Management of Sepsis in the Pediatric Patient

Journal of Radiology Nursing xxx (2019) 1e8

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Management of Sepsis in the Pediatric Patient Sara P. Rooney, PharmD, BCPS, BCPPS a,*, Joshua C. Heffren, PharmD a, Boh L. Song, PharmD, BCPPS a, Alicia C. Sanchez, PharmD b a b

Department of Pharmacy, Children's National Health System, Washington, DC, USA Children's Hospital of Georgia, Augusta University Health, Augusta, GA, USA

a b s t r a c t Keywords: Sepsis Septic shock Fluid resuscitation Inotrope therapy Antibiotics

Sepsis is a life-threatening condition requiring prompt recognition and aggressive, multidisciplinary treatment. This treatment consists of, but is not limited to, cardiovascular support via fluids and vasoactive medications plus systemic, broad-spectrum antibiotics. This article reviews the guidelines as well as supporting primary literature surrounding fluids, vasoactive medications, and antibiotic recommendations for pediatric sepsis. © 2019 Association for Radiologic & Imaging Nursing. Published by Elsevier Inc. All rights reserved.

Introduction Sepsis is a life-threatening type of distributive shock leading to organ dysfunction secondary to a host's dysregulated response to an infection (Prusakowski and Chen, 2017). Pediatric and neonatal sepsis is distinct from adult sepsis in terms of definitions, pathophysiology, and treatment; however, regardless of age, prompt diagnosis and treatment improve mortality (Paul, 2018). Pediatric and neonatal sepsis has been increasing in frequency, and optimal management requires collaboration with many disciplines (Boomer and Feliz, 2019). Therefore, it is imperative for all of those caring for pediatric patients to have a thorough understanding of how to recognize and treat sepsis. Recent guidelines published on this topic encourage hospitals to create an institution-specific “recognition bundle” to screen patients for septic shock through a trigger tool. Any patients who screen positive via the trigger tool should have a prompt physical assessment performed by a clinician to allow for prompt initiation of resuscitation if sepsis is suspected. When clinicians are assessing patients at risk for septic shock, their examination should focus on common early signs and symptoms of septic shock. In pediatric and neonatal patients these include temperature irregularities (hyperthermia or hypothermia), altered mental status (confusion, drowsiness, inconsolability, irritability, unresponsive), and signs of altered perfusion (Davis et al., 2017). Altered perfusion is commonly assessed by evaluating capillary refill which can be either “flash,”

The authors of this article have nothing to disclose and have no conflicts of interest. * Corresponding author: Sara P. Rooney, Children's National Health System, 111 Michigan Ave NW, Washington, DC 20010. E-mail address: [email protected] (S.P. Rooney).

suggesting peripheral vasodilation (warm shock), or delayed, suggesting peripheral vasoconstriction (cold shock). Another surrogate marker for altered perfusion would be decreased urine output. It should be noted that for pediatric/neonatal septic shock, hypotension is a late sign and generally doesn't occur until patients are nearing cardiovascular collapse (Mathias et al., 2016). To rapidly diagnose, clear and consistent definitions are necessary. In pediatric sepsis, these are most commonly broken down into systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock (Mathias et al., 2016; Simmons et al., 2012). SIRS is diagnosed when there are two or more of the following present: alterations in core body temperature (hypothermia or hyperthermia), changes in leukocyte count (leukopenia or leukocytosis), effects in heart rate (age-specific bradycardia or tachycardia), and/or age-specific tachypnea. Sepsis is defined as a patient with a diagnosis of SIRS in the presence of a known or suspected infection. Severe sepsis is sepsis plus either cardiovascular dysfunction, acute respiratory distress syndrome, or
2 organ dysfunction. Finally, septic shock is severe sepsis plus specifically cardiovascular dysfunction (Mathias et al., 2016). Once sepsis has been diagnosed, institution-specific “resuscitation bundle” and “stabilization bundle” should be used to guide next steps in therapy. Establishment of such bundles will help with appropriate and rapid management of the patient with suspected septic shock to achieve hemodynamic goals and will drive adherence to best practice at the institution. The guidelines recommend that “resuscitation bundle” focus around intravenous/intraosseous access, appropriate fluid management, initiation of broad-spectrum antibiotics, and initiation of appropriate vasopressors for fluid-refractory shock. “Stabilization bundle” should focus on multimodal monitoring to obtain hemodynamic goals and confirmation of appropriate antimicrobial therapy and source control (Davis et al., 2017).

