Conference Lectures

Dr. Raja V Lakshmanan

SHOCK IN PAEDIATRICS
Definition:
Shock results from the inadequate delivery of oxygen to the tissues relative to tissue metabolic demand, usually characterized by inadequate perfusion.
Classification:
(A)       Shock severity is usually categorized by its effect on systolic blood pressure:

1. Compensated: Systolic BP maintained within normal range for age by compensatory mechanisms (↑HR,↑SVR,↑Inotropy)
2. Decompensated: Systolic BP low ie., compensatory mechanism unable to maintain a normal systolic BP

(B)       Based on the etiology, shock may also be classified as follows:

SHOCK	EXAMPLE(S)	PATHOPHYSIOLOGY	HEMODYNAMIC CHANGE(S)
Hypovolemic	Hemorrhage, gastroenteritis, burns, sepsis	Absolute deficiency of intravascular blood volume	↓preload
Distributive	Anaphylaxis, neurologic, sepsis	Loss of sympathetic tone leading to inappropriate vasodilation and inability to mount a tachycardic response	↓preload, afterload and contractility
Cardiogenic	CCF,myocarditis, cardiomyopathy, sepsis	Impairment of cardiac contractility	↓stroke volume and contractility
Obstructive	Coarctation, tamponade, massive PE,hypertrophic cardiomyopathy	Direct obstruction of cardiac output	↓stroke volume
Septic	Sepsis	Vasodilation, disrupted capillary integrity, depressed myocardial function	↓preload, afterload, contractility and stroke volume

(C)       Based on hemodynamics, shock may also be classified as:
(1) ‘Cold’: Normal/↓CO and ↑SVR); the most common presentation in paediatric shock(1)
(2)  ‘Warm’(normal or ↑CO and ↓SVR)
Hypovolemia resulting from gastroenteritis is the major cause of shock in the developing regions while sepsis is the leading cause in developed countries(2).

EVALUATION:
Bedside clinical evaluation, supplemented by simple non-invasive monitoring is essential for rapid recognition of life threatening conditions and to assess the severity and nature of shock. The important question to answer is ‘Is the child sick or not’. The Paediatric Assessment Triangle is a valuable tool:

1. Appearance:               Tone, interactivity, consolability, look/gaze, speech, cry
2. Work of breathing:    Abnormal breath sounds, abnormal positioning, retractions
3. Circulation:                 Pallor, mottling, cyanosis, bleeding

Other clinical signs include:
(A)Tachycardia: A non-specific, early indicator of shock. A normal heart rate with signs of compensated shock can occur with spinal cord injury. Bradycardia can occur as a result of hypoxia, betablocker overdose or as an agonal event
(B)Skin changes: Vasoconstriction results in redirecting blood from the peripheral, splanchnic and renal vessels to maintain coronary and cerebral perfusion. Cool, clammy, pale or mottled appearance is typical. Exceptions include distributive shock, toxins.
(C)Mental status: Signs of impaired cerebral perfusion include listlessness, agitation, not interacting with caregivers, deteriorating to obtundation and coma
(D)Oliguria: Universal feature resulting from redirection of renal blood flow to other vital organs and fall in intraglomerular pressure  leading to decreased GFR
(E)Hypotension: Late and ominous finding in children! Compensatory vasoconstriction in children is so pronounced that systemic blood pressure can be maintained within the normal range, despite significant circulatory compromise. Hypotension is defined as a systolic blood pressure less than the fifth percentile of normal for age: <60mmHg in term neonates, 70mmHg in infants (1 to 12 months), 70+(2 X Age in years) in children 1 to 10 yrs, 90 mmHg in children 10yrs or older

Further evaluation to identify the etiology or severity are as follows (treatment should not be delayed to perform these investigations):

