CLINICAL MANAGEMENT GUIDELINES OF PEDIATRIC SEPTIC SHOCK
C. Praveen Khilnani, MD, FAAP(USA), FCCM(USA) *
Pediatric Intensivist, Apollo Center for Advanced Pediatrics, IP Apollo hospital, New Delhi.*
Introduction:

Surviving Sepsis campaign guidelines for management of Severe sepsis in children:
In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for other supportive therapies in sepsis that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and to improve outcome in severe sepsis.(1)The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences and electronic-based discussion among subgroups and among the entire committee. Pediatric representatives attended the various section meetings and workshops to contrast adult and pediatric management.

Surviving sepsis campaign guidelines are now published for adults(1) with pediatric considerations(2) as a small section based on the available evidence.

Guidelines of hemodynamic support for pediatrics are also published(3). Practical application of this information in Indian set up in a child with septic shock will be discussed. In 1992 ACCP/SCCM consensus guidelines for definitions of sepsis were published by Bone et al(4). Definitions have also been recently revised for pediatrics recently ,as follows(5).

Definitions(5)
Hypovolemia is the most common cause of pediatric shock.
Septic shock is the prototype combination of hypovolemia, cardiogenic and distributive shock. Following are the latest definitions published in 2005, related to sepsis and septic shock.

SIRS(a)(Systemic Inflammatory Response Syndrome)
The presence of at least two of the following four criteria, one of which must be abnormal temperature or leukocyte count:
  • Core(b) temperature of > 38.5°C or < 36°C
  • Tachycardia, defined as a mean heart rate > 2 SD above normal for age in the absence of external stimulus, chronic drugs or painful stimuli; or otherwise unexplained persistent elevation over a 0.5- to 4-hr time period OR for children "<1 yr old: bradycardia, defined as a mean heart rate <10th percentile for age in the absence of external vagal stimulus, beta-blocker drugs, or congenital heart disease; or otherwise unexplained persistent depression over a 0.5-hr time period.
  • Mean respiratory rate > 2 SD above normal for age or mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia.
  • Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) or >10% immature neutrophils.

Infection:
A suspected or proven (by positive culture, tissue stain, or polymerase chain reaction test) infection caused by any pathogen OR a clinical syndrome associated with a high probability of infection. Evidence of infection includes positive findings on clinical exam, imaging or laboratory tests (e.g.,white blood cells in a normally sterile body fluid, perforated viscus, chest radiograph consistent with pneumonia, petechial or purpuric rash, or purpura fulminans)

Sepsis:
SIRS in the presence of or as a result of suspected or proven infection.

Severe sepsis:
Sepsis plus one of the following: cardiovascular organ dysfunction OR acute respiratory distress syndrome OR two or more other organ dysfunctions. Organ dysfunctions are defined in Table 2.


Septic shock:
Sepsis and cardiovascular organ dysfunction as defined in Table 2.

(Modifications from the adult definitions are highlighted in boldface.
a See Table1 for age-specific ranges for physiologic and laboratory variables; b core temperature must be measured by rectal, bladder, oral, or central catheter probe).

Table 1: Age-specific Vital signs and Laboratory values
Age group

 

Heart rate

Respiratory rate (breaths/min)

Leukocyte count x 1000/cu mm

SBP

Tachycardia

Bradycardia

  0-1

  >180 <100 >50

  >34

  <65

1wk-1mo   >180 <100 >40

  >19,5 or<5

  <75

1mo-1yr   >180 <90 >34

  >17.5 or <5

  <100

  2-5yr   >140   NA >22

  >15.5 or <6

  <94

  6-12yrs

  >130   NA >18

  >13.5 or<4.5

  <105

  13 -< 18yr   >110   NA >14

  >11or <4.5

  <117



*lower values for Heart rate, Leukocyte count, SBP (Systolic Blood Pressure) are for the 5th percentile and upper values for Heart rate, Respiratory rate or Leucocyte count for the 95th percentile