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Sedation for invasive procedure or intubation Consistent with Pediatric Advanced Life Support guidelines, evaluation, identification, and intervention should begin immediately on caring for these critically ill patients (Chameides and Samson, 2011). On initial evaluation, most patients with sepsis will be experiencing neurological, cardiovascular, and respiratory alterations which will require intervention. Respiratory support, in the form of supplemental oxygen, should be provided to all patients in shock with escalation to invasive respiratory support in any child with persistent or worsening shock (Davis et al., 2017). Further therapies targeting cardiovascular compromise are administered systemically. Therefore, obtaining vascular access is a crucial initial step, with central venous access being preferred. This, as well as other invasive procedures, requires pain and sedation management, but patients in shock are generally very susceptible to hemodynamic adverse effects of many medications used for sedation necessary for these invasive procedures. Therefore, preferably, fluid resuscitation (ideally at least 2 fluid boluses) will have begun before administration of sedative and analgesic agents. Ketamine is a dissociative anesthetic with sedative, analgesic, and anesthetic properties (Gales and Maxwell, 2018). Ketamine, plus or minus atropine pretreatment, is the most common regimen recommended because of minimal cardiovascular effects (Davis et al, 2017). However, ketamine is not without adverse effects and/or contraindications. Specifically in catecholamine depleted patients, ketamine can actually worsen hypotension which can lead to further cardiovascular compromise and collapse (Miller et al., 2016). Therefore, this agent might not be ideal in patients who have been in shock for an extended period of time. If ketamine is unavailable or undesirable, fentanyl can be considered. Other agents such as etomidate, benzodiazepines, and morphine have undesirable adverse effects for patients in septic shock so recommendations generally avoid these (Davis et al., 2017). Fluid therapy The recent updates on pediatric and neonatal sepsis guidelines recommend the initiation of appropriate fluid resuscitation within 30 minutes of septic shock recognition (Davis et al., 2017). Pediatric septic shock, in comparison to adult septic shock, is typically characterized by hypovolemia, leading to decreased cardiovascular output (Davis et al., 2017; Parker et al., 1983). Therefore, pediatric patients tend to respond well to aggressive volume resuscitation. Rapid fluid management in septic shock can aid in the restoration of hemodynamic status and reversing shock in intravascularly depleted patients. Every additional hour of delay in the reversal of shock has been associated with at least a 2-fold increased odd of mortality in patients with septic shock (Han et al., 2003). However, excessive fluid resuscitation leading to positive fluid balance has shown to worsen outcomes in pediatric patients with initially low mortality risk (Abulebda et al., 2014). Before the initiation of fluid resuscitation, patients should be assessed for rales, crackles, and/or hepatomegaly, as they are signs of fluid overload. Fluid resuscitation for pediatric patients should happen in increments of 20 mL/kg up to 3 rounds (in neonates 10 mL/kg up to 4 rounds). Appropriate perfusion, rales, crackles, or hepatomegaly should be assessed with every round of bolus (Davis et al., 2017). If rales, crackles, or hepatomegaly exist on a patient in need of additional hemodynamic support, appropriate inotropic support should be started in lieu of further fluid boluses. Similar to other stages of sepsis management, fluid resuscitation should be executed with the goal of achieving normal blood pressure for age and capillary refill of less than 3 seconds. Once central line access and arterial line access have been obtained, more invasive form of

monitoring can be used for goal-directed therapy (Davis et al., 2017). When choosing fluids for resuscitation, crystalloids (normal saline, lactated ringers [LR]) are usually preferred over colloids (albumin, hetastarch). This is because crystalloids are more readily available and economical in comparison to colloids. Isotonic saline is commonly used as initial crystalloids, but some adult population studies suggest that LR may be better crystalloids for initial fluid resuscitation. Fluid resuscitation with LR as opposed to the traditionally preferred isotonic saline showed reduced renal injury, renal replacement therapy, and mortality in adults (Emrath et al. 2017; Raghunathan et al., 2014; Yunos et al., 2012). Limited studies comparing the effect of crystalloids versus albumin for fluid resuscitation have shown that the use of albumin is associated with higher survival, improvement in organ dysfunction, and shorter hospitalization (Annane et al., 2013; Caironi et al., 2014; Finfer et al., 2004). However, such results have not been duplicated consistently to suggest the superiority of albumin over crystalloids in initial fluid resuscitation. Additional studies that support the use of albumin as the more effective initial fluid resuscitation of choice in pediatric patients are needed. For patients in shock with hypoalbuminemia (serum albumin <3 mg/dL), 5% albumin is a reasonable option for fluid expansion beyond 60 mL/kg of saline or LR. Studies comparing the effect of hetastarch and crystalloids in the adult population have shown a significant increase in mortality and the need for renal replacement therapies in patients receiving hetastarch. Therefore, hetastarch is not recommended in either pediatric or adult septic shock fluid resuscitation (Myburgh et al., 2012). Some pediatric studies explore the option of using blood as volume expanders instead of crystalloids/colloids, but use of blood over crystalloids/colloids was not highly recommended by the investigators (Lucking et al., 1990; Mink and Pollack, 1990). However, the pediatric sepsis guidelines recommend a hemoglobin goal of greater than 10 g/dL in pediatric patients (greater than 12 g/dL in neonates), and utilization of blood as volume expanders may be considered in patients with low hemoglobin (Davis et al., 2017). Currently, pediatric sepsis guidelines recommend the use of crystalloids for volume expansion without specifying a specific type (Davis et al., 2017). Antibiotic therapy Antibiotics should be given as soon as possible, within 1 hour, of recognition of sepsis or septic shock (Davis et al., 2017; Kawasaki 2017; Mathias et al., 2016; Prusakowski and Chen, 2017). In adult patients with sepsis or septic shock, delay in antibiotic administration greater than 1 hour has shown increased morbidity and mortality (Davis et al., 2017). A retrospective analysis of pediatric patients treated for severe sepsis or septic shock evaluated timing of antimicrobial administration and its impact on pediatric intensive care unit (PICU) mortality, organ failureefree days, vasoactivefree days, ventilator-free days, and PICU length of stay (LOS). In these patients, an increased risk of PICU mortality was observed with each hour delay from sepsis recognition to antimicrobial administration; a statistically significant difference was noted in patients in whom antimicrobial initiation was delayed by greater than 3 hours (odds ratio [OR], 3.92; 95% confidence interval [CI], 1.27e12.06). Patients who received antimicrobial agents more than 3 hours from sepsis recognition had fewer organ failureefree days (median 16 [interquartile range {IQR}, 1e23] vs. 20 [IQR, 6e26]; p ¼ .04). However, there was no difference in vasoactive-free days, ventilator-free days, or PICU LOS (Weiss et al., 2014). Microbiologic cultures, including at least two sets of blood cultures (aerobic and anaerobic) should be obtained before initiation of antimicrobial therapy, if doing so does not result in a significant

