In the whole world, around 29,000 children younger than 5 years die every day. More than 70% of these deaths are attributed to six big causes: diarrhea, severe malaria, neonatal infection, pneumonia, premature birth, or neonatal asphyxia. The infectious causes represent the majority of the cases and culminate with severe sepsis or septic shock (1). Sepsis is therefore the most common cause of death of children in the world, and the risk of death increases in association with comorbidities and organ dysfunction (2).
In adult patients, vasomotor paralysis represents the predominant cause of mortality; myocardial dysfunction is manifested as reduced ejection fraction, and the cardiac output is usually maintained or increased by tachycardia and ventricular dilation. On the other hand, mortality in pediatric sepsis is associated with severe hypovolemia and low cardiac output. Also differently from adults, oxygen delivery in children, not oxygen extraction, is the major determinant of oxygen consumption (3).
The American College of Critical Care Medicine-Pediatric Advanced Life Support (ACCM-PALS) guidelines, published in 2002 and reviewed last year, represent an organized approach and state that early recognition, adequate fluid resuscitation, appropriate cardiovascular therapies, and timely and appropriate antibiotic therapy and source control are all crucial to optimal outcome (3, 4). Although current ACCM-PALS guidelines represent best practice, stronger evidence is lacking to confirm the components of these recommendations, and the Surviving Sepsis Campaign has shown that almost all recommendations in pediatric septic shock treatment are level C or D, with the single exception of the recommendation against the use of activated C protein in children, which is a level B evidence (5).
But some retrospective studies came out and successfully showed, at the same time, the positive effects arising from the utilization of ACCM-PALS guidelines and the existing barriers to its implementation. In general, the effectiveness of interventions to improve guidelines adherence does not depend on the intervention itself, but also on the existence and intensity of barriers, which can be related to lack of awareness, lack of familiarity, lack of agreement, lack of self-efficacy, lack of outcome expectancy, the inertia of previous practice, and external barriers (6). The following studies evidence positive results and also barriers associated with sepsis treatment guidelines.
In the first study, the Pittsburgh group analyzed the records of 91 patients, who had been transported from secondary hospitals, and showed that shock reversal within 75 min was associated with 96% survival rate, and ACCM-PALS guidelines consistent treatment was associated with 93% survival rate. But these objectives were obtained in only 26% and 30%, respectively, of the patients. Additionally, this study revealed that the same amount of resuscitation fluid was administered to responders and nonresponders, indicating the lack of an individualized approach. The main barriers reported were difficulties with specialized technical skills, especially airway management and central venous lines placement, educational gap, and lack of early recognition of severe sepsis and septic shock diagnosis (7).
Similarly, the analysis of the emergency management of 200 children with severe sepsis in the United Kingdom showed a mortality rate of 6% in the group of patients who reversed shock, against 25% among patients who did not reverse shock. But the study revealed also that the ACCM-PALS algorithm was not followed in the majority of children who were shocked. Only 8% of the children received treatment according to ACCM-PALS guidelines, and, even not taking into account the recommendation to give steroids, still only 38% of the patients received ACCM-PALS guidelines consistent treatment. The authors revealed that lack of early recognition and treatment delay, waiting for the placement of central venous line, were the main barriers observed in this study (8). It is important to notice that, at the time this study was performed, the ACCM-PALS still did not recommend the initiation of peripheral inotropes. This recommendation was included in the 2007 revision of the guidelines (4).
Finally, our group in São Paulo retrospectively analyzed 90 patients, between 1 month and 18 years of age, with severe sepsis and septic shock and showed that the mortality rate was higher for those who received less than 40 mL · kg−1 of normal saline in the first hour and for those whose treatment was not initiated in the first 30 min after the diagnosis of septic shock. We also reported, on the other hand, that treatment was considered adequate in few patients, with the whole study group receiving less than 30 mL · kg−1 in the first hour (27 mL · kg−1 for survivors, and 16 mL · kg−1 for nonsurvivors) and long time intervals between diagnosis and intensive care unit admission and between diagnosis and administration of vasoactive drugs. In our experience, the identified barriers to the implementation of ACCM-PALS guidelines were difficulties in attaining adequate vascular access, lack of early recognition, shortage of health care providers, absence of goals and treatment protocols, absence of specialized transportation, restricted number of pediatric intensive care unit beds, and nurses being not prepared (9).
