Hi, my name is Jeff Chess, and I'm a pediatric clinical pharmacy specialist. I would like to welcome you to this advanced pharmacotherapy module titled, Not Tiny Adults, Considerations for Pediatric Shock. Here are my relevant disclosures related to this presentation. The objectives of this module are listed for you here, with the first being to explain the pathophysiology of shock in a pediatric patient, describe the similarities in the treatment approach to pediatric shock versus shock in an adult patient, describe the differences in the treatment approach to pediatric shock versus shock in an adult patient, and finally, to determine the optimal dosing strategy for fluids and vasopressors in pediatric shock. We will now begin with the first objective, to explain the pathophysiology of shock in a pediatric patient. Shock is defined by a relative imbalance between the delivery of oxygen and metabolic substrates and the metabolic demands of the cells and tissues of the body. Under normal resting conditions with adequate cardiac output, oxygen delivery, or DO2, is more than adequate to meet the oxygen requirements of the tissues needed to maintain aerobic metabolism. The excess delivery, referred to as oxygen reserve, can oftentimes serve as a buffer when there is a reduction in oxygen delivery, and this reserve can help with compensation by increasing extraction of the delivered oxygen without any significant reduction in oxygen consumption. Now, during stress or vigorous exercise, oxygen consumption can obviously markedly increase, as does oxygen delivery. Very little oxygen is stored in the cells and tissues of the body. As oxygen delivery decreases in the setting of shock, oxygen extraction must increase to meet the body's metabolic demands. Now, there is a critical level of oxygen delivery at which the body's compensatory mechanisms are no longer able to keep up with the metabolic needs of the body. This point is referred to as the anaerobic threshold. Once oxygen delivery falls below this anaerobic threshold, oxygen consumption also falls, and notably, lactate production increases significantly and can then be detected in the peripheral blood. During shock, the body's compensatory mechanisms attempt to maintain vital organ function. The subsequent progression of shock is commonly divided into three phases, the first being compensated shock, the next uncompensated shock, and the third classification being irreversible shock. During compensated shock, oxygen delivery to the brain, heart, and kidney is maintained at the expense of less vital organs. Signs and symptoms of shock may be apparent during compensated shock, and commonly, patients will have increased peripheral vascular tone and an increased heart rate in an effort to maintain a normal cardiac output as well as a normal blood pressure. Notably, hypotension is not present during the compensated stage of shock. As shock state continues to progress to uncompensated shock, the body's compensatory mechanisms eventually contribute to this progression of shock, meaning blood is commonly shunted away from the skin, muscles, and GI tract in order to maintain perfusion of the brain, heart, and kidneys. As a result of that blood shunting away from the GI tract, you will commonly lead to ischemia in these vascular beds with subsequent releases of toxic substances further perpetuating the shock state. Cellular function continues to deteriorate further, ultimately culminating in end-organ dysfunction. The third stage, or irreversible stage of shock, implies exactly its name, irreversible organ injury, especially of the vital organs, meaning the brain, heart, and kidneys. Intervention at this late stage is usually unsuccessful, and death commonly occurs even if therapeutic interventions are able to restore parameters such as heart rate, blood pressure, cardiac output, and oxygen saturation. The term pediatric encompasses a wide range of age distributions, starting from day zero or neonates all the way up to older children and adolescents. So to put things in perspective and try and have an idea of what the definition of hypotension is, that is what is listed for you here in this slide. You will see several different definitions based on the age of the patient. So specifically for neonates, those children being less than 28 days old, definition of hypotension is as defined as a systolic blood pressure less than 60 millimeters of mercury. For children between one to 12 months of age or infants, hypotension is defined as a systolic blood pressure less than 70 millimeters of mercury. Once patients are one year of age and up to 10 years of age, the Pediatric Advanced Life Support, or PALS, program uses the formula that you see listed for you there. You can take the patient's age in years, multiply that number by 2, and add it to 70. And if that patient's systolic blood pressure is less than that value, then they would be considered to have hypotension. For example, if I had a two-year-old child, I would multiply their age in years, which is 2 by 2, 2 times 2 is 4, and I would add that to 70, which is 74. If I had a two-year-old and their systolic blood pressure was less than 74 millimeters of mercury, then that two-year-old child would be considered as being hypotensive. Once your child or children are 10 years of age and older, we can use the very common threshold that we see in our adult patients of a systolic blood pressure less than 