(A)Full blood count: Hemoglobin and hematocrit help to identify anemia and dehydration respectively. WBC count (high or low) is a useful non-specific marker of infection. Changes in platelet count may point to abnormalities in coagulation
(B)Electrolytes: Hypernatremia and/elevated urea and creatinine levels indicate degree of hypovolemia. Damage to other organ systems may also appear as deranged metabolic profile (Eg. elevated liver enzymes secondary to hypoxic ischemic damage to liver). Glucose levels may be decreased (limited glycogen stores in children, especially neonates) or increased (relative insulin-resistance)
(C)Chest X-ray: Cardiomegaly (enlarged cardiac silhouette), pulmonary disorders (Eg. pneumonia, ARDS) may be visible.
(D)Arterial blood gas (ABG): Useful to assess degree of oxygenation  and acid-base status. pH, lactate and bicarbonate levels are valuable in the assessment of degree and type of acidosis.
(E)Central venous cannulation: Useful to evaluate CVP and mixed venous oxygen saturation. Although CVP on its own can be a misleading number, in context with clinical examination findings and re-evaluation, may help to determine clinical status. Pressures higher than 10 cmH2O may reflect volume overload or poor right-sided compliance or function. Mixed venous sample from right atrium can be used to measure oxygen saturation (ScVO2) – normal value 70-80%. American College of Critical Care Medicine (ACCM) guidelines recommend resuscitating children with septic shock to an ScVO2 of more than 70% (3). Oxygen extraction (the difference between SaO2 and ScVO2) >33% may indicate reduced perfusion to capillary bed (ie, shock) while <25% may indicate shunting (resulting from vasodilation) or intracellular metabolic defect
(F)Cardiac Index (CI): Cardiac output determined by invasive or non-invasive methods is used to calculate CI (normal=3.5-5.5 l/min/m2). Values between 3.3-6 l/min/m2 have been associated with optimal outcomes from pediatric shock (4).

TREATMENT
The aim is to restore adequate perfusion to the tissues and organs of the body as soon as possible. For every extra hour a child remains in shock the mortality rate doubles(5). Irrespective of the etiology, the basic principles in the management of pediatric shock remain same:

1. Stabilization of the airway, breathing and circulation takes precedence over any work-up that may delay resuscitation.
2. Evaluation, treatment and reassessment should be done frequently
3. Volume expansion should be early, aggressive and appropriate
4. Early goal directed fluid therapy improves outcome(6)

Airway and breathing stabilization may involve early endotracheal intubation and positive pressure ventilation, following rapid sequence induction (Ketamine is the preferred drug,if not contraindicated). This can maximize oxygenation, decrease the work of breathing and redistribute blood flow from the respiratory muscles to more vital organs. Appropriate fluid boluses and inotropes should be prepared in anticipation of deterioration in cardiovascular parameters at induction. Circulatory improvement is aimed at ensuring adequate systemic oxygen delivery via volume expansion and if necessary, pharmacologic therapy.

Early Goal Directed Therapy:
Found to have the largest mortality benefit of any sepsis study in adults(6).
Within the initial 5 to 15 mins the following actions should commence:

1. Life threatening conditions recognized and addressed
2. Vascular/intraosseous access established (ideally two)
3. Isotonic crystalloid infusion started (Ringer’s lactate or normal saline)
4. Rapid measurement of blood glucose performed
5. Obvious signs of trauma/haemorrhage – managed appropriately

Within 15 to 30 mins the following should be performed:

1. Abnormalities in calcium and electrolyte measurements should be identified and treatment initiated
2. Appropriate antibiotics should be administered
3. Ongoing fluid resuscitation as indicated (see below)
4. Vasoactive drug therapy in fluid resistant shock (see below)
5. Evaluation for therapeutic endpoints

Although the ACCM algorithm for the management of paediatric sepsis is predominantly aimed at management of septic shock, the basic principles in management remains the same irrespective of the etiology:

 

(ACCM algorithm for the management of Paediatric sepsis (3))

Therapeutic endpoints within the first 60 mins:

1. Normalization of heart rate
2. Blood pressure within normal range for age
3. Capillary refill time ≤2 seconds
4. Normal pulses with no differential between central and peripheral
5. Warm extremities
6. Urine output≥1ml/kg/hr
7. Normal mental status

Children who have not improved after 30-60 mins:
(1)  Evaluate for other causes of shock
(2)  Consultation with pediatric critical care specialists/trauma surgeons (if required)
(3)  Evaluate need for colloid or blood transfusion
(4)  Evaluate need for corticosteroid therapy
(5)  Admission to paediatric intensive care unit for invasive monitoring

VOLUME EXPANSION:
Children who receive appropriate, yet aggressive fluid resuscitation early have the best chance of surviving severe septic shock or shock and dehydration(7) especially when inititated within the first hour of resuscitation(8). Initial 20ml/kg bolus of isotonic crystalloid infusion over 5 minutes or less. If patient retains the clinical appearance of shock, immediately infuse another 20ml/kg and repeat the cycle (may require more than 60ml/kg in the first hour of resuscitation). Consider blood or packed RBCs especially in a child at risk for hemorrhage. There is no strong evidence to support the use of colloid over crystalloid(9). In children with fluid refractory shock, central venous and arterial pressure monitoring can guide on-going resuscitation.

Aggressive fluid resuscitation may be harmful for children who are not hypovolemic or have compensated shock and in children with certain comorbidities in whom cerebral edema can occur (Eg. SIADH, cardiogenic shock, diabetic ketoacidosis), in malaria (hemodilution may worsen the underlying anemia and thereby oxygen carrying capacity), in severe malnutrition or in resource limited settings (see below)

(A)Malnutrition:
These children pose a special challenge as they do not tolerate aggressive fluid resuscitation (increased risk of congestive cardiac failure from overhydration). This can be particularly complicated because malnutrition and dehydration frequently coexist. Furthermore, resource limitation for treatment (ie.,lack of critical care support) may be a key factor in areas where malnutrition is more prevalent. Slow IV rehydration with an infusion of 15ml/kg Ringer’s lactate 5%dextrose, should be given over one hour; if there are signs of improvement, a repeat bolus can be given slowly, followed by oral or nasogastric rehydration. If the patient does not improve after one hour, a blood transfusion should be considered (10ml/kg slowly over 3 hours).

FEAST (‘Fluid Expansion As Supportive Therapy’)(10), a large study in African children with apparent sepsis (but without hypotension) in resource-limited facilities, demonstrated a worse outcome for children treated with standard fluid resuscitation ie., 20-40ml/kg fluid bolus (saline or albumin) when compared to local practice of no fluid bolus resuscitation. The fluid bolus group had increased mortality at 48 hours and a 4% higher risk of death and neurologic sequelae at 4 weeks. This may represent a  population in whom over hydration will not be well-tolerated, particularly if mechanical ventilation and inotropic support are not available. Traditional recommendation of aggressive bolus fluid resuscitation should not be used in such children.The authors suggest that further study is warranted.
(B)Severe febrile illness in resource-limited settings: The problem here again is two fold: (i) Children may be frequently malnourished (ii)Limited critical care capability.The recommendation is no fluid boluses; just maintenance fluid therapy ± blood transfusion.
(C)Children in resource-limited settings with signs of shock: Receive fluid resuscitation according to the emergency triage assessment and treatment guidelines developed by the WHO (based on presence of dehydration and malnutrition either in combination or alone). The recommendation is, if signs of severe dehydration and diarrhoea are present and no signs of severe malnutrition, then 20ml/kg isotonic crystalloids as rapidly as possible and repeated, as required upto 3 times. After the third bolus, use colloid
(D)Cardiogenic shock: Suspect in children with signs such as hepatomegaly, jugular venous distension, pulmonary rales and gallop rhythm; smaller isotonic crystalloid bolus (5-10ml/kg over 10-20 mins)
(E)Diabetic ketoacidosis: Careful resuscitation with one bolus of 10ml/kg over one hour (in order to avoid cerebral edema, a rare complication of DKA)