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S.P. Rooney et al. / Journal of Radiology Nursing xxx (2019) 1e8

delay in initiation (Davis et al., 2017). In patients with intravascular catheters in place for >48 hours, at least one blood culture set should be obtained from the catheter, in addition to peripheral blood cultures (Davis et al., 2017). Cultures from sources such as cerebral spinal fluid, urine, wounds, respiratory secretions, or other body fluids should be obtained as indicated. The International Guidelines for Management of Sepsis and Septic Shock suggest a time of 45 minutes as what may be considered a significant delay in initiation of antimicrobial therapy while cultures are being obtained (Davis et al., 2017). Initial therapy should be broad enough to cover all likely pathogens, including bacterial and potentially viral or fungal coverage, and multiple factors should be considered when choosing appropriate antimicrobial agents (Davis et al., 2017). Some factors that should be considered when selecting empiric antimicrobials include age of patient, local antibiotic resistance patterns, previous microbiologic cultures and comorbidities, suspected source of infection, and drug allergies (Davis et al., 2017; Prusakowski and Chen, 2017) (see Table 1). For neonates, recommendations include ampicillin and gentamicin or cefotaxime (Polin, 2012). However, cefotaxime is no longer manufactured and alternative regimens are being used (ASHP, 2019). Third-generation cephalosporins such as ceftriaxone and ceftazidime or fourth-generation cephalosporin and cefepime have been used as alternatives to cefotaxime. Ceftriaxone historically was not used in neonates or infants but, in 2009, the FDA released a revised statement regarding the use of ceftriaxone and calcium containing intravenous (IV) fluids in neonates and infants (Bradley and Bocchini, 2019). Currently, recommendations are to avoid concomitant use of ceftriaxone and calcium containing IV fluids in neonates aged 28 days. In infants aged >28 days, ceftriaxone and calcium containing IV fluids can be used concomitantly, with caution. If ceftriaxone and calcium containing IV fluids are administered in the same line, the line should be thoroughly flushed between infusions; ceftriaxone should not be administered simultaneously with IV calcium-containing solutions (Bradley and Bocchini, 2019). Due to the risk of kernicterus, use of ceftriaxone should be limited to patients aged >28 days with a corrected gestational age of 41 weeks (ceftriaxone package insert). For infants aged
28 days with a corrected gestational age 41 weeks, a regimen containing ceftazidime or cefepime may be used. Ceftazidime has less gram-positive coverage than cefepime, and combination therapy may be necessary (Cefepime and Ceftazidime Package Inserts). Common empiric regimens for children include a beta-lactam with gram-positive and gram-negative bacterial coverage (see Tables 1 and 2). Vancomycin is typically added for methicillin-