90 millimeters of mercury being defined as hypotensive. The body's compensatory mechanisms can be divided into three general classifications, the first being maintaining effective blood volume, the second being optimizing cardiac performance, and the third being maintaining perfusion of vital organs. And we will discuss each of these more in depth. The first classification of compensatory mechanisms is to maintain effective blood volume. This can be accomplished in several different ways. The first is to decrease venous capacitance via vasoconstriction by increasing sympathetic tone. This can be accomplished as a result of epinephrine release from the adrenal medulla, as well as activation of the renin-angiotensin-aldosterone system, which increases the production of A2. As we all know, angiotensin II is a potent vasoconstrictor in the periphery. Additionally, the RAAS can also increase vasopressin, and we know vasopressin can also be a vasoconstrictor in the periphery as well. The second way that maintaining effective blood volume can be accomplished is through decreasing renal fluid losses. So the body can result in a decreased GFR or glomerular filtration rate, we can decrease the amount of blood going to the kidneys so that we're not having increased losses through the kidneys. Similarly, the RAAS activation can increase aldosterone secretion and increase secretion of ADH or vasopressin, and similarly, vasopressin can then insert the water channels or aquaporins into the kidneys that will allow us to then reabsorb more water back through the kidney to then put back into the circulating peripheral volume. Lastly, in an effort to maintain effective blood volume, the body can redistribute fluid back to the vascular space. The second classification of compensatory mechanisms is to optimize cardiac performance. This can be done by increasing heart rate, increasing contractility, and by optimizing or maximizing preload to then subsequently increase cardiac output. Epinephrine being released from the adrenal medulla can help accomplish both increasing heart rate as well as increasing contractility or the forcefulness of the contractions of the left ventricle. Optimizing or maximizing preload to help facilitate cardiac output, if we are able to fill the tank up, make sure we have an adequate volume coming back to the right side of the heart, that can then be pumped out via the left side of the heart. Maximizing preload typically is done by the practitioners when patients present in shock states. The third classification of compensatory mechanisms is to maintain perfusion of vital organs. This is most commonly done through regulation of systemic arterial tone as well as our body's auto-regulation of blood flow to vital organs such as the brain, the heart, and the kidneys. Shock can be classified into one of four classes of shock, the first being hypovolemic shock, the second being cardiogenic shock, the third being obstructive shock, the fourth being distributive shock, and we will describe each of these a little bit more in depth. Hypovolemic shock is shock as a result of inadequate circulating volume. Inadequate circulating volume can be caused by fluid and electrolyte losses, which you can see on the left side of the table, as a result of things like vomiting, diarrhea, and G-tube loss, renal losses, fever or excessive sweating, heat stroke, water deprivation, sepsis and burns, moderate to severe burns typically, as well as pancreatitis and small bowel obstruction. Similarly, inadequate circulating volume can be a result of trauma, GI bleeding or surgery, which typically is more of a hemorrhage, which you see on the right side of the table. So hypovolemic shock, again, typically a result of inadequate circulating volume, and there are many causes, as you can see listed in the table, that can bring about inadequate circulating volume. Cardiogenic shock is shock as a result of primary pump failure. The pump failure can be caused by things such as myocarditis, cardiomyopathy, myocardial ischemia, ventricular outflow tract obstruction, acute dysrhythmias, as well as post cardiopulmonary bypass. Obstructive shock is shock as a result of the inability of blood getting to and from the heart. Obstructive shock can be caused by things such as tension pneumothorax, cardiac tamponade, and pulmonary embolism. Distributive shock is shock as a result of maldistribution of circulating volume. Obstructive shock can be caused by things such as sepsis, anaphylaxis, as well as neurogenic shock. Next, we will discuss our second objective, which is to describe the similarities in the treatment approach to pediatric shock versus shock in an adult patient. There are several similarities between shock in children and adults, the first being that for every hour delay in guideline-driven therapy, mortality has been shown to increase. Secondly, early recognition and early treatment also reduces mortality. Lastly, bundles of care, such as resuscitation protocols and screening tools to identify patients with shock and or sepsis, have all been shown to have benefit in reducing morbidity as well as reducing mortality. Prompt identification and treatment of the source of infection are the primary therapeutic interventions for septic shock. This can be caused by bacterial, viral, fungal, parasitic, and rickettsial infections. Empiric broad-spectrum parenteral antimicrobial therapy should be initiated ideally