit-uations and favoring states where DO₂ is optimal is mandatory to avoid the D_O2 dependency state which can have adverse effects on postoperative recovery [23].

GDFHT, TGDP and ERAS share the same goals. These are optimization of DO₂, VO₂ and O₂ER to prevent morbidity due to organ dysfunction. These goal directed therapies are related via the VO₂-DO₂ interaction. To reach ERAS, GDFHT and TGDP are necessary. The aimed outcome of GDFHT, TGDP and ERAS is the prevention of postoperative organ dysfunction and the reduction of postoperative length of hospital stay and thus the improvement of outcome. Determinants of DO₂, VO₂, oxygen extraction and perfusion pressure underly the physiology of goal directed therapies in children. Understanding these determinants are important for optimal patient management.

1. http://www.theses.fr/s232762
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