Table 2: Organ Dysfunction Criteria

Cardiovascular dysfunction
Despite administration of isotonic intravenous fluid bolus > 40 mL/kg in 1 hr
  • Decrease in BP (hypotension) <5th percentile for age or systolic BP > 2 SD below normal for age a
    OR
  • Need for vasoactive drug to maintain BP in normal range (dopamine>5 mcg/kg/min or dobutamine, epinephrine or norepinephrine at any dose)
    OR
  • Two of the following
    Unexplained metabolic acidosis: base deficit > 5.0 mEq/L
    Increased arterial lactate > 2 times upper limit of normal
    Oliguria: urine output <0.5 ml/kg/hr
    Prolonged capillary refill: > 5 secs Core to peripheral temperature gap > 3°C
    Respiratory b
  • PaO2/FIO2 < 300 in absence of cyanotic heart disease or preexisting lung disease
    OR
  • PaCO2 > 65 TORR or 20 mm Hg over baseline PaCO2
    OR
  • Proven need c or > 50% FIO2 to maintain saturation > 92%
    OR
  • Need for non-elective invasive or non-invasive mechanical ventilation d
    Neurologic
  • Glasgow Coma Score <11
    OR
  • Acute change in mental status with a decrease in Glasgow Coma Score>3 points from abnormal baseline
    Hematologic
  • Platelet count 80,000/mm3 or a decline of 50% in Platelet count from highest value recorded over the past 3 days (for chronic hematology/oncology patients)
    OR
  • International normalized ratio > 2
    Renal
  • Serum creatinine > 2 times upper limit of normal for age or 2-fold increase in baseline creatinine
    Hepatic
  • Total bilirubin > 4 mg/dL (not applicable for newborn)
    OR
  • ALT 2 times upper limit of normal for age
    (BP, blood pressure; ALT, alanine transaminase. a See Table 1; b acute respiratory distress syndrome must include a PaO2/FIO2 ratio <200 mm Hg, bilateral infiltrates, acute onset, and no evidence of left heart failure. Acute lung injury is defined identically except the PaO2/FIO2 ratio must be <300 mm Hg; c proven need assumes oxygen requirement was tested by decreasing flow with subsequent increase in flow if required; d in post-operative patients, this requirement can be met if the patient has developed an acute inflammatory or infectious process in the lungs that prevents him or her from being extubated.)

The detection of altered organ function in the acutely ill patient constitutes multiple organ dysfunction syndrome (two or more organ involvement). The terminology dysfunction identifies this process as a phenomenon in which organ function is not capable of maintaining homeostasis. This process which may be absolute or relative can be more readily identified as a continuum of change over time.

The detection of altered organ function in the acutely ill patient constitutes multiple organ dysfunction syndrome (two or more organ involvement). The terminology dysfunction identifies this process as a phenomenon in which organ function is not capable of maintaining homeostasis. This process which may be absolute or relative, can be more readily identified as a continuum of change over time.

Rapid cardiopulmonary assessment and clinical examination of a patient in shock: The most effective and sensitive physiological monitoring available is repeated and careful physical examination by an experienced and competent observer. Because the shock can be rapidly fatal the child must be assessed immediately and comprehensively. In a healthy child, the cardiovascular system has remarkable compensatory capability, so there is generally a stability of blood pressure and only an increase in pulse until there is sudden decompensation which may lead to precipitous cardiac arrest.

In clinical examination one must note following points very carefully:
  1. Mental status: Restless, agitated, anxious, progressive lethargy
  2. Skin: Temperature, colour, turgor, peticheal rash may be present in meningococcemia or disseminated intravascular coagulation.
  3. Cardiovascular: By far, the most significant physical findings in septic shock results from autonomic responses to stress. In children tachycardia occurs early. The younger the child, cardiac output is more dependent on heart rate rather than on increase in stroke volume.
    Alteration in blood pressure is a late manifestation of hypovolemia in children, occurring faster in children. Diastolic blood pressure begins to fall early as vascular tone begins to decrease. Systolic Blood pressure is well maintained initially and only begins to fall once hemodynamic compromise is severe. Decreasing blood pressure signifies decompensated stage of shock.
    In warm phase of septic shock, capillary refill time may be normal, however signs of hyperdynamic circulation, widened pulse pressure, hyperdynamic apex beat are important signs. Capillary refill time of more than 5 seconds is always abnormal.
  4. Respiratory: Respiratory rate is increased to compensate for metabolic acidosis, secondly if ARDS is developing, progressive worsening of respiratory distress may occur.
  5. Urine output: Oliguria is common leading to anuria.
    It is important to remember that physical findings will vary according to the stage of shock.