within an hour of the recognition of septic shock. In children with sepsis without shock, the 2020 Surviving Sepsis Campaign Guidelines recommend starting antimicrobial therapy after appropriate evaluation and within the first three hours of recognition. Those recommendations are predominantly based on two studies, which I have listed for you here on the slide. The first was a study of 130 children with sepsis that have an overall mortality of about 12%. Now, of the 130 children, 103, so just under 80% of them, had septic shock. When antimicrobials were given within 60 minutes of sepsis recognition, there was a reduction in mortality with an odds ratio being 0.6 and the 95% confidence interval listed for you there. The second study that supported the recommendations of having antimicrobial therapies within a specific timeframe for children without shock results from a study of 189 children, of which 112 had severe sepsis and 77 had septic shock. Delayed antimicrobial administration being delayed beyond three hours was associated with a 3.85 times higher mortality rate, and the 95% confidence interval is listed for you there. Institutional implementation of evidence-based resuscitation protocols, screening tools, and sepsis bundles of care have been shown to improve early identification of septic children, adherence to best practices, decreased time to therapy, as well as improving outcomes in pediatric septic shock. These bundles of care usually consist of protocol-driven care to assist in sepsis recognition and subsequently prompt initiation of treatment. These bundles are associated with improved outcomes that extend beyond reductions in mortality, and various studies have demonstrated reduced hospital length of stay as well as reductions in acute kidney injury. I've listed for you here on the slide three different studies that support the recommendations of bundles of care. The first was a study of a little over 1,000 children, which included 69% with septic shock across 54 hospitals in New York State. And the sepsis bundle that was deployed within one hour of recognition was shown to decrease mortality with an odds ratio of 0.59, and the 95% confidence interval listed for you there with a statistically significant p-value of 0.02. The second study that supports this recommendation was a study of about 1,380 children with septic shock receiving bundle-compliant care that demonstrated that these children had a fivefold decrease in mortality with an odds ratio of 0.2, and the 95% confidence interval listed for you there. Lastly, the third study was a little bit smaller study of 189 children with sepsis-induced organ dysfunction, where a sepsis protocol was implemented that demonstrated a reduction in the number of children without organ dysfunction on day two as a result of that sepsis protocol with an odds ratio of 4.2, and the 95% confidence interval listed for you there. Next, we will discuss our third objective, which is to describe the differences in the treatment approach to pediatric shock versus shock in an adult patient. Neonatal septic shock is often complicated by lack of the physiologic transition from fetal to neonatal circulation. In utero, about 85% of fetal circulation will bypass the lungs through what's called the patent ductus arteriosus and foramen ovale into the aorta. Prenatally, this flow pattern is maintained by supersystemic pulmonary artery pressures, but at birth, inhalation of oxygen triggers a cascade of biochemical events, leading to a reduction of pulmonary artery pressure. The closure of the patent ductus arteriosus, or PDA, and foramen ovale results in blood flow being directed to the pulmonary circulation, thereby completing the transition from fetal to neonatal circulation. Sepsis-induced acidosis and hypoxia increase pulmonary vascular resistance and pulmonary artery pressures, leading to PDA, or patent ductus arteriosus, persistent pulmonary hypertension, or PPHN, and persistent fetal circulation, or PFC, in the newborn. Another developmental difference in shock as it relates to neonates versus adults has to do with neonatal septic shock with persistent pulmonary hypertension, or PPHN, which is associated with increased right ventricular afterload, cardiac failure, tricuspid regurgitation, as well as hepatomegaly. Due to supersystemic pulmonary artery pressures, therapies that are directed at reduction of pulmonary artery pressure are likely to benefit the critically ill neonate. Examples of some of these therapies that are potentially lifesaving in the newborn and infants include inhaled nitric oxide, PDE3 or phosphodiesterase 3 inhibitors, such as milrinone, sodenafil, and tadalafil, prostaglandins, such as epiprostanil, treprostanil, iloprost, or alprostadil, and endothelial receptor antagonists, such as bosentin or ambrosentin. In contrast, adult septic shock has been associated with increased production of nitric oxide, leading to hypotension and development of multiple organ failure. This table highlights the four main developmental differences seen in neonates, infants, and children that can lead to shock. So starting on the left-hand side of the table, you will see sepsis in red, and as you come down to the green box, the resuscitation parameters for neonates, infants, and children have listed for you there, whether you're using a mean arterial pressure or MAP, SCV02, as well as cardiac index measurements, they're going to be the