Septic shock: Ongoing management after resuscitation in children

19-05-2013

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Septic shock: Ongoing management after resuscitation in children Authors Scott L Weiss, MD Wendy J Pomerantz, MD, MS Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2013. | This topic last updated: Feb 15, 2013. Section Editors Susan B Torrey, MD Adrienne G Randolph, MD, MSc Sheldon L Kaplan, MD Deputy Editor James F Wiley, II, MD, MPH

INTRODUCTION Sepsis is a clinical syndrome complicating severe infection that is characterized by systemic inflammation, immune dysregulation, microcirculatory derangements, and end-organ dysfunction. There is a continuity of severity ranging from sepsis to severe sepsis and septic shock. Severe sepsis and septic shock are characterized by dysfunction of 2 organ systems and cardiovascular dysfunction, respectively [1]. With increased attention to rapid recognition, aggressive fluid administration, and early administration of vasoactive agents and antibiotics, pediatric mortality from severe sepsis and septic shock has decreased markedly [2-7]. The management of severe sepsis and septic shock in children after the first hour of resuscitation is reviewed here. The rapid recognition and initial resuscitation of pediatric septic shock and the definitions, epidemiology, and clinical manifestations of sepsis in children are discussed separately. (See "Septic shock: Rapid recognition and initial resuscitation in children" and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".) RESUSCITATION The key interventions in the initial resuscitation of children from septic shock are discussed in detail separately. (See "Septic shock: Rapid recognition and initial resuscitation in children".) OVERVIEW Repeated, frequent assessment of the patient in septic shock is essential. In children who have responded to therapy with resolution of hypotension, ongoing monitoring, antimicrobial therapy, and optimal respiratory support are essential. In patients with fluid-refractory hypotension, ongoing aggressive resuscitation should continue after the initial resuscitation of pediatric septic shock according to the principles of goal-directed therapy, (algorithm 1). (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Physiologic indicators and target goals'.) Whenever possible, children requiring resuscitation for septic shock should receive ongoing management by a pediatric critical care specialist or pediatrician with similar expertise in a pediatric intensive care unit. Priorities for continued management of children with septic shock include: Control the infection by identifying the optimal choice of antimicrobial therapy based upon culture results and by ensuring that the source of infection is controlled Ongoing monitoring of respiratory status and provision of optimal respiratory support Ongoing monitoring of tissue perfusion and blood pressure Correction of electrolyte and metabolic derangements (eg, hypoglycemia, hypocalcemia) In the subpopulation of children with fluid-refractory septic shock requiring continued vasopressor support, additional priorities include: Placement of invasive monitoring devices (eg, central venous catheter, arterial line, bladder catheter) to accurately assess blood pressure and to deliver vasopressor infusions safely Continued fluid resuscitation and vasopressor delivery targeted to principles of goal-directed therapy Administration of blood products, when needed, to treat anemia and coagulopathy Treatment of adrenal insufficiency and evaluation of other potential underlying causes (eg, hypothyroidism) Provision of advanced therapies in patients who do not respond to conventional therapy If physiologic goals have been achieved, indicating that perfusion is improved, the patient should continue to receive supportive treatment and careful monitoring. The goals of treatment include achieving a normal blood pressure, improved mental status and good perfusion for the patient who is hypotensive. For children with compensated shock and normal blood pressures, therapeutic endpoints based upon noninvasive indicators are reasonable targets, but may be unreliable. (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Physiologic indicators and target goals'.) Eradicate infection Prompt identification and treatment of the source of infection are essential to successful management of septic shock and constitute critical interventions that can reverse septic shock. In contrast, other therapies (eg, fluid administration, vasoactive drug infusion, or mechanical ventilation) are purely supportive in nature [8-10]. A careful history and physical examination may yield clues to the source of sepsis and help guide subsequent microbiologic evaluation (table 1). Gram stain of suspicious fluids may give early clues to the etiology of infection while cultures are incubating. In addition to cultures of specific sites, blood should be drawn and inoculated into standard blood culture media. Blood cultures should be incubated both aerobically and anaerobically. (See "Blood cultures for the detection of bacteremia".) Eradication of the inciting infection is essential for the successful treatment of septic shock. This includes prompt administration of antimicrobial therapy and source control. Initial antimicrobial therapy should provide broad spectrum coverage tailored to host factors, such as age and underlying medical conditions, and be administered as soon as possible after presentation. (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Initial
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antimicrobial therapy'.) Source control (physical measures undertaken to eradicate a focus of infection, to eliminate ongoing microbial contamination, and to render a site inhospitable to microbial growth and invasion) should be undertaken when possible because localized foci of infection (ie, abscess) may not respond to antibiotics alone (table 1). As examples, potentially infected foreign bodies should be removed and abscesses, infected fluid collections, or tissues should be percutaneously or surgically drained and dbrided. (See "Necrotizing soft tissue infections", section on 'Treatment'.) Continue respiratory support Oxygenation should be monitored using continuous pulse oximetry (SpO2). Patients should continue to receive supplemental oxygen to maintain oxygen saturation at 100 percent (patients with continued shock) or 97 percent (patients with restored perfusion and blood pressure). In patients with continued shock, endotracheal intubation should be performed if not already accomplished. Mechanical ventilation should be performed with the following goals in mind [11,12]: Keep plateau pressure 30 cmH2O Keep tidal volume under 10 mL/kg ideal body weight. Tidal volume may need to be decreased as low as 4 to 6 ml/kg in patients with very low lung compliance using lung protective ventilation strategies to achieve a plateau pressure 30 cmH2O [13,14] Maintain arterial pH between 7.30 and 7.45 Titrate fraction of inspired oxygen (FiO2) and positive end-expiratory pressure to maintain arterial oxygen concentration (PaO2) between 60 and 80 mmHg (8 to 10.7 kPa) or pulse oximetry 90 to 97 percent in patients with hypoxia who require FiO2 50 percent Maintain hemoglobin 10 g/dL (see 'Blood transfusion' below) Ongoing and invasive monitoring During initial management, monitoring of tissue perfusion using physiologic indicators and target goals continues. (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Physiologic indicators and target goals'.) In addition, the clinician should determine the need for invasive monitoring via intraarterial and central venous cannulas: Intraarterial cannula placement Although noninvasive blood pressure measurement is acceptable in patients who have markedly improved or had total reversal of septic shock, automated blood pressures overestimate systolic blood pressure relative to intraarterial or Doppler ultrasound measurements in hypotensive children and underestimate systolic blood pressure among hypertension patients [15]. Thus, insertion of an intraarterial catheter is suggested if blood pressure is labile or if restoration of arterial perfusion pressures is expected to be a protracted process. However, efforts to obtain intraarterial access should not interfere with the resuscitation of septic shock. Procedures for obtaining intraarterial access in children are discussed separately. (See "Arterial puncture and cannulation in children", section on 'Arterial cannulation'.) Central venous access Central venous access is indicated in patients who require infusion of vasoactive drugs to maintain adequate tissue perfusion, and in patients with catecholamine-resistant septic shock who warrant monitoring of central venous pressures (CVP) and central venous oxygen saturation (ScvO2). In the absence of an elevated intraabdominal pressure, the correlation between femoral vein pressure and CVP is good, though absolute values may differ slightly [16,17]. Changes in central venous oxygen saturation (ScvO2), which provides reliable information regarding tissue oxygenation should also be frequently monitored [18]. If direct measure of ScvO2 is not available, limited evidence suggests that a capillary refill time 2 seconds is associated with a ScvO2 70 percent. However, capillary refill time can be brisk despite significant hemodynamic derangement in children with septic shock. (See "Initial management of shock in children", section on 'Physiologic indicators and target goals'.) Continue fluid administration The need for aggressive administration of fluids to optimize tissue perfusion and to achieve physiologic goals typically continues beyond the first hour of care in children with septic shock. In patients with persistent poor perfusion or hypotension, boluses of fluids should continue until the central venous pressure is 8 to 12 cmH2O (12 to15 cmH2O in mechanically ventilated patients) or evidence of cardiac insufficiency (eg, pulmonary edema, enlarged heart) occurs. The volume per bolus and types of fluid are as for the resuscitation period (algorithm 1). Fluid input and output should be carefully monitored on an hourly basis. (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Intravenous fluid therapy'.) Fluid overload Interstitial edema is common in sepsis due to increased vascular permeability. In patients with clinical findings of significant fluid overload (eg, pitting edema, anasarca, or pulmonary edema), early initiation of diuretic therapy (eg, furosemide) may be appropriate in patients with hypoxia and pulmonary edema after a period of 12 to 24 hours of sustained hemodynamic stability off vasoactive infusions. Patients in whom urine output remains insufficient may warrant renal replacement therapy (eg, continuous veno-venous hemofiltration or intermittent hemodialysis). Observational studies in critically ill children, including children with sepsis who received renal replacement therapies, indicate that more than 10 percent fluid overload is associated with mortality [19,20]. However, the evidence is not sufficient to determine whether or not fluid overload has an independent deleterious effect on survival. Nonsurvivors may have had more severe septic shock and therefore, required greater amount of fluid and were more likely to develop renal insufficiency. Blood transfusion Hemoglobin is the primary determinant of blood oxygen carrying capacity and, therefore, of tissue oxygen delivery. Thus, maintaining adequate hemoglobin levels is a critical aspect of managing children with septic shock. We suggest a hemoglobin goal of 10 g/dL (equivalent to 30 percent hematocrit) as a target to maintain with blood transfusion during resuscitation and ongoing management of children with septic shock (algorithm 1) [12]. The safety of tolerating a lower hemoglobin in unstable patients with vasopressor-dependent hypotension from sepsis has not been studied. Once shock has resolved, a lower hematocrit threshold for blood transfusion is likely to be safe. As an example, in a multicenter unblinded trial of 137 stabilized children with sepsis (mean systemic arterial pressure was not below two standard deviations of normal for age and cardiovascular support was not increased for at least two hours before enrollment) that compared restrictive transfusion (transfusion for hemoglobin <7.0 g/dL) with liberal transfusion (transfusion for hemoglobin <9.5 g/dL), no clinically significant differences were found for the occurrence of new or progressive multiple organ dysfunction syndrome (18.8 versus 19.1 percent), PICU length of stay (13 days in both groups), or PICU mortality (7 versus 3 percent, respectively) [21]. However, two additional patients died in the restrictive transfusion group after discharge from the pediatric intensive care unit. Given that a restrictive approach to transfusion in patients with sepsis does not appear inferior to more liberal management in stable patients recovering from septic shock, we typically use a hemoglobin of 7 g/dL as the threshold for blood transfusion in stable patients recovering from septic shock instead of 10 g/dL which we suggest for patients with ongoing hemodynamic instability. Treat disseminated intravascular coagulation Patients with septic shock frequently have disseminated intravascular coagulopathy that may warrant treatment. Thus, baseline measures of clotting status should be routinely obtained in children with septic shock. (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Suggestive laboratory findings'.)