resistant Staphylococcus aureus coverage in the patient with septic shock. Preferably, 2 vascular access points should be established to ensure ability to administer fluids, inotropes (if necessary), and antimicrobials in a timely manner. Medications that can be pushed or administered quickly should be administered first, followed by those with longer infusion times (i.e., push ceftriaxone and then administer vancomycin). If medications have similar infusion time, the antimicrobial treating the most likely pathogen should be administered first. Once causative organism and susceptibilities are identified, antimicrobial therapy should be narrowed, and duration of therapy can be tailored based on source of infection and patient response to therapy. Vasoactive medications Vasopressors and inotropes are cornerstone in the management of fluid-refractory septic shock to reestablish compromised perfusion. Timely initiation within the first 60 minutes of resuscitation and only after prompt intravascular volume repletion is associated with decreased length of ICU stay and mortality (Davis et al., 2017). Based on a retrospective review, each additional hour of persistent shock beyond 60 minutes without vasopressor initiation was associated with a two-fold increase in odds of mortality (Han et al., 2003). Generally speaking, vasopressors result in alpha-1 receptoremediated vasoconstriction, whereas inotropes intensify cardiac contractility via stimulation of beta-1 receptors (Stratton et al., 2017). In reality, each specific drug is producing both effects, with varying amounts depending on the relative potency for the alpha-1 or beta-1 receptor. When instituting vasopressor therapy, the dose should always be initiated at the low end of the range (see Table 3) and titrated to achieve desired mean arterial pressure (MAP) for age (Table 4). Clinicians should be mindful that shock is an evolving process and that manipulation of vasopressor agent and dose is warranted to maintain adequate perfusion and tissue oxygenation. Furthermore, tissue perfusion to the liver and kidney can affect vasopressor kinetics, resulting in decreased clearance and therefore increased concentrations within the body. This can manifest as worsening perfusion or arrhythmias, all the more reason to support continued re-evaluation of perfusion parameters in patients receiving vasopressor therapy. When selecting a vasopressor, it's important to consider fundamental physiology and variables that impact blood pressure. Blood pressure is the product of cardiac output (CO) and systemic vascular resistance (SVR). Meanwhile, CO is the product of stroke volume and heart rate. Therefore, augmentation of blood

Table 1 Antimicrobial selection (Gilbert et al., 2017; Prusakoswski and Chen, 2017) Patient population

Typical pathogens

Antibiotic recommendations

Neonates (28 days)

Escherichia coli, group b Streptococcus, Listeria monocytogenes, herpes simplex virus Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae

Ampicillin and gentamicin ± vancomycin ± acyclovir

Infants aged > 28 days and children

Intra-abdominal source

Anaerobes

Asplenic

Encapsulated organisms (Streptococcus pneumonia, Haemophilus influenzae, Neisseria meningitidis) All pathogens including opportunistic infections

Suspected or confirmed neutropenia or immunosuppressed including organ/ bone marrow transplant Encephalitis Toxin-mediated reaction Tick-borne concerns

3

Herpes simplex virus Staphylococcus aureus, group A Streptococcus Rickettsia, Borrelia, and Ehrlichia

Third-generation cephalosporin (ceftriaxone) ± vancomycin If penicillin allergydmeropenem If unable to receive carbapenem or penicillindaztreonam OR ciprofloxacin þ clindamycin Ceftriaxone and metronidazole Piperacillin-Tazobactam Ceftriaxone If penicillin allergydclindamycin or levofloxacin Antipseudomonal beta-lactam ± aminoglycoside ± vancomycin Consider antifungals Add acyclovir Add clindamycin Add doxycycline

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Table 2 Select antimicrobial administration information (Lexicomp, Micromedex) Medication

Route of administration

Other pearls

Acyclovir Ampicillin

Intermittent IV over at least 60 min IM IV push: doses 500 mg 3e5 min, > 500 mg 10e15 min Intermittent IV: 10e15 min IM IV push: 3e5 min Intermittent IV: 20e60 min IM Intermittent IV: 30 min

Maintain adequate hydration to prevent crystal-induced nephropathy Short stability (duration of stability dependent on concentration and temperature)

Aztreonam

Cefepime

Ceftriaxone

Ceftazidime

Ciprofloxacin Clindamycin Gentamicin

Levofloxacin

IM IV push: 2e5 min Intermittent IV: Neonates: 60 min Infants, children, adolescents: 15e30 min IM IV push: 3e5 min Intermittent IV: 15e30 min Intermittent IV: 60 min IM Intermittent IV: 10e30 min IM Intermittent IV: 30e120 min Conventional doses may be infused over <30 min Intermittent IV: 60e90 min (<500 mg: over 60 min, >/ ¼ 500 mg: over 90 min)

Metronidazole Piperacillin-Tazobactam

IV push
3 mo, children, and adolescents: 3e5 min Intermittent IV: Infants < 3 mo 30 min Infants
3 mo, children, adolescents 15e30 min Intermittent IV: 30e60 min Intermittent IV: 30 min

Vancomycin

Intermittent IV: over 60 min

Meropenem

Adult clinical trials have described administration over 3e5 minutes at final concentration 40 mg/mL and 100 mg/mL Avoid IV push administration in young infantsdmay be a risk factor for cardiopulmonary events occurring from interactions between ceftriaxone and calcium (Bradley, 2009). Avoid in hyperbilirubinemiadcan displace bilirubin from albumin

IMdslower absorption and lower peak concentrations Requires PK monitoring Maintain adequate hydration Avoid administration through IV line with solution containing multivalent cations