According to the 1984's definitions, the resuscitation stage of septic shock was defined as "≥2 therapeutic efforts to control hypotensive episodes per 6 h beginning with the initial resuscitation." In fact, the entire classification was based on 6-h periods, and there was a single resuscitation end point: blood pressure (10) (Table 1).
Analyzing the presented retrospective studies, it is possible to state that, at present, some patients are getting adequate treatment, oriented by ACCM-PALS guidelines. These patients are treated quickly and aggressively. The appropriated amount of fluid is administered, with subsequent adequate cardiovascular support, guided by multiple therapeutic end points such as capillary refill for 2 s or less, normal pulses, normal mental status, urine output greater than 1 mL · kg−1 · h−1, normal perfusion pressure for age, cardiac index between 3.3 and 6 L · min−1 · m−2, and central venous oxygen saturation (ScvO2) greater than 70%. And the outcome of these patients is truly favorable. However, at the same time, and at the same settings, a considerable percentage of children are still being treated as 25 years ago: late diagnosis, delayed and inadequate fluid resuscitation, and treatment based solely on blood pressure values.
The barriers pointed out by these studies allow us to speculate that late diagnosis and inadequate fluid and cardiovascular support could be, at least partially, overcome with the utilization of a tool capable of distinguishing those cases with worst prognosis and capable of translating the needs of further therapeutic efforts. Several inflammatory, anti-inflammatory, metabolic, and hemodynamic markers have been postulated to be this tool. ScvO2 is one of the most studied, and perhaps the most successful, of these markers.
The role of ScvO2 in clinical practice started to be defined in the 1990s, when, based on observations that patients who survived critical conditions had values for cardiac index and oxygen delivery higher than those who died, and even higher than physiologic values, an important study with adult patients tested the hypothesis that supranormal cardiac index or supranormal oxygen delivery would lead to higher survival rates. More than 750 critical patients were randomly assigned to receive standard care (control group), treatment directed to maintain cardiac index greater than 4.5 · min−1 · m−2 (cardiac-index group), or treatment directed to maintain mixed venous saturation (SvO2) 70% or greater (oxygen-saturation group). However, although the hemodynamic targets were reached by 45% of the cardiac-index group and 67% of the oxygen-saturation group, the mortality was very similar (around 50%) between the three groups. Even when septic patients were analyzed separately, no positive effect on the outcome was observed, rejecting the study hypothesis and frustrating one of the first initiatives to use a therapeutic goal derived from the balance between oxygen delivery and demand (11).
But shortly after the publication of this study, important questions were raised, as they could have obliterated the impact of the therapeutic interventions. First, there was an important heterogeneity of the population, although they have performed subgroup analysis, and second, and most importantly, patients were randomized at 48 h after admission, which is, we can say today, clearly beyond the so-called "golden hours" of the septic shock natural history. Perhaps this delay was responsible for the lack of significant impact associated to the treatment directed to optimize cardiac index and oxygen delivery.
This doubt persisted for a few years, until another randomized trial came out testing the effect of a goal-directed treatment, applied in the early phase of severe sepsis or septic shock (12). This study was designed to investigate the impact of therapeutic interventions, guided by the continuous reading of ScvO2, in the first 6 h of treatment, based on the hypothesis that the transition to serious illness occurs during these critical golden hours, when definitive recognition and treatment could provide maximum benefit. Two hundred sixty-six patients were assigned to receive 6 h of conventional treatment, or fluid resuscitation and inotropic support directed to ScvO2 of 70% or greater. The results showed that patients in the early goal-directed therapy group received more fluid, inotropes, and blood in the emergency department and, most importantly, presented a significantly lower in-hospital mortality rate (30.5% vs. 46.5% in the control group). According to the authors, this landmark study reinforced the knowledge that the hemodynamic evaluation of the patient, based on physical examination, vital signs, central venous pressure, and urine output is not sufficient to detect persistent tissue hypoxia (12).
Although there still may be questions about this study (13), the results were relevant and supported the concept that ScvO2-oriented treatment represents a resuscitation strategy that manipulates cardiac preload, afterload, and contractility, with the objective to attain an adequate balance between oxygen delivery and oxygen demand.