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There have been no trials to study the efficacy of platelet, fresh frozen plasma (FFP), or cryoprecipitate transfusions in children with sepsis and DIC. Nevertheless, the use of these agents seems rational in patients with significant bleeding (melena, or prolonged bleeding from venipuncture sites) due to thrombocytopenia and clotting factor consumption or significant risk of bleeding (eg, pre- or postoperative patients). (See "Disseminated intravascular coagulation in infants and children", section on 'Replacement therapy'.) The goal of replacement therapy is to reduce or stop significant bleeding. Although replacement therapy should not be used to normalize laboratory tests (which often is impossible), a reasonable guide for the judicious use of blood components in the setting of significant bleeding includes maintaining platelet counts >50,000 per mm and fibrinogen concentration >100 mg/dL (1 mol/L). (See "Disseminated intravascular coagulation in infants and children", section on 'Replacement therapy'.). Clotting factors can be replaced by either FFP or cryoprecipitate. FFP provides both procoagulant and anticoagulant proteins and is administered every 12 to 24 hours at a dose of 10 to 15 mL/kg per infusion. Cryoprecipitate has higher concentrations of factor VIII and fibrinogen, and can be used to correct hypofibrinogenemia. It is administered every six hours as needed at a dose of 10 mL/kg per infusion. Platelet transfusions are administered with a goal of maintaining the platelet counts >50,000 per mm. (See "Disseminated intravascular coagulation in infants and children", section on 'Replacement therapy'.) Although initial observational studies indicated that children with sepsis frequently have low circulating levels of activated protein C, administration of recombinant human activated protein C (drotrecogin alfa) has shown no benefit and may be harmful. As an example, in a multicenter randomized trial comparing drotrecogin alpha with placebo for the treatment of children with severe sepsis, interim analysis demonstrated no benefit for treatment with drotrecogin alpha and an increased incidence of central nervous system bleeding, particularly in those younger than 60 days [22]. As a result, this trial was discontinued. A systematic review that included this trial concluded that recombinant human activated protein C should not be used for any children or for adults who are not severely ill [23]. In October 2011, drotrecogin alpha was voluntarily removed from the worldwide market by Eli Lilly due to a negative second trial in adults with severe septic shock. Observational and dose finding studies of protein C concentrate in selected children with severe meningococcal septic shock, and purpura fulminans have shown potential promise. Protein C concentrate is not biologically active on administration (requires conversion to activated protein C by thrombin or thrombin bound to endothelial thrombomodulin) and is used mainly in patients with severe congenital protein C deficiency. (See "Treatment and prevention of meningococcal infection", section on 'Protein C concentrate' and "Protein C deficiency".) Manage glucose abnormalities Hypoglycemia remains a concern during the initial management phase of septic shock. Children have limited glycogen stores and may develop profound hypoglycemia during periods of stress. Thus, blood glucose should be monitored frequently upon admission and at least every six hours while the patient is unstable and corrected (table 2). (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Treat hypoglycemia and hypocalcemia'.) Once tissue perfusion is restored and shock is resolved, children should receive intravenous fluid that contains dextrose sufficient to maintain euglycemia. This therapy typically consists of 5 to 10 percent dextrose in electrolyte solution appropriate to the patients ongoing sodium and potassium requirements. The glucose dose is determined by age: 8 mg/kg per minute (neonates), 4 mg/kg per minute (children), 2 mg/kg per minute (adolescents) [24]. Hyperglycemia is commonly present in children with septic shock. Data regarding exogenous insulin as a means to maintain euglycemia in these patients is as follows: In one small observational study of 57 children with septic shock, children who died had higher peak serum glucose levels than survivors (262 versus 168 mg/dL) [25]. In one small series of 16 children with meningococcal sepsis or septic shock, hyperglycemia reflected hypoinsulinemia rather than insulin resistance in those patients with septic shock [26]. In a trial of 700 critically ill infants and children admitted to a pediatric intensive care unit (PICU) that compared conventional versus intensive control of serum glucose, duration of PICU stay was shortest in the intensive versus conventional treatment group (5.5 versus 6.2 days). However, hypoglycemia (defined as blood glucose 40 mg/dL [2.22 mmol/L]) was more common in children receiving intensive glucose control (25 versus 1 percent, respectively). Nine (3 percent) patients died in the intensively treated group versus 20 (6 percent) in the conventional group (p = 0.038) [27]. At a median of four years of follow-up, children who had been treated with tight glycemic control during their ICU admission did not have a worse measure of intelligence than those who had received usual care [28]. In a trial of 980 children (0 to 36 months of age), undergoing surgery with cardiopulmonary bypass randomized to either tight glycemic control (with the use of an insulin-dosing algorithm) targeting a blood glucose level of 80 to 110 mg/dL (4.44 to 6.12 mmol/L) or standard care in the cardiac intensive care unit, no difference was found in the rate of health care-associated infections (8.6 versus 9.9 per 1000 patient-days) or other secondary outcomes [29]. This study used continuous glucose monitoring to guide the frequency of blood glucose measurement and to detect impending hypoglycemia, with only 3 percent of the patients in the tight glycemic control group exhibiting severe hypoglycemia (blood glucose <40 mg/dl [2.22 mmol/L]). Taken together, the evidence suggests that there are no clear benefits to tight glycemic control in critically ill children. Until further data are available, insulin therapy is warranted to avoid long periods of hyperglycemia >180 mg/dL (9.99 mmol/L) while also avoiding hypoglycemia. We do not advocate tight glycemic control. However, there is no universally accepted insulin regimen, and the optimal approach to hyperglycemia in children with septic shock awaits further study. Glycemic control in adults with critical illness is discussed separately. (See "Glycemic control and intensive insulin therapy in critical illness", section on 'Glycemic control'.) Avoid hypocalcemia Adequate calcium stores are essential for maintaining myocardial contractility. Thus, ionized blood calcium levels should be monitored every one to two hours during initial management of septic shock. Patients with persistent shock and an ionized calcium <1.1 mmol/L (4.8 mg/dL) or those with symptomatic hypocalcemia (eg, positive Chvostek or Trousseau signs, seizures, prolonged QT interval on EKG, or cardiac arrhythmias) in association with a an ionized calcium <1.1 mmol/L (4.8 mg/dL) should undergo correction with calcium gluconate 10 percent solution in a dose of 50 mg/kg (0.5 mL/kg), maximum dose 2 g (20 mL) by slow intravenous or intraosseous infusion over five minutes. This suggested dose is equivalent to elemental calcium 5 mg/kg (0.15 mmol/kg), up to 180 mg elemental (4.5 mmol) per single dose Calcium should be administered in a larger vein or, preferably, a central line. Sodium bicarbonate should not be introduced into the IV or IO without flushing before and after administration because of potential precipitation. Calcium chloride 10 percent in a dose of 10 to 20 mg/kg (0.1 to 0.2 mL/kg), maximum dose 1 g (10 mL) provides an equivalent dose but should only be administered through a central line. Patients receiving a calcium infusion warrant continuous cardiac monitoring. Treat known hormonal deficiencies Patients with septic shock who are receiving replacement therapy for adrenal insufficiency should receive stress