Extended IV infusion (over 3e4 hours) has been used for treatment of multidrug-resistant organisms Slow down infusion (over 90e120 min) if Red Man Syndrome occurs Administration of antihistamines before infusion may prevent/minimize Requires PK monitoring

IM ¼ intramuscular; IV ¼ intravenous; PK ¼ pharmacokinetic.

pressure can occur by (1) increasing heart rate via beta-1 receptors and/or (2) increasing SVR via alpha-1 receptoremediated vasoconstriction. A summary of vasoactive medications used in sepsis can be found in Table 5 and Figure 1. Historically, dopamine has been favored as the vasopressor of choice for pediatric sepsis. However, in light of the 2016 Surviving Sepsis Campaign geared toward adults and the 2017 American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock, dopamine has been scrutinized as a first-line agent, aside from the neonatal population (Davis et al., 2017; Rhodes et al., 2017). Slight differences exist as it relates to shock in pediatrics relative to adults when faced with a patient's initial physical examination findings, which should dictate vasopressor selection. The pediatric population has an increased likelihood to present with “cold shock,” a state of elevated SVR and low CO, whereby adults and some adolescents

are more likely to present with “warm shock,” a state of low SVR and normal or increased CO. For this reason and contrary to the adult population, low CO, and not low SVR, is associated with mortality in pediatric septic shock, given this population's inability to increase heart rate and stroke volume as a compensatory mechanism (Davis et al., 2017; Martin and Weiss, 2015). Epinephrine In contrast to adult recommendations, epinephrine, a nonselective alpha and beta receptor agonist, is often considered first line in pediatric patients for hemodynamic improvement in the setting of cold shock (i.e., weak peripheral pulses, cold distal extremities, and prolonged capillary refill time) (Davis et al., 2017). At lower doses (i.e., 0.1 mcg/kg/min), epinephrine primarily works to augment heart rate and cardiac contractility through its effects on

Table 3 Vasopressor/inotrope dosing Vasopressor

Dose range

Common dose titrations

Dopamine Epinephrine Norepinephrine Vasopressin

5e20 mcg/kg/min 0.05e1 mcg/kg/min 0.05e1 mcg/kg/min 0.3e2 milliunits/kg/min

5 mcg/kg/min 0.05e0.1 mcg/kg/min 0.05e0.1 mcg/kg/min 0.1e0.5 milliunits/kg/min

0.5e20 mcg/kg/min Loading dose (optional): 50 mcg/kg over 10e60 min Continuous infusion: 0.25e0.75 mcg/kg/min

1e2 mcg/kg/min 0.25 mcg/kg/min

Inotrope Dobutamine Milrinone

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S.P. Rooney et al. / Journal of Radiology Nursing xxx (2019) 1e8 Table 4 Goal MAP based on age Age

MAP goal

0e12 months 1e3 years 3e5 years 5e10 years 10e14 years
14 years

40e55 45e60 50e70 55e75 60e75 65e75

MAP ¼ mean arterial pressure.

beta-1 adrenergic receptors. As doses rise (i.e., >0.1 mcg/kg/min), the alpha-1 receptoremediated vasoconstriction predominates. The results of a prospective, double-blind, randomized control trial revealed no difference in the MAP achieved nor the median time to achieve the desired MAP goal (35.1 h vs. 40 h, p ¼ .26) with norepinephrine relative to epinephrine in a population of critically ill adult patients (Mysburgh et al., 2008). Despite epinephrine's association with the development of tachycardia, lactic acidosis, and increased insulin requirements, no difference in 28- or 90-day mortality was observed between the two drugs. Lactic acidosis and lower arterial pH values associated with epinephrine has been reported in patients with severe sepsis; however, findings to suggest worse outcomes have yet to be proven (Stratton et al., 2017). Interestingly, adult guidelines do not recommend epinephrine as a first-line vasopressor because of its ability to increase lactate production via beta-2 adrenergic receptor stimulation, preventing the use of lactate as a surrogate to guide resuscitation (Rhodes et al., 2017). However, given the physiology of pediatric shock, epinephrine is more efficacious to overcome the low CO state, which is less likely to be an issue in the adult population. Norepinephrine The 2016 revision to the Surviving Sepsis Campaign recommends norepinephrine as the first-line vasopressor for adults (Rhodes et al., 2017). However, in the 2017 guidelines for pediatrics, norepinephrine is recommended as first line only in patients presenting with warm shock or low SVR (i.e., bounding pulses, pink extremities, and “flash” capillary refill, widened pulse pressure) (Davis et al., 2017). Norepinephrine can also be considered as an adjunct to epinephrine in the setting of sustained cold shock when hemodynamic improvement is not obtained with monotherapy. Norepinephrine, a dopamine derivative, acts on alpha and beta

receptors but preferentially targets the alpha receptors. This results in vasoconstriction and an increase in MAP (Stratton et al., 2017; Rhodes et al., 2017). Relative to dopamine, norepinephrine induces minimal change in heart rate and stroke volume. Avni et al. published a systematic review in 2015 comprising 32 trials (3,544 patients) of which 11 specifically compared norepinephrine to dopamine in adults. This review demonstrated an 11% absolute risk reduction and decreased all-cause mortality with norepinephrine relative to dopamine (Avni et al., 2015). Furthermore, the risk for arrhythmias was nearly double with dopamine when compared with norepinephrine, risk reduction (RR) 0.48 (95% CI, 0.40e0.58), corresponding to an absolute RR of 52%.