same regardless of what the ultimate cause of shock is. Now, as you progress down the table from the green, and let's say on the very left-hand side you're following the red down, if you have a patient that has sepsis, you're going to follow that red arrow down to the bottom, and AMs being antimicrobials and respiratory support are going to be the therapy that we would look to initiate because the cause was sepsis. Now, as you move over to the blue box and arrows, PPHN or persistent pulmonary hypertension in the newborn, similar resuscitation goals if the shock is a result of PPHN, but there the intervention that we would most likely institute would be pulmonary vasodilators. Similarly, moving over to the orange box and orange arrows, CHD or congenital heart disease and or heart failure in neonates, infants, or children would have also similar resuscitation goals based on MAP, SCV02, and cardiac index. The primary therapy there that we initiate most commonly in our neonatal population would be alprosadil to open the PDA to make sure that we actually have some blood flow going down to the lower portion of the body. And then lastly, the very right-hand column, we have the purple boxes and arrows where we have a result of hypovolemia or metabolic causes, again, similar resuscitation goals which you see in the box in green, but then the intervention most commonly that would be utilized there would be fluids and or blood therapy. The presentation of septic shock is different in adults as compared to children. Approximately 90% of the adult patients present with a hyperdynamic shock syndrome or what we would classically usually refer to as warm shock. This hemodynamic response typically includes a low systemic vascular resistance or low SVR, hypotension, normal or increased cardiac output, tachycardia, and an elevated oxygen concentration in pulmonary artery blood. Now despite the hyperdynamic state, these patients typically exhibit myocardial depression, which is characterized by decreased ejection fraction, ventricular dilatation, as well as a flattening of the Frank-Starling curve after fluid resuscitation. Tachycardia and a reduction in SVR are the primary compensatory mechanism for the resulting decreased cardiac output. In comparison, the hemodynamic response to sepsis is remarkably different in neonates and older children. Typically severe hypovolemia is the hallmark of pediatric septic shock, therefore children typically frequently respond very well to aggressive volume resuscitation. Approximately 50% of children with septic shock present with cold clamped down extremities, low cardiac output, and an elevated SVR, systemic vascular resistance, which was often typically referred to as the old cold shock. Now children have a limited cardiac reserve compared to adults. Now for example, if an adult has a resting heart rate of approximately 70, that adult could have a twofold increase in their heart rate from 70 to 140 beats per minute, and that can easily be tolerated and used to maintain cardiac output when stroke volume is possibly decreased or diminished. Now this similar mechanism is not exactly possible in babies and small infants because if they have a resting heart rate of 140 beats per minute, that 140 cannot be doubled to 280 beats per minute because this would not allow enough time for diastolic filling. Therefore the predominant response to decreased cardiac output in children is vasoconstriction. Now this elevated SVR makes hypotension a late sign of shock in children. This is typically more common in children less than one year of age, and as a general metric, it's about 10 times greater in infancy compared with childhood and adolescence. In children less than one year of age, the primary site of infection is going to be bacteremia, and as you can see the graph on the right-hand side of the slide, if you have those children less than one and you're just looking at number and percent of patients that develop sepsis, you have a much higher percentage in those children that are less than one year of age. And then in the first year of age, second year of age, as your age increases, the number of patients presenting or percent of those patients with that age with sepsis is obviously going to be decreasing as you go down, and then leveling off somewhere in the 7, 8, 9, 10, and then maybe having some individual spikes maybe a couple years in adolescence around 15, 17, 19, but relatively leveling off significantly decrease in comparison to those children less than one year of age. Now comorbid conditions can often play a significant role in the development of shock and ultimately sepsis. This study was conducted in Japan and it looked at the incident of patients presenting from the community that developed community-onset septic shock and subsequently presented to their hospital for care. There was a total of 761 patients. The median age was three years with an interquartile range of zero to 11 years. And when they looked at the underlying conditions that these patients that presented with shock and subsequently septic shock had, 57% of these patients had some underlying condition, at least one. And the types of underlying conditions that they had, you can then see subsequently further divided below that. So things such as care dependence, neuromuscular, cardiovascular, hematological, malignancy or transplant, congenital genetic, as well as respiratory. And of these