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doses of corticosteroids. (See 'Address adrenal insufficiency' below.) Similarly, children with septic shock and hypothyroidism should continue to receive thyroid replacement with levothyroxine [24]. (See "Treatment and prognosis of congenital hypothyroidism", section on 'Dose of L-T4' and "Acquired hypothyroidism in childhood and adolescence", section on 'T4 dose'.) REFRACTORY SEPTIC SHOCK The initial treatment of septic shock including management recommendations for fluid-refractory septic shock are described in the algorithm and discussed in detail separately (algorithm 1). Fluid-refractory, catecholamine-resistant shock is defined as cardiovascular dysfunction despite at least 60 mL/kg of fluid resuscitation and dopamine 10 mcg/kg/min and/or direct-acting catecholamines (epinephrine, norepinephrine). Principles of management for children with refractory septic shock include treatment of reversible etiologies, stress dose corticosteroid therapy for patients with absolute adrenal insufficiency, and combination vasoactive drug therapy targeted to maintaining central venous oxygen saturation 70 percent and normalizing blood lactate levels. Although cardiac index targets are mentioned in previous pediatric septic shock guidelines [24], evidence of improved outcomes from routine measurement of cardiac index is lacking (algorithm 1). If performed, the target range is 3.3 to 6.0 L/min/m2. Treat reversible etiologies Pneumothorax, pericardial tamponade, and intra-abdominal hypertension (eg, peritonitis or ascites) comprise mechanical causes of shock that can be reversed by chest tube thoracostomy, pericardiocentesis, or abdominal decompression surgery, respectively. (See "Placement and management of thoracostomy tubes", section on 'Tube thoracostomy' and "Emergency pericardiocentesis", section on 'Technique overview'.) Drainage or debridement of infection sites (eg, necrotizing fasciitis) or broadening of antimicrobial coverage are additional actions that may be warranted. (See 'Eradicate infection' above and "Necrotizing soft tissue infections", section on 'Treatment'.) Uncontrolled hemorrhage, typically caused by spontaneous bleeding secondary to disseminated intravascular coagulopathy warrants timely administration of blood and blood products. (See 'Treat disseminated intravascular coagulation' above.) In rare instances, persistent shock may reflect anaphylaxis to administered antibiotic agents. These patients warrant treatment with antihistamines, epinephrine, corticosteroids, and removal of the inciting agent (table 3). (See "Anaphylaxis: Rapid recognition and treatment", section on 'Immediate management'.) Obtain cardiac evaluation Patients with refractory septic shock warrant an electrocardiogram to assess for signs of myocardial ischemia or infarction and heart failure. Pediatric cardiology consultation and echocardiography is also advised to assess for signs of myocarditis or, especially in neonates and young infants, signs of congenital heart disease. Patients with myocarditis diagnosed by endomyocardial biopsy may benefit from intravenous gamma globulin, although evidence is very limited. Corticosteroids or other immunosuppressive agents may be appropriate for patients with myocarditis caused by systemic autoimmune disease in addition to infection. (See "Treatment and prognosis of myocarditis in children", section on 'Immunosuppressive therapy'.) Address adrenal insufficiency Adrenal insufficiency is a clinical condition frequently associated with fluid- and catecholamine-resistant septic shock [24,30,31]. We suggest that children with fluid-refractory, catecholamine-resistant septic shock receive stress dose glucocorticoids (eg, hydrocortisone 50 to 100 mg/m2 per dose or 1 to 2 mg/kg [maximum 100 mg] per dose followed by 50 to 100 mg/m2 [1 to 2 mg/kg [maximum 100 mg] per day either given continuously or divided every four or six hours) [12,24,32-35]. Corticosteroid therapy should be discontinued when the patient becomes hemodynamically stable and no longer requires vasoactive medication administration. Practice varies regarding whether corticosteroids are abruptly discontinued or tapered in children with septic shock. Adult guidelines suggest tapering of corticosteroids but there is insufficient data in children. However, tapering is suggested if duration of corticosteroid use is long enough to potentially have caused adrenal suppression or adrenal suppression is identified by provocative testing. (See "Corticosteroid therapy in septic shock", section on 'Administration'.) Stress-dose corticosteroids should not be given to children with septic shock who never required or who no longer require vasopressor support unless the patient has pre-existing known adrenal insufficiency. Whether to use baseline cortisol measurements, adrenocorticotropin stimulation testing, or persistent hemodynamic instability alone as indicators for initiating and continuing corticosteroid therapy in children with refractory septic shock is debated and evidence for the best approach is lacking. Adrenal insufficiency (AI) is often defined in the critically ill pediatric population by an insufficient response to an adrenocorticotropic hormone (ACTH) stimulation test with a change in cortisol from baseline to one hour after the intravenous cosyntropin of <9 mcg/dL. Using this definition, one multicenter study showed that 30 percent of 381 critically ill children met criteria for AI during the first day of intensive care with a similar frequency occurring in the 59 patients with sepsis [36]. Patients receiving catecholamines had a higher rate of AI (43 percent). The median baseline cortisol was 28.6 ug/dL in the children with AI, versus 16.7 in those without AI. Among patients who did not receive corticosteroids and were re-tested 24 hours later, <20 percent met criteria for AI. Thus, AI can exist in critically ill patients with a relatively high random cortisol level, and AI can resolve without specific treatment. These findings have led some experts to suggest the use of stress dose corticosteroids in children with refractory septic shock without specific testing for AI. Corticosteroids are not without risk and should not be routinely used in children with septic shock. In an observational study of 6693 children with severe sepsis treated in childrens hospitals, corticosteroid treatment was associated with clinically significantly increased mortality (adjusted odds ratio 1.9 [95% CI 1.7, 2.1) [37]. Neonates who received 2 days of corticosteroids had a greater absolute increase in mortality than older patients (12 percent versus 6 percent increased mortality). Thus, further evidence is needed to better guide the use of corticosteroid administration in children with septic shock, including those patients who are most likely to benefit or experience adverse effects. Combination vasoactive drug therapy The ongoing management of vasoactive drug therapy in children with septic shock should be performed by clinicians with pediatric critical care expertise whenever possible. The approach provided here is for patients with septic shock who have already received a rapid infusion of at least 40 to 60 mL/kg of crystalloid and continuous infusions of dopamine or epinephrine (patients with cold shock) or norepinephrine (patients with warm shock) (algorithm 1). The physical findings of cold and warm shock are discussed separately. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Shock'.) Additional vasoactive therapy should be based upon the type of persistent shock (cold or warm shock) and the central venous oxygen saturation (ScvO2) as follows (algorithm 1) [24]: Warm shock with low blood pressure, ScvO2 <70 percent If initially receiving dopamine, addition of a norepinephrine infusion is warranted. Patients who do not respond to norepinephrine infusion may receive vasopressin or its long-acting formulation, terlipressin, if available, although use of these agents is controversial [24]. Case reports, case series, and one trial indicate that administration of either vasopressin or terlipressin is associated with an increase in mean arterial blood pressure and urine output in children with fluid-refractory, catecholamine-resistant septic shock [38http://www.uptodate.com/contents/septic-shock-ongoing-management-after-resuscitation-in-children?topicKey=EM%2F86881&elapsedTimeMs=0&source=see_link&view=print&displayedView=full 4 / 13