PHARMACOLOGIC THERAPY:
Inotropes and vasopressors should be inititated only after adequate volume expansion ie.,  in fluid refractory shock. The choice depends on intravascular volume, contractile state of the heart and peripheral vascular resistance.  As a general rule in  ‘cold’ shock  consider Dopamine (adrenaline and phosphodiesterase inhibitors if refractory) and in ‘warm’ shock consider Noradrenaline (Vasopressin if refractory, but no evidence in Paediatrics (11))
(A)Dopamine (5-15mcg/kg/min): In low doses (2-5mcg/kg/min), dopamine acts on renal and splanchnic dopaminergic receptors causing vasodilation in the vascular bed. In mid range doses (5-15mcg/kg/min), it acts on ß adrenergic receptors to increase heart rate and contractility, improve cardiac output and enhance conduction. In high doses (15-20 mcg/kg/min), it acts on αadrenergic receptors to increase systemic vascular resistance and raise blood pressure. Usual starting dose is 0.5-1mcg/kg/min with increase by 1-4 mcg/kg/min every 10-30 minutes until an optimal response is obtained (not to exceed 40 mcg/kg/min)
(B)Dobutamine (5-20mcg/kg/min): It is an inodilator (pure inotrope due to ß1 and vasodilation due to ß2 effects).  Useful in cardiogenic shock. Less likely to precipitate ventricular dysrhythmias than epinephrine.
(C)Epinephrine(0.05-2mcg/kg/min): α(increased peripheral vascular resistance) and ß(inotropy, chronotropy & bronchodilation) effects. Useful in a range of cardiovascular, respiratory and life threatening emergencies.
(D)Nor-epinephrine (0.05-2mcg/kg/min): Predominantlyαeffect. Useful in protracted hypotension following adequate fluid-volume replacement.
(E)Milrinone (0.3-0.75 mcg/kg/min): Phosphodiesterase inhibitor. Increases intracellular cAMP levels which raises intracellular calcium levels improving cardiac inotropy and peripheral vasodilation (increased contractility, decreased afterload). Useful in patients who have adequate intravascular volume but who need increased cardiac contractility and better peripheral perfusion. Care must be taken when choosing to start phosphodiesterase inhibitors because of their vasodilator effects and long half life
(F) PGE1(0.05-0.1 mcg/kg/min): Can be life-saving; to maintain patency of ductus arteriosus in neonates with features of  obstructive shock that develops because of closure of the ductus (Shock in a neonate associated with large liver, enlarged cardiac silhouette, or heart murmur)

ELECTROLYTES:
(A)Glucose: Neonates and infants have limited glycogen stores which may be rapidly depleted during shock. Neonates have higher requirements (8mg/kg/min) while children (5mg/kg/min) and adolescents (2mg/kg/min) have lower requirements. Hyperglycemia should be treated with an insulin infusion (hyperglycemia is a risk factor for increased mortality (12))
(B)Calcium: Essential for excitation-contraction coupling and many other biochemical processes. Levels may be influenced by a number of processes including acid base status and administration of blood products. Calcium chloride produces higher and more consistent levels of available calcium than calcium gluconate and, is therefore recommended (13). Recommended dose is 10-20mg/kg IV administered at an infusion rate that does not exceed 100mg/min IV
(C)Bicarbonate: Use of bicarbonate in the treatment of shock is controversial (risk of intracellular acidosis, hypernatremia, osmolar load, lack of evidence to improve survival rates).  In patients with persistent shock or ongoing bicarbonate loss, careful replacement of bicarbonate may be indicated.