patients, considering they had a high rate of comorbid conditions, about 57%, Of the 761 patients, there were 244 deaths, so the mortality rate here in these patients with comorbid conditions was 32 percent as a result of having a comorbid condition, and 77 of the deaths, so 31 percent of the total 244 deaths occurred on day one, and then the remainder occurred within three days of hospitalization. Since inadequate circulating volume is one of the main causes of shock in children, this slide will hopefully highlight some of the body fluid distribution concerns as it relates to pediatric patients. So as we know, total body water, TBW, decreases with increasing age as a percentage of body weight, so very commonly you'll hear people refer to babies as little bags of water, so when we look at things such as drugs that we try and deliver to babies, the total milligram per kilo dose that we would deliver to them as compared to their adult counterparts for drugs that are mostly hydrophilic would be a much larger milligram per kilo dose as compared to their older adult counterparts. So similarly, fluid losses are typically greater per kilogram of weight in children. If we take, for example, a six-month-old child who is seven kilograms, and that patient has 10 percent dehydration, they have a 700 ml volume deficit, whereas if we have a 50-year-old patient who weighs 70 kilos and we give them a similar 10 percent dehydration status, then that patient's equivalent loss of fluids would be 7,000 ml. Similarly, as it relates to ECF or extracellular fluid compartment, it's broken up between plasma volume, which is approximately 5 percent, and interstitial volume, which is about 15 percent. Now the ECF compartment will decrease rapidly in the first year of life, and commonly you will have a higher ECF to ICF ratio in children in the first year of life, and this predisposes pediatric patients to rapid fluid loss and ultimately hypovolemic shock. While decreased intravascular volume is the most frequent cause of shock in children, abnormalities in basal regulation and myocardial dysfunction usually play a larger role in neonates and young infants. There are significant differences in both myocardial structure and function that compromise the compensatory response to sepsis. For example, important changes in excitation-contraction coupling occur due to the immaturity of the calcium regulation system in neonates and small infants. These developmental differences can affect alterations in the normal mechanisms leading to the calcium-calmodulin complexes that trigger excitation-contraction coupling, such that the neonatal myocardium is more dependent upon extracellular calcium versus intracellular calcium for contractility compared to an older child, adolescent, or an adult. Now these developmental differences further explain the extreme sensitivity of neonates to calcium channel antagonists as well. Left ventricular systolic performance in neonates and young infants is critically dependent upon afterload. An abrupt increase in afterload in the setting of shock and vasoconstriction can result in markedly reduced left ventricular systolic performance and myocardial dysfunction. The neonatal myocardium has a relatively decreased left ventricular mass in comparison to the adult myocardium, as well as an increased ratio of type 1 collagen to type 3 collagen. Of note, the remodeling that occurs following an acute myocardial infarction leads to a similar increase of ratio of type 1 to type 3 collagen, which may explain in part the decrease in myocardial function that occurs in adults following an acute MI. Similar changes are observed in the myocardium of patients with dilated cardiomyopathy. Additionally, the neonatal myocardium functions at a relatively high contractile state, even at baseline. Collectively, these developmental changes result in a relatively limited capacity to increase stroke volume during stress, and neonates and young infants are critically dependent upon an increase in heart rate to generate increased cardiac output during stress. As it relates to respiratory function, children are typically predisposed to acute respiratory failure, and there are several key developmental differences that predispose them to this. In Vincent, young children have fewer alveoli compared to adults. There's approximately 20 million alveoli after birth compared to the 300 million alveoli by the age of eight years. Similarly, the size of each of the individual alveolus is smaller in children, somewhere in the range of 150 to 180 micrometers diameter versus 250 to 300 micrometer diameter. Together, these two anatomic differences markedly decrease the surface area which is available for gas exchange, and respiratory failure is a major cause of morbidity, mortality, and critically ill children with sepsis. Developmental differences contribute to the prevalence and impact of the management of acute respiratory failure in the pediatric age group, as the airways enlarge both in length and diameter However, growth of the distal airways lag behind that of proximal airways during the first five years of life, which can account for the increased peripheral versus central airway resistance in children relative to adults. The developmental differences on respiratory mechanics are also critically important. For example, the ribs are more horizontally aligned in young infants and children compared to adults, which makes it