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40]. However, in a multicenter trial of 65 children with vasodilatory shock, low-dose vasopressin did not decrease the time to hemodynamic stability off vasopressor agents versus placebo (49.7 versus 47.1 hours) [41]. Patients receiving low-dose vasopressin had higher mortality (30 versus 16 percent) although this difference was not statistically significant. Cold shock with normal or low blood pressure, ScvO2 <70 percent If initially receiving dopamine, addition of an epinephrine infusion is warranted. If ScvO2 remains below 70 percent, addition of agents with inotropic properties and afterload reduction (eg, dobutamine, milrinone) or rapid-acting vasodilators for afterload reduction (eg, nitroprusside) may be helpful (algorithm 1) [12]. Since hypotension could be exacerbated by addition of vasodilating agents, these should be titrated carefully with close attention to hemodynamic changes. Vasodilators should be discontinued if hypotension worsens. In a small trial of 12 children with refractory catecholamine-resistant shock, administration of milrinone was associated with improved cardiac index and increased oxygen delivery although improved survival was not demonstrated [42]. Milrinone is a phosphodiesterase inhibitor that provides both increased cardiac contractility and vasodilation with afterload reduction. However, long-term use of milrinone is associated with an increased frequency of ventricular arrhythmias, including torsade des pointes. Patients receiving milrinone warrant close monitoring for hypotension, given its long half life. Alternatively, use of a vasodilator (eg, nitroprusside) for afterload reduction may be beneficial in selected patients. If nitroprusside is used, the medication should be protected from light, and doses in excess of 1.8 mcg/kg per minute should be avoided. Concomitant administration of thiosulfate to scavenge the cyanide produced by nitroprusside metabolism is suggested, either prophylactically or if cyanide levels are elevated. Advanced therapies Extracorporeal membrane oxygenation (ECMO) We and the American College of Critical Care Medicine (ACCM) suggest that children with persistent catecholamine-resistant shock in whom physiologic targets (eg, ScvO2 70 percent) cannot be attained with fluid repletion, vasoactive infusion, and hormonal therapy; who do not have an immediately reversible cause, such as myocarditis, pneumothorax, or pericardial effusion; and who have a high likelihood of mortality, be evaluated for extracorporeal membrane oxygenation (ECMO) support, if available (algorithm 1) [12]. If ECMO is not available at the facility in which the child is receiving care then the potential benefits of ECMO must be weighed against the likelihood that the patient can tolerate transfer. Severe sepsis and septic shock were previously considered to be contraindications to extracorporeal membrane oxygenation (ECMO) [24]. However, more recent data suggest that for patients who receive ECMO, survival to hospital discharge approaches 50 percent in pediatric refractory septic shock and 80 percent for neonatal refractory septic shock. As an example, in a small case series of 23 children with refractory septic shock in which central cannulation was used to achieve higher blood flow rates, 18 (78 percent) patients survived to be decannulated off ECMO and 17 (74 percent) children survived to hospital discharge [43]. Our experience suggests that the chances of survival in such patients with conventional therapy alone are otherwise very remote. Intravenous immune globulin Adjuvant therapy with intravenous immune globulin (IVIG) has been proposed but evidence for benefit in children with septic shock remains inconclusive. A trial of polyclonal IVIG in 100 children with pediatric sepsis syndrome showed a significant reduction in mortality (28 versus 44 percent), length of stay (six versus nine days), and less progression to complications (8 versus 32 percent) [44]. However, a more recent multicenter trial of polyclonal IVIG in 3493 neonates receiving antibiotics for suspected or proven serious infection found no significant difference in the rate of the primary outcome of death or major disability at the age of two years (relative risk, 1.00; 95% CI, 0.9 to 1.1) [45]. Evidence in adult patients with septic shock suggests that IVIG has no benefit in this population. (See "Investigational and ineffective therapies for sepsis", section on 'Intravenous immunoglobulin'.) For patients with toxic shock syndrome, IVIG may have clinical utility. IVIG for this indication is discussed separately. (See "Staphylococcal toxic shock syndrome", section on 'Intravenous immune globulin'.) EXPERIMENTAL THERAPIES Plasma exchange or plasmapheresis There has been considerable interest in extracorporeal filtration of circulating inflammatory mediators in sepsis. Although multiple studies in adults have been published on plasma exchange and plasmapheresis in sepsis, most are limited by small sample size at single institutions with considerable variability in the protocols utilized. Thus, current evidence is conflicting as to clinical benefit. (See "Investigational and ineffective therapies for sepsis", section on 'Hemofiltration'.) In addition, the practical limitations of inserting a large catheter for plasma exchange in young children (often with disseminated intravascular coagulopathy and increased risk of bleeding), the intensive resources necessary to perform plasma exchange or plasmapheresis, and the potential to worsen hypotension in hemodynamically unstable patients has limited this therapy in pediatric sepsis. One small trial of 10 children demonstrated a survival benefit in patients with the clinical phenotype of thrombocytopenia-associated multiple organ failure or TAMOF receiving plasmapheresis versus standard therapy (five of five versus one of five surviving) [46]. In this study, low levels of the von Willebrand factor cleaving protease, ADAMTS-13, activity were reversed with daily plasma exchange, which the authors suggested as the potential benefit of this therapy. Until further data becomes available, plasma exchange for pediatric patients with sepsis, including TAMOF with decreased ADAMTS-13 activity, remains an experimental therapy. Other therapies A variety of therapies have been investigated or are being evaluated to improve clinical outcomes in sepsis. Those therapies that appear promising as well as ones that have been proven to be ineffective are discussed in detail separately. (See "Investigational and ineffective therapies for sepsis".) GUIDELINE IMPLEMENTATION The early recognition and management of pediatric severe sepsis and septic shock can be improved through the establishment of institutional care guidelines. As an example, in an observational study of the impact of guidelines for sepsis management in a childrens hospital emergency department versus baseline actions before implementation, significant gains were documented for several key therapeutic actions including more timely fluid resuscitation (70 versus 43 percent receiving 20 mL/kg of normal saline in the first hour), antibiotic administration (90 versus 53 percent receiving antibiotics within three hours), and blood lactate determination (measured in 70 versus 10 percent of patients with possible septic shock) [47]. Median length of hospital stay decreased clinically significantly after implementation of the guidelines (181 to 140 hours). Mortality was not significantly different (6 versus 7 percent). PROGNOSIS Factors related to the host, site of infections, and microbiology may influence the progression from systemic inflammatory response syndrome to severe sepsis to septic shock and provide predictors of mortality. Severity of illness, progression to multiple organ failure, and treatment requirements are also important prognostic indicators: Host factors Case fatality rates in children with severe sepsis are highest for infants 1 to 12 months of age (approximately 11 percent) and are higher