Vasopressin Vasopressin, an endogenous peptide hormone that results in contraction of vascular smooth muscle through V1 receptors, is considered a viable adjunct to norepinephrine in the setting of vasodilatory-mediated hypotension unresponsive to high doses of norepinephrine alone (Davis et al., 2017; Rhodes et al., 2017; Stratton et al., 2017). For this reason, vasopressin is most efficacious when initiated in the setting of warm shock, given its ability to increase SVR via a noncatecholamine-mediated mechanism. Vasopressin can also be used as an adjunct to reduce norepinephrine dosages, but its use as monotherapy is not recommended (Rhodes et al., 2017). Given its noncatecholamine-mediated mechanism, vasopressin's efficacy is preserved in the setting of alpha-adrenergic receptor downregulation. Depletion of endogenous vasopressin can occur within hours of septic shock, and repletion exogenously can improve hypotension via peripheral vasoconstriction (Stratton et al., 2017). Despite prior studies establishing improved blood pressure, reduced catecholamine requirements, and enhanced renal function associated with vasopressin, Russell et al., 2008 conducted a multicenter, randomized, double-blind trial to determine if low-dose vasopressin in combination with norepinephrine relative to norepinephrine alone would decrease mortality. The results of the study concluded no significant difference in 28-day or 90-day mortality between the two groups. However, in the predefined group of less-severe septic shock, 28-day mortality was lower in the vasopressin group relative to the norepinephrine group (26.5% vs. 35.7%, p ¼ .05). In addition, the dose of norepinephrine was significantly lower in the combination therapy arm during the first 4 days relative to the

Table 5 Summary of vasoactive medications used in sepsis (Sutton et al.) Agent

Norepinephrine Epinephrine <0.1 mcg/kg/min Epinephrine
0.1 mcg/kg/min Vasopressin

Receptor binding

Use/pearls

b1

b2

a1

þþþ þþþþ

þþ þþþ

þþþþþ

V1

V2

DA First line for warm shock Hinders lactate as a marker of resuscitation efforts First line for cold shock

þþþþþ þþþ

þþþ þþþþþ

Dopamine 1e5 mcg/kg/min Dopamine 6e15 mcg/kg/min Dopamine >15 mcg/kg/min Dobutamine

þþþþþ

Milrinone

Increased cAMP

þþþþ

þþ

Adjunct to high-dose norepinephrine if persistent hypotension and signs of warm shock Tachyarrhythmias (highest risk) Low dose is an alternative to epinephrine for cold shock High dose is an alternative to norepinephrine for warm shock First line for shock in neonates

þþþ þþþ

5

þ

Decrease in SVR and hypotension (b2 mediated) can be offset with norepinephrine Loading dose optional due to hypotension cAMP-mediated excess vasodilatory hypotension can be offset with norepinephrine

cAMP ¼ cyclic adenylate monophosphate; DA = dopamine; SVR ¼ systemic vascular resistance.