difficult to generate a greater negative intrathoracic pressure in the presence of poor lung compliance. Similarly, the elastic recoil pressure of the alveoli is reduced in children, which increases the risk of alveolar collapse in the presence of altered lung compliance. Similarly, the infant's chest wall is soft and compliant, providing little opposition to the natural recoil of the lungs. This can lead to a lower functional residual capacity in pediatric patients than in adults, which in young infants may even approach the critical closing volume of the alveolus. Additionally, ventilation perfusion mismatching is one of the most common causes of hypoxemia in pediatric patients with sepsis. In an effort to highlight some of these size differences between the airways of infants and adults, hopefully this slide will put some of that into perspective. So if you look at the left-hand side of the table, you can look at the size of an airway in terms of diameter and radius of a normal airway in an infant that is approximately four millimeters. Now below that, you have the diameter of an adult airway, which is approximately eight millimeters. Now moving over one column in the setting of edema, these patients that are infants, if the edema is significant enough to take the airway size from four millimeters down to two millimeters, now you have a 50% change in diameter of that airway for that infant. Similarly, a similar two millimeter decrease in the airway from an adult from eight millimeters to six millimeters, that is only a decrease of about 25% if you have that same two millimeter decrease. Now when you look at the very far right-hand column of the table and you look at what that results in terms of a change in resistance, that two millimeter decrease or 50% change in diameter for that pediatric infant airway causes an increase of resistance of 16-fold. Similarly, that same two millimeter decrease from eight to six millimeters in an adult airway has a 25% reduction in diameter, but the change in resistance is only three-fold as compared to 16-fold in that infant. There's also a significant difference as it relates to the coagulation cascade in children versus adults. Children less than one year of age typically have an increased rate of bleeding complications, and this can be as a result of lower circulating levels of vitamin K dependent clotting factors, as well as a lower intrinsic capacity to produce thrombin, and also decreased circulating levels of coagulation inhibitors. Now the table listed for you here was based on a study that looked at the influence of age on mortality and severity of clotting abnormalities in 79 children who had a mean age of 3.1 years with meningococcal sepsis. The parameters of coagulation and fibrinolysis and plasma levels of cytokines were prospectively measured on admission. Overall, in this cohort, the mortality rate was 27%. Now the age of survivors was significantly different from that of non-survivors with a statistically significant p-value. With the exception of factor VIII, von Willebrand's factor in tPA, the parameters of coagulation and fibrinolysis, as well as plasma cytokine levels, were all related to the outcome. Patients were then subsequently divided into two groups, those patients being less than or equal to three years of age, and those children being greater than three years of age. In contrast to cytokine levels, which were not different between the two age groups, factors of fibrinogen, prothrombin, factors V, VII, VIII, von Willebrand factor, protein C, antithrombin, FTP, and the ratio of pA1 to 1 slash tPA were related to age, which indicates a more severe coagulopathy in children that were three years of age or younger. Now a relative deficiency of coagulation factors due to an immature state of the clotting system, as well as an inadequate fibrinolytic response, both related to age may have caused this more severe coagulation response in younger children, and may have contributed to the higher mortality rate. There are also differences as it relates to the immune system response in the setting of shock in children as compared to their adult counterparts. There appears to be a greater compensatory anti-inflammatory response in children compared with adults, suggests that there are higher circulating levels of tumor necrosis factor alpha in children, higher circulating levels of interleukin-6 in children as well, as well as greater interleukin-10 production, and IL-10 production has been linked to a measure of anti-inflammatory response. So this has some different graphs for you here on this slide, and these were studies that were conducted with LPS or lipopolysaccharide, and LPS induced a 50-fold increase in interleukin-10 anti-inflammatory cytokine production in pediatric versus adult peritoneal macrophages. So in the very bottom left table, you can see there was an adult control, a pediatric control, adult simulated shock state, and a pediatric simulated shock state. And when you look at the amount of tumor necrosis factor alpha here on the y-axis, and you compare the pediatric simulated to adult and the pediatric to the control, pediatric and adult controls, a significantly increased amount of tumor necrosis factor alpha that was produced in the setting of pediatric shock compared to adult. Now if you look at the middle table here, similarly looking now specifically at IL-10 on the y-axis, again the four same groups, adult