Emergency Management:
Management of child with septic shock is best started by aggressive goal-directed management in the emergency department.

The treatment of septic shock in children is aimed at optimizing perfusion of critical vascular beds and preventing or correcting metabolic abnormalities arising due to cellular hypoperfusion. The ultimate goals are to prevent or reverse the defects in cellular substrate delivery and metabolism and to support entire patient until homoeostasis is restored. For all forms of shock, treating the underlying cause is mandatory. Speed is essential.

Delays in making the diagnosis and initiating treatment (fluid resuscitation as well as appropriate antibiotics), as well as suboptimal resuscitation, contribute to the developments of peripheral vascular failure and irreversible defects in oxygen use which can culminate in vital organ dysfunction.

Priorities of Treatment:

Two major priorities in treatment of septic shock are:
  1. Rapid assessment of patient's disease process
  2. Achievement of cardiopulmonary stability

VIP approach can be used in initial treatment of shock
V standing for ventilation
I for infusion
P for pumping or cardiovascular support
Initial resuscitation of child in shock involves assessment of airway, administration of oxygen and establishment of intravenous access.

Airway and respiratory Support (Ventilation):
The first priority is to secure the airway. Ensure adequate oxygenation and ventilation. High flow oxygen system (eg Venturi masks) must be used. Oxygen supply is optimized by maintaining arterial oxygen saturation by correcting anemia and by increasing cardiac output and systemic blood flow. If airway is unstable and adequate oxygenation and ventilation is not achieved, do endotracheal intubation and provide mechanical ventilation. Because mechanical ventilation abolishes or minimises work of breathing, reduces oxygen consumption and improves oxygenation, early respiratory support benefits patients with severe shock in addition to those with ARDS/ Pulmonary edema.

Cardiovascular Support:
Tissue blood flow must be restored by achieving and maintaining an adequate cardiac output and by ensuring that systematic blood pressure is sufficient to maintain perfusion of vital organs. Cardiovascular support involves manipulation of heart rate and rhythm and of three determinants of stroke volume (preload, myocardial contractility and after load).

Rate and Rhythm:
Assuring adequate heart rate and rhythm is basic to life support. Monitoring of heart rate is essential in guiding therapy. It is important to keep in mind that heart rate varies according to age and heart rates are acceptable within a wide range of normal for age. That includes correction of hypoxia, acidosis and electrolyte disturbances.

Preload And Volume Replacement:
Fluid therapy by peripheral, intraosseous or central venous access should be initiated after adequate control of airway and breathing has been accomplished.
Preload optimisation is most efficient way of increasing cardiac output. Rapid intravascular volume expansion guided by repeated clinical examination and urine output is frequently adequate to restore blood pressure and peripheral perfusion.
Pulmonary edema with volume overload is rare in child patients. Volume replacement of 10-20 ml/kg with isotonic solutions such as normal saline or ringers lactate can be safely given and repeated if necessary (typically 40-80 ml/Kg may be required). Controversy continues about whether colloids or crystalloids are preferable (5-8). At present, a judicious mixture of crystalloids, blood products to maintain hemoglobin and clotting factors and colloids to maintain colloid oncotic pressure seems most appropriate and reasonable. As well as being fundamental to the management of hypovolemic shock, replacement of circulating volume is important in managing patients with distributive shock.

Choice Of Fluid For Volume Replacement
Blood
: To maintain hemoglobin at around 10 gm.
Crystalloids: Cheap, convenient to use, free of side-effects. Rapidly distributed across intravascular and interstitial spaces. Volume 2-4 times of colloid required for same volume expansion, transient volume expansion.
Colloids (starch, gelatins) produce greater and more sustained increase in plasma volume. Fresh frozen plasma supplies clotting factors.
Albumin: Should be used only in special circumstances eg burns and septic shock. Cost of therapy is an issue while considering colloid solutions for expansion of plasma volume.