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across all age groups for children with comorbidities, especially in children with cancer or human immunodeficiency virus infection (12 to 16 percent) [3,48]. Site of infection Children with endocarditis, central nervous system infection, and primary bacteremia have high case fatality rates (15 to 20 percent) [3]. The case fatality rate is lowest for genitourinary tract infections (approximately 4 percent). Microbiology Case fatality is increased in children with pneumococcal and fungal infections (15 and 13 percent, respectively) [3]. Infection with organisms resistant to antibiotics (eg, methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococcus species) is associated with a marked increased mortality from sepsis. (See "Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis", section on 'Type of infection'.) Severity of illness Mortality increases markedly depending upon the severity of illness in children with sepsis. As an example, in a multicenter observational study of 1051 children between one month and 18 years of age treated for sepsis in pediatric ICUs, mortality increased from 1 percent in children with sepsis to 6 percent and 34 percent in children with severe sepsis and septic shock, respectively [6]. Multiple organ failure The development of multiple organ dysfunction indicates an increased severity of illness in patients with sepsis and is associated with a higher mortality estimated as 0 to 7 percent for patients with one affected organ system and 20 to 50 percent with two or more failing organ systems [3,48-50]. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Sepsis'.) Treatment requirements The need for multiple vasoactive infusions predicts a poor prognosis. As an example, in an observational study of 96 episodes of pediatric septic shock in 80 patients, mortality was significantly higher for patients receiving multiple rather than one vasoactive agent (43 versus 0 percent, respectively) [48]. SUMMARY AND RECOMMENDATIONS The rapid recognition and initial resuscitation of children with septic shock is discussed separately. (See "Septic shock: Rapid recognition and initial resuscitation in children".) Ongoing aggressive resuscitation should continue after the initial resuscitation of pediatric septic shock according to the principles of goal-directed therapy, especially when managing children in whom adequate circulation has not been restored (algorithm 1). (See 'Overview' above.) Whenever possible, children requiring resuscitation for septic shock should receive ongoing management by a pediatric critical care specialist or pediatrician with similar expertise in a pediatric intensive care unit. (See 'Overview' above.) Eradication of infection can reverse septic shock. Antimicrobial treatment should be optimized based upon culture results. Source control (physical measures undertaken to eradicate a focus of infection, to eliminate ongoing microbial contamination, and to render a site inhospitable to microbial growth and invasion) should be undertaken when possible because localized foci of infection (ie, abscess) may not respond to antibiotics alone (table 1). (See 'Eradicate infection' above.) During initial management, continuation of respiratory support, monitoring of tissue perfusion using physiologic indicators and target goals, aggressive administration of fluids, and titration of vasoactive infusions continue. In addition, the clinician should determine the need for invasive monitoring via intraarterial and central venous cannulas. (See 'Ongoing and invasive monitoring' above and "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Physiologic indicators and target goals' and 'Continue fluid administration' above.) Maintaining adequate hemoglobin levels is a critical aspect of managing children with septic shock. We and the American College of Critical Care Medicine (ACCM) guidelines suggest a hemoglobin goal of 10 g/dL (equivalent to 30 percent hematocrit) as a target to maintain with blood transfusion during resuscitation and ongoing management of children with septic shock (Grade 2C). Once shock has resolved, a lower hematocrit threshold for blood transfusion may be safe. (See 'Blood transfusion' above.) Platelets, fresh frozen plasma, and/or cryoprecipitate should be provided to patients with disseminated intravascular coagulopathy and significant bleeding. (See 'Treat disseminated intravascular coagulation' above.) Other important interventions include management of glucose abnormalities, treatment of symptomatic hypocalcemia, and replacement therapy for known adrenal insufficiency or hypothyroidism. (See 'Manage glucose abnormalities' above and 'Avoid hypocalcemia' above and 'Treat known hormonal deficiencies' above.) Principles of management for children with refractory septic shock include (see 'Refractory septic shock' above): Treatment of reversible causes (eg, pneumothorax, pericardial tamponade, hemorrhage) Assessment for and treatment of adrenal insufficiency Combination vasoactive therapy targeted to central venous oxygen saturation and other measures of tissue perfusion (eg, capillary refill time, urine output, mental status, and serum lactate levels) We suggest that children with refractory catecholamine-resistant septic shock receive stress dose corticosteroids (eg, hydrocortisone 50 to 100 mg/m2 per dose or 1 to 2 mg/kg [maximum 100 mg] per dose followed by 50 to 100 mg/m2 [1 to 2 mg/kg [maximum 100 mg] per day either given continuously or divided every four or six hours) (Grade 2C). Whether to use baseline cortisol measurements, adrenocorticotropin stimulation testing, or persistent hemodynamic instability alone as indicators for continued therapy is debated and evidence for the best approach in children is lacking. Corticosteroid therapy should be discontinued when the patient becomes hemodynamically stable. Stress-dose corticosteroids should not be given to children with septic shock who never required or who no longer require vasopressor support unless the patient has pre-existing known adrenal insufficiency. (See 'Address adrenal insufficiency' above.) We and the ACCM guidelines suggest that children with persistent catecholamine-resistant shock in whom physiologic targets (eg, ScvO2 70 percent) cannot be attained with fluid repletion, vasoactive infusion, and hormonal therapy; who do not have a reversible cause, such as myocarditis, pneumothorax, or pericardial effusion; and who have a high likelihood of mortality, be evaluated for extracorporeal membrane oxygenation (ECMO) support, if available (algorithm 1) (Grade 2C). If the patient is an ECMO candidate and ECMO is not available at the facility in which the child is receiving care then the potential benefits of ECMO must be weighed against the likelihood that the patient can tolerate transfer. (See 'Extracorporeal membrane oxygenation (ECMO)' above.)