control, pediatric control, adult simulated, and pediatric simulated, the amount of IL-10 that was produced in the pediatric simulated shock as compared to the adult simulated and the other two control groups, a much higher proportion of IL-10 that was produced. Similarly, if we now look at the very far right-hand table, and we are now looking at the relative ratio of IL-10 to TNF, which gives us an idea of how robust an immune response is, again the pediatric immune response appears to be much significantly greater and higher than the adult immune response and the setting of a simulated shock state. Lastly, we will discuss the fourth objective of this presentation, which is to determine the optimal dosing strategy for fluids and vasopressors in pediatric shock. Fluid therapy was one area that was addressed in the 2020 Surviving Sepsis Campaign Guidelines for Pediatrics. I have some of the recommendations from that section of the 2020 SCCM Surviving Sepsis Campaign Guidelines for Children listed here. So the first bullet relates to whether a pediatric intensive care unit is available upon transfer or available at the presenting institution. So the first recommendation is if a PICU is available, administer up to 40 to 60 mLs per kilo in bolus fluids during the first hour and monitor for signs of fluid overload, SR being a strong recommendation. Second recommendation is if a PICU is unavailable, administer fluids only in the presence of hypotension up to 40 mLs per kilo in bolus fluids during the first hour and discontinue of signs of fluid overload with a WR, meaning a weak recommendation. Third bullet is if a PICU is unavailable and in the absence of hypotension, no fluid boluses are recommended, meaning just maintenance fluids should be initiated. The fourth bullet says to use balanced or buffered crystalloids rather than albumin or normal saline for the initial resuscitation, that being a weak recommendation. And lastly, to avoid starches, specifically hydroxyethyl starch or gelatin in acute resuscitation, and that bore a strong recommendation. So depending on the setting of where children with shock present, whether they are high-income countries or low-middle-income countries, since the Surviving Sepsis Campaign Guidelines was attempting to provide recommendations for children throughout the world, that is where the recommendations try and decipher whether you have advanced supportive care available or you do not. So for right now at this time, we will talk about fluid therapy when advanced supportive care is available. The recommendations were predominantly based on three randomized controlled trials that were published with different volume resuscitation strategies, of which they included a total of 316 children, and they found that there was no difference in mortality between a restrictive and a liberal resuscitation group. In the setting of not having advanced supportive care available, the recommendations were predominantly based on one randomized controlled trial that was published with different volume resuscitation strategies being evaluated. This was from a low-resource setting in Africa that evaluated children between 60 days and 12 years of age. They evaluated about 3,100 patients that presented with malaria and anemia, predominantly due to the nature of the area in Africa that the study took place. Patients were given 20 mLs per kilo of normal saline or 5% albumin versus no bolus and just maintenance IV fluids. And when mortality was evaluated at 48 hours in the restrictive fluid group, there was a reduction with a relative risk of 0.72 and the 95% confidence interval listed for you there. Fluid therapy for children as it relates to how much to give. For pediatric patients, fluid boluses are typically given in aliquots of 10 to 20 mLs per kilo. Recommendations when the setting of an intensive care unit or advanced supportive care is available, 60 mLs per kilo is recommended to be given within the first hour of shock or specifically septic shock. Now in the setting where advanced supportive care is not available or in limited resource areas, 40 mLs per kilo is the limit for patients with hypotension. And this is a result of not having availability of an ICU for airway management or circulatory support. To discuss which type of fluids to use for shock, the use of balance or buffer crystalloids in preference to albumin or 9.9% saline or normal saline is recommended for the initial resuscitation, which is a weak recommendation from the surviving sepsis campaign guidelines. Now balance crystalloids, the thought behind using them has to do with the fact that it has a composition closer to plasma with a reduced chloride content. There are things such as MES or multiple electrolyte solutions, which is a type of a balance crystalloid. One of the ones available, at least in the United States, is a solution called Plasma Light A. Additionally, lactated ringers is also considered a balance crystalloid. Now typically the balance crystalloids or buffer crystalloids are recommended to be used for initial fluid boluses and not for maintenance IV fluids. Data to support the use of balance crystalloids for fluid resuscitation include the following study, which had a primary outcome of new endor progressive acute kidney injury within the first seven days after a fluid resuscitation. Secondary outcomes included hyperchloremia, any adverse event at 24, 48, and 72 hours, as well