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norepinephrine monotherapy arm (p < .001). These findings are consistent with other studies, which have yielded similar results as it relates to vasopressin's lack of an effect on improving mortality but does exhibit a favorable sparing effect on norepinephrine dose (Rhodes et al., 2017). Interestingly, Choong et al. evaluated the addition of low-dose vasopressin or placebo in addition to catecholamine therapy in a pediatric population with vasodilatory shock, which demonstrated no difference in time to hemodynamic stability but a nonstatistically significant trend toward increased mortality (Choong et al., 2009). Dopamine According to the latest adult guidelines, dopamine can be substituted for norepinephrine only in those with low risk of tachyarrhythmias or bradycardia and is no longer considered to be first-line treatment for hypotension in sepsis (Rhodes et al., 2017). That said, in the pediatric population, dopamine at low doses can be used as an alternative to epinephrine for cold shock and at high doses as an alternative to norepinephrine for warm shock. The hemodynamic effects of dopamine are dose dependent. Low doses, in the range of 1e5 mcg/kg/min, act on dopaminergic receptors, to produce renal and mesenteric vasodilation, augmenting renal blood flow and urine output. Historically, low-dose dopamine was recommended for renal protection as it was theorized to re-establish renal perfusion and offer protection against acute kidney injury. However, low-dose dopamine for renal protection is no longer recommended. Bellomo et al. conducted a study in 2000 which demonstrated low-dose dopamine at 2 mcg/kg/min conferred no difference in peak serum creatinine concentration relative to placebo (Bellomo et al., 2000). Several studies since this time have yielded similar findings (Stratton et al., 2017). Intermediate doses of 5e15 mcg/kg/min activate beta-1 receptors, increasing heart rate, cardiac contractility, and CO. Higher doses of dopamine (i.e., >15 mcg/kg/min) produce alpha-adrenergic effects, resulting in vasoconstriction, and increased MAP. Dosages greater than 20 mcg/kg/ min are not recommended due to significant vasoconstriction and possible ischemia. The guidelines do not favor dopamine because of more tachycardia, precipitating arrhythmias, and overall less potency relative to norepinephrine, making it less effective at reversing hypotension in patients with septic shock. That said, the guidelines do mention that given dopamine's ability to augment CO, it may have favorable effects in pediatric patients with diminished systolic function and low CO state. Of note, Ventura et al. conducted a study comparing dopamine (5e10 mcg/kg/min) to epinephrine (0.1e0.3 mcg/kg/ min) in the setting of pediatric septic shock, which concluded dopamine's association with an increased risk of death relative to epinephrine (Ventura et al., 2015). That said, this study is not without limitations, as the mechanism of action for dopamine at the dose used in the study relative to epinephrine is not a fair comparison. Patients randomized to the dopamine arm might have benefited from early initiation of an alpha agonist if vasodilation was the main reason for shock, in which case one would have expected those in the dopamine group to respond poorly, given lack of alpha-adrenergic vasoconstriction at the dose used. A study published a year later in 2016 using higher dose dopamine (10e20 mcg/ kg/min) relative to epinephrine (0.1e0.3 mcg/kg/min) in a pediatric population demonstrated that those randomized to receive epinephrine were significantly more likely to have resolution of shock within the first hour than those who received dopamine (12 of 29 versus 4 of 31 patients; OR, 4.8; 95% CI, 1.3e17.2) (Ramaswamy et al., 2016). Patients randomized to receive epinephrine also had significantly better organ function on day 3 of treatment and more organ failureefree days. Overall mortality did not statistically differ

between groups. Although epinephrine is the first-line vasopressor recommended in the latest guidelines for pediatric septic shock, and studies favor epinephrine over dopamine, it's currently recommended by experts that neonates should receive dopamine for fluid-refractory shock with or without dobutamine before considering epinephrine (Davis et al., 2017). Dobutamine Dobutamine, an inotrope, works predominantly on beta-1 receptors to augment contractility and heart rate, while decreasing SVR through its beta-2 receptor effects. According to the latest pediatric septic shock guidelines, dobutamine can be instituted in patients demonstrating low CO with adequate or increased SVR (Davis et al., 2017). Ideally, the use of dobutamine should only be used in the setting of myocardial dysfunction. In these patients with decreased cardiac reserve, adequate CO is not achieved to permit oxygen delivery to tissues. The guidelines recognize that identification of patients with decreased cardiac reserve can present challenges and that consideration be given to dobutamine when signs of poor perfusion exist despite volume repletion and adequate MAP with fluids and vasopressors (Rhodes et al., 2017; Stratton et al., 2017). Routine administration of dobutamine in an effort to improve tissue perfusion and oxygen delivery by augmenting CO in all patients does not improve outcomes as proven by two separate trials (Annane et al., 2007; Hayes et al., 1994). Milrinone Milrinone, a phosphodiesterase inhibitor, has similar effects as dobutamine in that it improves contractility and heart rate and reduces SVR but has the additional benefit of inducing relaxation of the myocardium. Like dobutamine, this effect can be beneficial in the setting of myocardial dysfunction. Barton et al. evaluated the addition of milrinone to catecholamines in a population of pediatric patients with septic shock, which demonstrated the addition of milrinone significantly increased cardiac index, stroke volume, and oxygen delivery relative to placebo (Barton et al., 1996.) Milrinone in combination with beta-adrenergic agonists can have a synergistic effect, given their ability to each potentiate cyclic adenylate monophosphate (cAMP) production (Davis et al., 2017). Furthermore, milrinone can offer additional benefit, given its mechanism in improving CO is preserved in the setting of beta-adrenergic receptor downregulation, one that would render beta-adrenergic agonists less effective. Milrinone's main downside is accumulation in the setting of renal dysfunction, given its clearance mechanism and long half-life. If hypotension-related toxicity ensues, norepinephrine can be administered to counteract the cAMP-mediated vasodilatory effects by inducing alpha-adrenergic vasoconstriction. A loading dose administered before a continuous infusion is optional, but according to the latest guidelines for pediatric septic shock is not recommended. If clinicians elect to administer a loading dose, a fluid bolus administered concomitantly is suggested to offset milrinone's ability to decrease SVR and blood pressure. Vasoactive Administration A common misconception is administration of vasopressors must be through a central line as opposed to a peripheral line. Data are lacking on level of risk as it relates to tissue damage among the various vasopressors. The guidelines mention risk is likely related to concentration of agent used and duration of infiltration before recognition. The latest guidelines imply norepinephrine and highdose dopamine be administered centrally as opposed to peripherally (Davis et al., 2017).