Inotropic And Vasoactive Agents: Sepsis induced myocardial depression is well documented. Before cardiac output and perfusion pressure are restored with drugs,electrolyte abnormalities(such as ionized hypocalcemia) that might impair cardiac performances should be corrected. Metabolic acidosis secondary to tissue hypoxia should be managed by treating the cause. Sodium bicarbonate should be given only for severe acidosis that fails to respond to adequate resuscitation.

If signs of shock persist despite adequate volume replacement and perfusion of vital organs is jeopardized, Inotropic drugs may be used to improve cardiac output(9). The effects of particular drug in an individual patient are unpredictable and must be closely monitored. Drugs commonly used in pediatric ICU to increase myocardial contractility include:

Dopamine: It has alpha, beta and dopaminergic (delta) actions that are dose dependant. At low doses (<3 mcg/kg/min) it primarily causes weak renal and splanchnic vasodilatation,and at 3mcg to 10mcg/kg/min it exerts a positive myocardial inotropic efect. At higher doses (> 10 mcg/kg/min), it has strong vasoconstricting alpha effect, in addition to positive inotropic effect. So called 'Renal dose' of dopamine (2-5 mcg/kg/min) for renal vasodilation has been over emphasized and is of less practical significance in clinical setting. The primary indication for dopamine is the need to increase myocardial contractility after preload restoration. Usual dose is 5-20 mcg/kg/min titrated to desired effect. Dopamine(in doses > 5 mcg/kg/min) should preferably, be given via central line to prevent ischemic necrosis of the skin.

Dobutamine: It is selective beta 1 agonist. It causes an increase in cardiac contractility and reduces peripheral resistance. The reduction in afterload and improved myocardial performance lowers ventricular filling pressures. Usual dose is 5mcg to 20mcg/kg/min. It should not be used alone in septic shock due to risk of further drop in blood pressure. Dopamine or adrenaline can be used to prevent hypotension due to vasoconstrictive effect.

Adrenaline (Epinephrine): It is an alpha and beta adrenergic agonist. It is used in situations where dominant hemodynamic feature is peripheral vascular failure as in septic shock. At higher doses severe vasoconstriction can lead to lactic acidosis and renal and splanchnic ischemia. The usual dose is 0.1 mcg/kg/min to 1 mcg/kg/min. It should be titrated closely and minimum dose should be used for required.

Noradrenaline (Norepinephrine): An alpha and beta agonist (alpha> beta effect). Cardiac contractility is increased but it also causes massive increase in myocardial oxygen consumption and afterload, so cardiac output may not actually increase. Usual dose is 0.05 -1 mcg/ kg/ min. In severe septic shock with hypotension despite use of adrenaline secondary to intense vasodilatation,noradrenaline may be useful in increasing peripheral vascular resistance to improve blood pressure. Vasopressin In severe warm shock with hypotension resistant to noradrenaline, vasopressin may be tried.

Vasopressin:
In severe warm shock with hypotension resistant to noradrenaline,vasopressin may be tried.

Afterload reduction
Caution should be used in using afterload reduction indiscriminately in septic shock without simultaneous inotropic support. Both nitroprusside and nitroglycerin lower systemic vascular resistance in children and are useful afterload reducing agents. These agents act via generation of nitric oxide. Nitroprusside has potent peripheral arterial vasodilating effects. Nitroglycerin is more potent venodilator and pulmonary vasodilator. Close monitoring and volume augmentation are frequently required when vasodilators are used to decrease pulmonary vascular resistance.

Amrinone and milrinone are newer inotropic agents with properties of afterload reduction and myocardial diastolic relaxation (lusotropic effect)(10=12). Milrinone is commonly used for cardiogenic shock which is frequently associated with septic shock.

Table 4
ACCM Recommendations for neonatal and pediatric septic shock management.(3)
0 min Recognize mental status,poor perfusion

5 min: Maintain airway ,establish access push 20ml/kg up to 60ml/kg fluid.
Observe in PICU if + response
15min: Recognize fluid refractory shock,start central line ,dopamine, establish arterial monitoring.
if fluid refractory dopamine resistant shock(10mic/kg/min).start epinephrine for cold,norepinephrine for warm shock.
If Risk of adrenal insufficiency(38-39)
Give hydrocortisone
Normal BP, Cold shock SVC O2 sat <70 add vasodilator, consider volume
Low BP, Cold shock, SVC O2 sat <70
Titrate volume and Epinephrine
Low BP, Warm shock: give Norepinephrine, fluid, consider Vasopressin


Early goal directed therapy helps keep the cost and duration of hospital stay to a minimum.
Following section describes the current consensus on management of sepsis in children based on available evidence. (2) These guidelines mainly apply to the pediatric age group. These guidelines may not be applicable to the neonatal age group, though occasional reference has been made to the neonatal situations.