as ICU mortality. This study randomized 351 children to MES or multiple electrolyte solutions and 357 children to normal saline. The median age of the children included in the study was five years and 43% of the children were female. The AKI or acute kidney injury rate was found to be 21% with MES or multiple electrolyte solutions and compared to a rate of acute kidney injury of 33% with normal saline and the p-value was statistically significant. As it relates to any of the other secondary outcomes or variables that were looked at, there was no difference in any other secondary outcome or adverse event, but the rate of AKI was significantly reduced when multiple electrolyte solutions were used in comparison to normal saline. To determine when vasoactives can be used in the setting of shock for pediatric patients, we first have to have an understanding or an appreciation of what fluid refractory shock is. So fluid refractory shock is shock despite administration of 40 to 60 mls per kilo of appropriate fluid resuscitation. Vasoactives can be given via peripheral or IO access until central access can be established. Dopamine use historically had been considered first-line therapy vasoactive. In more recent times, its use has been associated with increased adverse events and has no longer been considered first-line therapy for the use in the setting of shock or sepsis. Now the concept of what used to be considered warm and cold shock for pediatric patients, those terms have been shown to be outdated as they have a poor correlation between clinical assessment, cardiac index, and systemic vascular resistance. With dopamine being associated with more adverse events and its use decreasing, epinephrine and norepinephrine have become the two primary agents for use in the setting of shock. Now regardless of which agent we're using, when we think about goals of therapy when using the vasoactive, typically we would shoot for a MAP or a mean arterial pressure somewhere between the 5th and the 50th percentile for age. Additionally, we would and can titrate our vasoactives for adequate urine output as well as adequate peripheral perfusion. Now when attempting to decide whether we're going to use epinephrine versus norepinephrine, epinephrine typically will be used in the setting of myocardial dysfunction with low cardiac output. Epinephrine is initiated usually at a dose of 0.05 to 0.1 micrograms per kilogram per minute. When looking to use norepinephrine as first-line therapy, typically done in a setting where a patient has more of a vasodilatory presentation with a decreased systemic vascular resistance, and the initiation dosing for norepinephrine is similar to epinephrine. It is initiated typically at a range of 0.05 to 0.1 micrograms per kilogram per minute. Vasopressin is also a vasoactive that can be utilized in the setting of pediatric shock. Now vasopressin is typically not recommended until patients progress to a scenario of what is considered or termed catecholamine-resistant shock, and this is still shock despite the adequate use of catecholamines or despite an appropriately dosed catecholamine. So what is catecholamine-resistant shock? So patients that already still have shock despite appropriate fluid resuscitation up to 60 mLs per kilo and have received an adequate trial of epinephrine in the dose range of 0.5 to 0.75 mgs per kilo per minute or an adequate trial of norepinephrine in a dose range of 0.5 to 0.75 mgs per kilo per minute. Despite those two things, that patients still have low cardiac output, that vasopressin can then be initiated in trial to see if there's any additional benefit in adding vasopressin. Vasopressin is typically initiated a dose of somewhere in the range of 0.5 to 2 milliunits per kilogram per minute. Similar to vasopressin, milrinone is another agent that can be used in the setting of catecholamine-resistant shock. So again, shock despite the use of adequate cholamine dose, meaning patient has had an adequate trial of fluid resuscitation up to 60 mLs per kilo, and they've had an adequate trial of epinephrine or norepinephrine somewhere in the range of 0.5 to 0.75 mgs per kilogram per minute. So milrinone is typically used in the setting of when patients still at that point have low cardiac output because milrinone can have a dual mechanism of action. So it can increase the contractility of the heart and increase cardiac output with that increased contractility, and it can also cause a vasodilation to decrease afterload. So kind of getting a dual mechanism there in patients that have catecholamine-resistant shock and still showing signs of low cardiac output. Milrinone is typically initiated at a dose of 0.25 to 0.5 mgs per kilogram per minute. Hopefully during this presentation you have come to appreciate that children are not little adults. There are drastic differences in shock between children and adults, and there are more differences than there are similarities. As such, treatment approaches are also different and need to be individualized based on the mechanism of shock in the pediatric patient and the patient presentation. And with that, I say thank you for listening to this advanced pharmacotherapy lecture, and I appreciate your time and willingness to learn about pediatric shock.

pediatric shock

pathophysiology

treatment approaches

dosing strategies

fluids

vasopressors

age-related developmental factors

tailored treatment strategies