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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6:2. 2. Odetola FO, Gebremariam A, Freed GL. Patient and hospital correlates of clinical outcomes and resource utilization in severe pediatric sepsis. Pediatrics 2007; 119:487. 3. Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med 2003; 167:695. 4. Han YY, Carcillo JA, Dragotta MA, et al. Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome. Pediatrics 2003; 112:793. 5. Weiss SL, Parker B, Bullock ME, et al. Defining pediatric sepsis by different criteria: discrepancies in populations and implications for clinical practice. Pediatr Crit Care Med 2012; 13:e219. 6. Jaramillo-Bustamante JC, Marn-Agudelo A, Fernndez-Laverde M, Bareo-Silva J. Epidemiology of sepsis in pediatric intensive care units: first Colombian multicenter study. Pediatr Crit Care Med 2012; 13:501. 7. Kutko MC, Glick RD, Butler LM, et al. Histone deacetylase inhibitors induce growth suppression and cell death in human rhabdomyosarcoma in vitro. Clin Cancer Res 2003; 9:5749. 8. Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 1995; 273:117. 9. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 1995; 274:968. 10. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 1999; 340:207. 11. Randolph AG. Management of acute lung injury and acute respiratory distress syndrome in children. Crit Care Med 2009; 37:2448. 12. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580. 13. Santschi M, Jouvet P, Leclerc F, et al. Acute lung injury in children: therapeutic practice and feasibility of international clinical trials. Pediatr Crit Care Med 2010; 11:681. 14. Hanson JH, Flori H. Application of the acute respiratory distress syndrome network low-tidal volume strategy to pediatric acute lung injury. Respir Care Clin N Am 2006; 12:349. 15. Holt TR, Withington DE, Mitchell E. Which pressure to believe? A comparison of direct arterial with indirect blood pressure measurement techniques in the pediatric intensive care unit. Pediatr Crit Care Med 2011; 12:e391. 16. Fernandez EG, Green TP, Sweeney M. Low inferior vena caval catheters for hemodynamic and pulmonary function monitoring in pediatric critical care patients. Pediatr Crit Care Med 2004; 5:14. 17. Yung M, Butt W. Inferior vena cava pressure as an estimate of central venous pressure. J Paediatr Child Health 1995; 31:399. 18. Carcillo JA, Fields AI, American College of Critical Care Medicine Task Force Committee Members. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002; 30:1365. 19. Foland JA, Fortenberry JD, Warshaw BL, et al. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med 2004; 32:1771. 20. Sutherland SM, Zappitelli M, Alexander SR, et al. Fluid overload and mortality in children receiving continuous renal replacement therapy: the prospective pediatric continuous renal replacement therapy registry. Am J Kidney Dis 2010; 55:316. 21. Karam O, Tucci M, Ducruet T, et al. Red blood cell transfusion thresholds in pediatric patients with sepsis. Pediatr Crit Care Med 2011; 12:512. 22. Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 2007; 369:836. 23. Mart-Carvajal AJ, Sol I, Gluud C, et al. Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database Syst Rev 2012; 12:CD004388. 24. Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37:666. 25. Branco RG, Garcia PC, Piva JP, et al. Glucose level and risk of mortality in pediatric septic shock. Pediatr Crit Care Med 2005; 6:470. 26. van Waardenburg DA, Jansen TC, Vos GD, Buurman WA. Hyperglycemia in children with meningococcal sepsis and septic shock: the relation between plasma levels of insulin and inflammatory mediators. J Clin Endocrinol Metab 2006; 91:3916. 27. Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet 2009; 373:547. 28. Mesotten D, Gielen M, Sterken C, et al. Neurocognitive development of children 4 years after critical illness and treatment with tight glucose control: a randomized controlled trial. JAMA 2012; 308:1641. 29. Agus MS, Steil GM, Wypij D, et al. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med 2012; 367:1208. 30. Sarthi M, Lodha R, Vivekanandhan S, Arora NK. Adrenal status in children with septic shock using low-dose stimulation test. Pediatr Crit Care Med 2007; 8:23. 31. Zimmerman JJ. Moving beyond Babel. Pediatr Crit Care Med 2007; 8:73. 32. Parker MM, Hazelzet JA, Carcillo JA. Pediatric considerations. Crit Care Med 2004; 32:S591. 33. Melendez E, Bachur R. Advances in the emergency management of pediatric sepsis. Curr Opin Pediatr 2006; 18:245. 34. Hauser, GJ. Early goal-directed therapy of pediatric septic shock in the emergency department. Isr J Emerg Med 2007; 7:5. 35. Langer M, Modi BP, Agus M. Adrenal insufficiency in the critically ill neonate and child. Curr Opin Pediatr 2006; 18:448. 36. Menon K, Ward RE, Lawson ML, et al. A prospective multicenter study of adrenal function in critically ill children. Am J Respir Crit Care Med 2010; 182:246. 37. Markovitz BP, Goodman DM, Watson RS, et al. A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: what is the role of steroids? Pediatr Crit Care Med 2005; 6:270. 38. Yildizdas D, Yapicioglu H, Celik U, et al. Terlipressin as a rescue therapy for catecholamine-resistant septic shock in children. Intensive Care Med 2008; 34:511. 39. Meyer S, Gortner L, McGuire W, et al. Vasopressin in catecholamine-refractory shock in children. Anaesthesia 2008; 63:228.
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40. Masutani S, Senzaki H, Ishido H, et al. Vasopressin in the treatment of vasodilatory shock in children. Pediatr Int 2005; 47:132. 41. Choong K, Bohn D, Fraser DD, et al. Vasopressin in pediatric vasodilatory shock: a multicenter randomized controlled trial. Am J Respir Crit Care Med 2009; 180:632. 42. Barton P, Garcia J, Kouatli A, et al. Hemodynamic effects of i.v. milrinone lactate in pediatric patients with septic shock. A prospective, double-blinded, randomized, placebo-controlled, interventional study. Chest 1996; 109:1302. 43. MacLaren G, Butt W, Best D, Donath S. Central extracorporeal membrane oxygenation for refractory pediatric septic shock. Pediatr Crit Care Med 2011; 12:133. 44. El-Nawawy A, El-Kinany H, Hamdy El-Sayed M, Boshra N. Intravenous polyclonal immunoglobulin administration to sepsis syndrome patients: a prospective study in a pediatric intensive care unit. J Trop Pediatr 2005; 51:271. 45. INIS Collaborative Group, Brocklehurst P, Farrell B, et al. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med 2011; 365:1201. 46. Nguyen TC, Han YY, Kiss JE, et al. Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia-associated multiple organ failure. Crit Care Med 2008; 36:2878. 47. Larsen GY, Mecham N, Greenberg R. An emergency department septic shock protocol and care guideline for children initiated at triage. Pediatrics 2011; 127:e1585. 48. Kutko MC, Calarco MP, Flaherty MB, et al. Mortality rates in pediatric septic shock with and without multiple organ system failure. Pediatr Crit Care Med 2003; 4:333. 49. Proulx F, Fayon M, Farrell CA, et al. Epidemiology of sepsis and multiple organ dysfunction syndrome in children. Chest 1996; 109:1033. 50. Graciano AL, Balko JA, Rahn DS, et al. The Pediatric Multiple Organ Dysfunction Score (P-MODS): development and validation of an objective scale to measure the severity of multiple organ dysfunction in critically ill children. Crit Care Med 2005; 33:1484. Topic 86881 Version 5.0