Need for early intubation and ventilation
Due to low functional residual capacity, young infants and neonates with severe sepsis may require early intubation (13). Unfortunately no objective clinical criteria specific to pediatric septic shock for timing of endotracheal intubation (other than the standard indications,which include shock) exist in literature. Therefore, it is reasonable to consider endotracheal intubation when shock is persistent even after a volume resuscitation of>40-60 ml/kg. Children with sepsis requiring aggressive fluid resuscitation frequently have worsening tachypnea and increasing oxygen requirement clinically depicting early acute respiratory distress syndrome(ARDS). These patients will require early intubation and mechanical ventilation. The principles of lung-protective strategies (low tidal volumes and permissive hypercapnia) are applied to children as they are to adults. In premature infants, additional attention is paid to avoiding hyperoxemia to prevent retinopathy.

Fluid Resuscitation:
Intravenous access for fluid resuscitation and inotrope/vasopressor infusion is more difficult to attain in children than in adults. The American Heart Association has well established Pediatric advanced life support(PALS) guidelines for emergency establishment of intravascular support ,including intraosseous access(14). On the basis of many studies, it is accepted that aggressive fluid resuscitation with crystalloids or colloids is of fundamental importance to survival of septic shock in children (8,15). There is only one randomized, controlled trial comparing the use of colloid with crystalloid resuscitation (dextran, gelatin, lactated Ringers, or saline) in children with dengue shock (8). All these children survived, regardless of the fluid used, but the longest time to recovery from shock occurred in children who received lactated Ringers. Among patients with the narrowest pulse pressure, there was a suggestion that colloids were more effective than crystalloids in restoring normal pulse pressure. Fluid infusion is best initiated with boluses of 20 mL/kg over 5-10 mins, titrated to clinical monitors of cardiac output, including heart rate, urine output, capillary refill and level of consciousness. A 60 ml syringe filled with fluid drawn via the fluid bag with a three way connection can be conveniently used to push fluid boluses in the absence of a volumetric pump.

Children normally have a lower blood pressure than adults and can prevent reduction in blood pressure by vasoconstriction and increasing heart rate. Therefore blood pressure by itself is not a reliable endpoint for assessing the adequacy of resuscitation. However once hypotension occurs, cardiovascular collapse may soon follow.

Hepatomegaly occurs in children who are fluid overloaded and can be a helpful sign of the adequacy of fluid resuscitation. Other practical ways to assess fluid overload are jugular venous distension, heart size and pulmonary congestion on chest x ray. Gold standard still remains the measurement of a central venous pressure.

Large fluid deficits typically exist and initial volume resuscitation usually requires 40-60 mL/kg but can be much higher (9,15,16). As a word of caution in neonates use of aggressive fluid therapy may be limited by patency of ductus arteriosus, risk of intraventricular hemorrhage and right heart failure due to pulmonary hypertension.

Vasopressors/Inotropes
(Should Only Be Used After Appropriate Volume Resuscitation)
Children with severe sepsis can present with low cardiac output and high systemic vascular resistance (cold shock, more common scenario), high cardiac output and low systemic vascular resistance or low cardiac output and low systemic vascular resistance shock. Early inotropic support should be started in the case of fluid refractory shock or a life threatening hypotension when fluid bolus has been initiated. Dopamine is the first choice of support for the pediatric patient with hypotension refractory to fluid resuscitation. The choice of vasoactive agent is determined by the clinical examination. Dopamine-refractory shock may reverse with epinephrine (adrenaline) or norepinephrine (noradrenaline) infusion (16). Pediatric patients with low cardiac output states may benefit from use of dobutamine. The use of vasodilators can reverse shock in pediatric patients who remain hemodynamically unstable with a high systemic vascular resistance state, despite fluid resuscitation and implementation of inotropic support (9,16). Nitrovasodilators with a very short half-life (nitroprusside or nitroglycerin) are used as first-line therapy for children with epinephrine-resistant low cardiac output and elevated systemic vascular-resistance shock. Inhaled nitric oxide reduced extracorporeal membrane oxygenation use when given to term neonates with persistent pulmonary artery hypertension of the newborn and sepsis in a randomized, controlled trial (17). When pediatric patients remain in a normotensive low cardiac output and high vascular resistance state, despite epinephrine and nitrovasodilator therapy, then the use of a phosphodiesterase inhibitor should be strongly considered, such as milrinone(12,18,19). Vasopressin therapy should be considered in warm shock unresponsive to fluid and norepinephrine.