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S.P. Rooney et al. / Journal of Radiology Nursing xxx (2019) 1e8

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Fluid refractory shock?

Cold Shock

Warm Shock

Titrate epinephrine

Titrate norepinephrine

Use dopamine 5-9 mcg/kg/min if epinephrine not availalbe

Use dopamine ≥ 10 mcg/kg/min if norepinephrine not available

Normal Blood Pressure, Cold Shock, on epinephrine?

Begin milrinone

Low Blood Pressure, Cold Shock, on epinephrine?

Low Blood Pressure, Warm Shock, on norepinephrine?

Add norepinephrine

Add vasopressin

Figure 1. Vasopressor algorithm for the management of hemodynamic support in infants and children (Davis et al., 2017).

One large retrospective cohort study evaluated pediatric patients who received various vasoactive medications peripherally and found of 102 patients, the peripheral IV infiltration rate was only 2%, none of which resulted in injury or intervention (Patregnani et al., 2017). Cardenas-Garcia et al. retrospectively evaluated the safety of different vasoactive medication administered via a peripheral line in the adult population (Cardenas-Garcia et al., 2015). The results report only 16 extravasations in 506 patients receiving norepinephrine. In all cases, identification was prompt and no tissue damage occurred after local injection of phentolamine, an alphaadrenergic antagonist. Furthermore, Lampin et al. retrospectively evaluated the safety of peripheral administration of norepinephrine in pediatric septic shock and demonstrated in the 19% of patients receiving norepinephrine peripherally (n ¼ 27/144), no adverse effects were observed (Lampin et al., 2012). Given low rate of complications, vasoactive medications are likely safe temporarily through a peripheral line, assuming frequent nursing checks, prompt recognition of infiltration, administration through a large bore (i.e., >20 gage), and readily available phentolamine as an antidote. Adjunct therapies In catecholamine-resistant shock, defined as failure of at least one and generally two vasoactive medications, guidelines consistently recommend addition of adjunct therapies based on clinical parameters or patient-specific risk factors. Although limited evidence exists, hydrocortisone is recommended for any patient at risk for adrenal insufficiency, such as patients with diseases requiring chronic steroid use or patients with hypothalamic-pituitary-adrenal axis disorders (Prusakowski and Chen, 2017; Simmons et al., 2012). Per the guidelines, hydrocortisone is recommended for any patient in shock despite therapy with epinephrine and norepinephrine and after a baseline random cortisol level is obtained (Davis et al., 2017). If all of these therapies fail, a patient is deemed to be in refractory shock and other more invasive therapies are considered such as extracorporeal membrane oxygenation (ECMO). Survival for septic patients placed on ECMO is approximately 50%, with some reports stating a 75% survival rate (Davis et al., 2017).

Performance bundle In addition to the use of “recognition” and “resuscitation and stabilization” bundles, the 2017 Pediatric and Neonatal Septic Shock guidelines recommend the development or adoption of a “performance” bundle to monitor, improve, and sustain adherence to best practices in the management of septic patients. A core component of the performance bundle is measuring adherence and achievement of goals outlined in both the “recognition” and “resuscitation and stabilization” bundles. Root cause analysis should then be performed to identify barriers to adherence, and an action plan to address identified barriers should be developed. Assessment of barriers to adherence and “unintended consequences” (i.e., inappropriate antibiotic duration and/or fluid overresuscitation) should also be a component of the performance bundle (Davis et al., 2017).

Conclusion To align with the latest guidelines, it is imperative that institutions adopt a “recognition” bundle, “resuscitation and stabilization” bundle, and a “performance” bundle to decrease morbidity and mortality associated with sepsis and septic shock. A sepsis screening tool to promptly detect patients at risk for septic shock using objective data (i.e., temperature, past medical history, heart rate, blood pressure, capillary refill, respiratory rate, and so forth) followed by immediate clinical assessment by a physician remains a hallmark component of the recognition bundle. The resuscitation and stabilization bundle involves timely initiation of fluids and vasopressors (if needed) to restore compromised perfusion and antibiotics to treat likely pathogens. The performance bundle is designed to monitor and adopt process improvement initiatives to promote compliance with the latest guideline recommendations. The aforementioned sepsis bundles are an integral component of best practice and should be incorporated to facilitate standardization of care, in hopes of improving outcomes as it relates to pediatric sepsis.

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Please cite this article in press as: Rooney SP et al., Management of Sepsis in the Pediatric Patient, Journal of Radiology Nursing, https://doi.org/ 10.1016/j.jradnu.2019.07.009