Based on the findings in adult patients, on the paucity of randomized control trials among pediatric patients, on the higher incidence of cardiac dysfunction in children with septic shock, on the knowledge that death in pediatric septic shock is related to progressive cardiac failure, rather than vascular failure, and on the existing barriers to early treatment demonstrated in observational studies, we have conducted a randomized controlled trial to determine whether ACCM-PALS guidelines, guided by ScvO2 70% or greater, reduced morbidity and mortality of severe sepsis and septic shock in children (14). One hundred two patients with severe sepsis or fluid refractory septic shock were included, with half of them receiving standard treatment, and the other half receiving ScvO2-guided treatment. The intervention group treatment protocol included, for those patients with ScvO2 of less than 70%, the recommendation to administer additional fluid, inotrope (dobutamine, milrinone, or low-dose epinephrine), or packed red blood cells (if hemoglobin <10 g · dL−1).
Two facts allowed us to postulate that the effect of early goal-directed treatment in children could be even more important than the effect observed in adults. First, the frequent association with cardiac dysfunction, which indicates the potential value of a tool that estimates cardiac output (allowing to aim a cardiac index between 3.3 and 6 L · min−1 · m−2 and/or ScvO2 >70%); second, the inherent difficulties to determine the hemodynamic profile based solely on the physical examination of children. Therefore, the results encountered in our study were not unexpected, when the difference in 28-day mortality between intervention and control patients was bigger than in adult patients (39.2% in the intervention group vs. 11.8% in the control group) (14).
Although the mortality reduction was the most important outcome, the analysis of organ dysfunction revealed another interesting finding, showing that patients who received ScvO2-guided treatment developed significantly less renal and neurological dysfunctions. That would have been a marked result per se, as those dysfunctions are usually associated to severe sequelae and to elevated consumption of health care resources (14).
Paralleling the study with adult patients (12), the intervention applied in children led to the administration of more fluid, inotropes, and red blood cells in the early phase of shock resuscitation. And it is worthy to observe that the treatment previous to the study entry was considered adequate in both groups, which waived the possibility of undertreatment of the control patients. Moreover, the analyses of cardiovascular agents showed that, in the control group patients, vasopressors were added 7.3 times more frequently than were inotropes, whereas in the intervention group, the proportion was the addition of one inotrope to 1.7 addition of vasopressors. The subgroup analyses also revealed that the benefits of the intervention were observed only among patients with ScvO2 of less than 70%, showing the effect was related to the measures directed to the optimization of oxygen delivery (14).
Similarly to the impact observed in adult patients, the early goal-directed therapy in children is one of the few therapeutic interventions that proved to be beneficial in septic shock treatment. Although the debate is still open, some important considerations indicate that the effect of the addition of a single resuscitation target arises from the combination of better and earlier identification of inadequate resuscitation and the individualization of the resuscitation efforts. Those factors could be able to alter the disease process and modify the inflammatory response (15).
Although this rationale may explain how the early-goal directed therapy changes the initial treatment of septic shock, it would perhaps be simpler to state that the most valuable tool of the ScvO2-guided resuscitation is time. Central venous oxygen saturation monitoring provokes additional actions within a shorter period and augments the chances of rescuing patients from cryptic shock. In other words, better outcomes will be achieved as long as therapeutic and monitoring interventions are placed at the emergency department, or closer to the diagnosis of severe sepsis. In that sense, less invasive, costless, and easy-to-operate methods or technologies have the potential to produce maximum benefits. Central venous oxygen saturation may be included in this kind of interventions, but monitors and catheters still have to be more suitable and affordable to be placed in every pediatric emergency department. Other methods worth mentioning are the alternatives to intravascular access (especially intraosseous access and ultrasound-guided venous access), the ultrasound cardiac output monitoring (16), and laboratory tests, mainly lactate and CO2 gap. Techniques that can be used instead of the pulmonary artery catheter, such as pulse contour analysis or femoral artery thermodilution, are still under investigation and are not widely available. The extracorporeal membrane oxygenation is indicated for children with refractory shock, although the expected survival with extracorporeal membrane oxygenation is not elevated (4).
In conclusion, early goal-directed therapy in pediatric septic shock is a successful method to optimize and parameterize treatment, but there is still a long way to turn septic shock resuscitation simpler and more widely spread. Advances in that path will consistently decrease mortality rates in any setting or country.
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