Early Antibiotics:
After appropriate cultures are taken, early use of broad-spectrum systemic anti-microbial therapy based on clinical suspicion is reasonable although no randomized studies exist in children. Adult data supports use early appropriate antibiotics to impact favourably on morbidity from septic shock

Therapeutic Endpoints:
Therapeutic endpoints are capillary refill of <2 secs, normal pulses with no differential between peripheral and central pulses, warm limbs, urine output of>1 mL/kg/hr, normal mental status, decreased lactate, and increased base deficit and superior vena cava or mixed venous oxygen saturation of>70%. When employing measurements to assist in identifying acceptable cardiac output in children with systemic arterial hypoxemia such as cyanotic congenital heart disease or severe pulmonary disease, arterial-venous oxygen content difference is a better marker than mixed venous hemoglobin saturation with oxygen. Optimizing preload optimizes cardiac index. As noted above, blood pressure by itself is not a reliable endpoint for resuscitation. Rarely, if a pulmonary artery catheter is utilized, therapeutic endpoints are cardiac index of >3.3 and <6.0 L/m/meter sq with normal perfusion pressure (mean arterial pressure-central venous pressure) for age. Use of pulmonary artery catheter has declined over the years due to no well demonstrated therapeutic benefit in patients with septic shock.
Table 4 shows a flow diagram summarizing an approach to pediatric septic shock (3).

Electrolyte balance:
An attempt should be made to check and correct common electrolyte problems related to sodium (hyponatremia), potassium and ionized calcium (ionized hypocalcemia).

Steroids:
Hydrocortisone therapy should be reserved for use in children with catecholamine resistance and suspected or proven adrenal insufficiency. Patients at risk include children with severe septic shock and purpura (20,21), children who have previously received steroid therapies for chronic illness, and children with pituitary or adrenal abnormalities. There are no strict definitions, but adrenal insufficiency in the case of catecholamine-resistant septic shock is assumed at a random total cortisol level of <18 µg/dL (496 nmol/L). There is no clear consensus for the role of steroids or best dose of steroids in children with septic shock. A post 30- or 60-min adrenocorticotropic hormone(ACTH) stimulation test increase in cortisol of =9 µg/dL (248 nmol/L) also makes that diagnosis. There are two randomized, controlled trials that used shock dose hydrocortisone (25 times higher than the stress dose) in children, both in dengue fever. The results were conflicting (22,23). Dose recommendations vary from 1-2 mg/kg for stress coverage (based on clinical diagnosis of adrenal insufficiency) to 50 mg/kg for empirical therapy of shock followed by the same dose as a 24-hr infusion.Thus dose of steroids remains controversial.

Conclusions:
Pediatric recommendations for management of severe sepsis in children include a more likely need for endotracheal intubation and mechanical ventilation due to low functional residual capacity.

Infants and children are recognized to have more difficult intravenous access, therefore necessitating use of intraosseous access as required.

Early fluid resuscitation based on weight with 40-60 mL kg or higher may be needed.

Decreased cardiac output and increased systemic vascular resistance tends to be most common hemodynamic profile. Dopamine is recommended as the initial agent for hemodynamic support.

Pediatric recommendations include greater use of physical examination therapeutic endpoints.

Issue of high-dose steroids for therapy of septic shock remains unsettled, although recommendation include use of steroids for catecholamine unresponsive shock in presence of a suspected or proven adrenal insufficiency.

There is greater risk of hypoglycemia with aggressive glucose control.
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