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GRAPHICS
Recommendations for stepwise management of hemodynamic support in infants and children with sepsis

Algorithm for time sensitive, goal-directed stepwise management of hemodynamic support in infants and children. Proceed to next step if shock persists. (1) First hour goalsRestore and maintain heart rate thresholds, capillary refill 2 sec, and normal blood pressure in the first hour/emergency department. Support oxygenation and ventilation as appropriate. (2) Subsequent intensive care unit goalsIf shock is not reversed, intervene to restore and maintain normal perfusion pressure (mean arterial pressure [MAP]-central venous pressure [CVP]) for age, central venous O2 saturation >70 percent, and CI >3.3, <6.0 L/min/m2 in pediatric intensive care unit (PICU).
Hgb: hemoglobin; PICCO: pulse contour cardiac output; FATD: femoral arterial thermodilution; ECMO: extracorporeal membrane oxygenation; CI: cardiac index; CRRT: continuous renal replacement therapy; IV: intravenous; IO: interosseous; IM: intramuscular. Reproduced with permission from: Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37:666. Copyright 2009 Lippincott Williams & Wilkins.

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Evaluation of common sources of sepsis

Suspected site
Upper respiratory tract Low er respiratory tract

Symptoms/signs
Pharyngeal inflammation plus exudate sw elling and lymphadenopathy Productive cough, pleuritic chest pain, consolidative auscultatory findings

Microbiologic evaluation
Throat sw ab for aerobic culture Sputum of good quality, rapid influenza testing, urinary antigen testing (eg, pneumococcus, legionella), quantitative culture of protected brush or bronchoalveolar lavage Urine microscopy show ing pyuria Culture of blood (from the catheter and a peripheral site), culture catheter tip (if removed) Culture of pleural fluid (through catheter), culture of catheter tip (if removed) Gram stain and culture of draining pus, w ound culture not reliable Culture blister fluid or draining pus; role of tissue aspirates not proven CSF microscopy, protein, glucose, culture, bacterial antigen test Stool culture for Salmonella, Shigella, and Campylobacter Aerobic and anaerobic culture of percutaneously or surgically drained abdominal fluid collections Cell count and culture of PD fluid W omen: Endocervical and high vaginal sw abs onto selective media Men: Urine Gram stain and culture

Urinary tract Vascular catheters: arterial, central venous Indw elling pleural catheter W ound or burn Skin/soft tissue Central nervous system Gastrointestinal Intraabdominal

Fever, urgency, dysuria, loin pain Redness or drainage at insertion site

Redness or drainage at insertion site Inflammation, edema, erythema, discharge of pus Erythema, edema, lymphangitis Signs of meningeal irritation Abdominal pain, distension, diarrhea, and vomiting Specific abdominal symptoms/signs

Peritoneal dialysis (PD) catheter Genital tract

Cloudy PD fluid, abdominal pain, fever W omen: Low abdominal pain, vaginal discharge Men: Dysuria, frequency, urgency, urge incontinence, cloudy urine, prostatic tenderness

Joint

Pain, w armth, decreased range of motion

Arthrocentesis w ith cell counts, Gram stain, and culture

CSF: cerebrospinal fluid; PD: peritoneal dialysis. Adapted from: Cohen J, Microbiologic requirements for studies of sepsis. In: Sibbald WJ, Vincent JL (eds), Clinical Trials for the Treatment of Sepsis, Springer-Verlag, Berlin, 1995, p.73.

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Rapid overview for hypoglycemia in adolescents and children, other than neonates
Clinical features
Any patient w ith acute lethargy or coma should have an immediate measurement of blood glucose to determine if hypoglycemia is a possible cause Other findings of hypoglycemia are nonspecific* and vary by age: Infants - Irritability - Lethargy - Jitteriness - Feeding problems - Hypothermia - Hypotonia - Tachypnea - Cyanosis - Apnea - Seizures Older children and adolescents - Autonomic response (tends to occur w ith blood glucose <50 to 65 mg/dL)
Sweating Tachycardia Palpitations Tremor Nervousness Hunger Paresthesias Pallor

- Neuroglycopenia
Irritability C onfusion Uncharacteristic behavior Weakness Seizures C oma Occasionally, transient focal neurologic deficits

Diagnosis
Obtain rapid bedside blood glucose concentration Confirm the presence of hypoglycemia w ith a simultaneously draw n plasma glucose Treat, as outlined below , if the bedside value is low (<70 mg/dL [3.89 mmol/L]) in symptomatic patients Obtain a blood sample for additional diagnostic studies prior to glucose administration, if possible, and collect the first voided urine after the hypoglycemic event in all infants and young children w ho are not being treated for diabetes mellitus or do not have a know n cause for hypoglycemia

Treatment
Do not delay treatment if symptomatic hypoglycemia is suspected. How ever, every reasonable effort should be made to obtain a rapid blood glucose measurement prior to administering glucose. Give glucose based upon the patients level of consciousness and ability to swallow safely (ie, alert enough to do so and with intact gag reflex) as follows: Conscious and able to drink and swallow safely:
Administer 0.3 grams/kg (10 to 20 grams) of a rapidly-absorbed carbohydrate (eg, 2 to 3 glucose tablets, a tube of gel with 15 grams, 4 oz (120 mL) sweetened fruit juice, non-diet soda, or a teaspoon (5 mL) of honey or table sugar. May repeat in 10 to 15 minutes.

Altered mental status, unable to swallow, or does not respond to oral glucose administration within 15 minutes:
Give an initial IV bolus of glucose of 0.25 grams/kg of dextrose (maximum single dose 25 grams). The volume and concentration of glucose bolus is infused slowly at 2 to 3 mL per minute and based upon age: 2.5 mL/kg of 10 percent dextrose solution (D10W) in infants and children up to 12 years of age (10 percent dextrose is 100 mg/mL) 1 mL/kg of 25 percent dextrose (D25W) or 0.5 mL/kg of 50 percent dextrose (D50W) in adolescents (25 percent dextrose is 250 mg/mL; 50 percent dextrose is 500 mg/mL)

Unable to receive oral glucose and unable to obtain IV access:

Give glucagon 0.03 mg/kg IM or SQ (maximum dose 1 mg): Perform blood glucose monitoring every 10 to 15 minutes as the effects of glucagon may be transient

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Establish vascular access as soon as possible

After initial hypoglycemia is reversed, provide additional glucose and treatment based upon suspected etiology: - Give children and adolescents w ith type I diabetes mellitus a normal diet - Give patients w ith an unknow n cause of hypoglycemia intravenous infusion of dextrose 10 percent (6 to 9 mg/kg per minute) titrated to maintain blood glucose in a safe and appropriate range (70 to 150 mg/dL [3.89 to 8.33 mmol/L]) - Give patients, w ho have ingested a sulfonylurea and have recurrent hypoglycemia, octreotide (dose: 1 to 1.5 mcg/kg IM or SQ, maximum dose 150 mcg every 6 hours) in addition to glucose. (Refer to UpToDate topic on sulfonylurea poisoning). Measure a rapid blood and plasma glucose 15 to 30 minutes after the initial IV glucose bolus and then monitor every 30 to 60 minutes until stable (minimum of four hours) to ensure that plasma glucose concentration is maintained in the normal range (>70 to 100 mg/dL [>3.89 to 5.55 mmol/L]) Obtain pediatric endocrinology consultation for patients w ith hypoglycemia of unknow n cause Obtain medical toxicology consultation for patients w ith ingestion of oral hypoglycemic agents by calling the United States Poison Control Netw ork at 1-800-222-1222 or access the W orld Health Organizations list of international poison centers (w w w .w ho.int/gho/phe/chemical_safety/poisons_centres/en/index.html) Admit the follow ing patients: - Cannot maintain normoglycemia w ith oral intake - Hypoglycemia of unknow n cause - Ingestion of long-acting hypoglycemic agents - Recurrent hypoglycemia during the period of observation IV: intravenous; IM: intramuscular; SQ: subcutaneous; D10W : 10 percent dextrose in w ater; D25W : 25 percent dextrose in w ater; D50W : 50 percent dextrose in w ater. * These findings may also occur in infants w ith sepsis, congenital heart disease, respiratory distress syndrome, intraventricular hemorrhage, other metabolic disorders, and in children and adolescents w ith a variety of underlying conditions. Specific laboratory studies to obtain in children include blood samples for glucose, insulin, C-peptide, beta-hydroxybutyrate, lactate (free flow ing blood must be obtained w ithout a tourniquet), plasma acylcarnitines, free fatty acids, grow th hormone, and cortisol. Higher doses of glucose (eg, 0.5 to 1 g/kg [5 to 10 mL/kg of 10 percent dextrose in w ater OR 2 to 4 mL/kg of 25 percent dextrose in w ater]) may be needed to correct hypoglycemia caused by sulfonylurea ingestion. (For more detail, refer to UpToDate topic on sulfonylurea agent poisoning). Glucagon w ill reverse hypoglycemia caused by excess endogenous or exogenous insulin and w ill not be effective in patients w ith inadequate glycogen stores (prolonged fasting), ketotic hypoglycemia, or are unable to mobilize glycogen (glycogen storage diseases). Of note, children may exhaust their glycogen stores in as little as 12 hours. Other conditions in w hich glycogen cannot be effectively mobilized include ethanol intoxication in children, adrenal insufficiency, and certain inborn errors of metabolism (eg, a disorder of glycogen synthesis and glycogen storage diseases).

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Rapid overview: Emergent management of anaphylaxis in infants and children*

DIAGNOSIS IS MADE CLINICALLY:
The most common signs and symptoms are cutaneous (eg, sudden onset of generalized urticaria, angioedema, flushing, pruritus). How ever, 10 to 20 percent of patients have no skin findings. Danger signs: Rapid progression of symptoms, evidence of respiratory distress (eg, stridor, wheezing, dyspnea, increased work of breathing, retractions, persistent cough, cyanosis), signs of poor perfusion, dysrhythmia, hypotension, collapse.

ACUTE MANAGEMENT:
The first and most important therapy in anaphylaxis is epinephrine. There are NO absolute contraindications to epinephrine in the setting of anaphylaxis. Airway: Immediate intubation if evidence of impending airw ay obstruction from angioedema; delay may lead to complete obstruction; intubation can be difficult and should be performed by the most experienced clinician available; cricothyrotomy may be necessary. IM Epinephrine (1 mg/mL preparation): Give epinephrine 0.01 mg per kilogram intramuscularly (maximum per dose: 0.5 mg), preferably in the mid-anterolateral thigh, can repeat every 5 to 15 minutes as needed. If signs of poor perfusion are present or symptoms are not responding to epinephrine injections, prepare IV epinephrine for infusion (see below ). Place patient in recumbent position, if tolerated, and elevate low er extremities. Oxygen: Give 6 to 8 liters per minute via face mask, or up to 100 percent oxygen as needed. Normal saline rapid bolus: Treat poor perfusion w ith rapid infusion of 20 mL per kilogram; reevaluate and repeat fluid boluses (20 mL per kilogram) as needed; massive fluid shifts w ith severe loss of intravascular volume can occur; monitor urine output. Albuterol: For bronchospasm resistant to IM epinephrine, give albuterol 0.15 mg per kilogram (minimum dose: 2.5 mg) in 3 mL saline inhaled via nebulizer; repeat as needed. H1 antihistamine: Consider giving diphenhydramine 1 mg per kilogram (max 40 mg) IV. H2 antihistamine: Consider giving ranitidine 1 mg per kilogram (max 50 mg) IV. Glucocorticoid: Consider giving methylprednisolone 1 mg per kilogram (max 125 mg) IV. Monitoring: Continuous noninvasive hemodynamic monitoring and pulse oximetry monitoring should be performed; urine output should be monitored in patients receiving IV fluid resuscitation for severe hypotension or shock.

TREATMENT OF REFRACTORY SYMPTOMS:

Epinephrine infusion: Patients w ith inadequate response to IM epinephrine and IV saline, give epinephrine continuous infusion at 0.1 to 1 microgram per kilogram per minute, titrated to effect. Vasopressors: Patients may require large amounts of IV crystalloid to maintain blood pressure; if response to epinephrine and saline is inadequate, dopamine (5 to 20 micrograms per kilogram per minute) can be given as continuous infusion, titrated to effect. * A child is defined as a prepubertal patient w eighing less than 40 kg. See the topic "Assessment of perfusion in pediatric resuscitation". All patients receiving an infusion of epinephrine and/or another vasopressor require continuous noninvasive monitoring of blood pressure, heart rate and function, and oxygen saturation. W e suggest that pediatric centers provide instructions for preparation of standard concentrations and also provide charts for established infusion rate for epinephrine and other vasopressors in infants and children.

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