ADDITIONAL THERAPY:
(A)Corticosteroids: Patients in severe septic shock may not have adequate levels of circulating glucocorticoids to support their physiology when severely stressed. But there is insufficient evidence to demonstrate improved outcome and there is some potential for morbidity(14) and therefore not to be used routinely(15). It is reserved for children with proven adrenal insufficiency, or at risk of adrenal insufficiency (Eg. on steroid therapy, pituitary or adrenal abnormalities) and in fluid-refractory, catecholamine-resistant shock. A baseline serum cortisol level and response to a 250 mcg corticotropin(ACTH) stimulation are performed. Therapy is initiated for patients who prove to have an absolute baseline cortisol  level of less than 20mcg/dl and/or a depressed response with a rise of less than 9mcg/dl at 30 and 60 mins (16).Dosage recommendation is variable, approximately 1-2mg/kg/day of hydrocortisone for stress cover and 50mg/m2/24 hours for shock reversal.
(B)Optimize ScVO2: ScVO2 can be used as an indirect measure of oxygen delivery. When a goal directed approach with target ScVO2 >70% based on ACCM was used, patients received more crystalloid, blood and inotropic support, resulting in a reduction in 28 day mortality from 39.2% to 11.8%(17)
(C)Lactate clearance: Normalising lactate clearance may be as effective as the use of ScVO2 as a resuscitation goal in the initial treatment of sepsis (18)
(D)Other therapies (based on etiology of shock):
-If sepsis is suspected, isolate the organism and treat with appropriate antibiotics (broad spectrum initially). Therapeutic drug monitoring and source control are important.
-If trauma is the cause, then ongoing bleeding may need to be surgically addressed
-If cardiogenic shock secondary to arrhythmias is suspected, then treatment should be aimed at converting to sinus rhythm
(E)Stress ulcer prophylaxis: If early enteral feeding is not possible then H2 blockers or proton pump inhibitors should be considered in patients with severe sepsis to prevent GI bleeds and ventilator-assoicated pneumonia.
(F)Transfusion: Target Hb>10g/dl to achieve an ScvO2>70%, to enhance oxygen delivery (2). After the initial resuscitation phase, the best haemoglobin level for critically ill children is unknown. As per the TRIPICU study, a threshold of 7g/dl decreased transfusion requirements without increasing adverse outcomes(19)
(G)Renal replacement:Early implementation of continuous renal replacement therapy is associated with improved survival compared to late implementation(20)
(H)ECMO:For cases of severe shock that have not responded to all conventional treatment strategies, extracorporeal membrane oxygenation (ECMO) and intravenous immunoglobulin may be considered(21)
FURTHER CARE:
Children with shock whose symptons resolve with treatment should be admitted to the hospital for observation. The cause of shock may persist, reoccur or may not be apparent. Children who have not improved or have worsened with initial management should be admitted to an intensive care unit.
PITFALLS IN THE MANAGEMENT OF PAEDIATRIC SHOCK:
(1)        Failure to recognize non-specific signs of compensated shock (ie, unexplained tachycardia, abnormal mental status, or poor skin perfusion)
(2)        Inadequate monitoring of response to treatment
(3)        Inappropriate volume for fluid resuscitation
(4)        Failure to consider possible causes of shock for children who are getting worse or not improving

REFERENCE

(1)Brierley J, Peters MJ. Distinct hemodynamic patterns of septic shock at presentation to pediatric intensive care. Pediatrics 2008;122:752-9
(2)Fisher JD, Nelson DG, Beyersdorf H, Satkowiak LJ. Clinical spectrum of shock in the paediatric emergency department. Paediatric Emergency Care. Sep 2010; 26(9):622-5
(3)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. Critical Care Medicine. Feb 2009; 37(2):666-88
(4)Pollack MM,Fields AI, Ruttimann UE. Distributions of cardiopulmonary variables in paediatric survivors and nonsurvivors of septic shock. Critical Care Medicine. June 1985;13(6): 454-9
(5)Han YY, Carcillo JA< Dragotta MA, Bills DM, Watson RS, Westerman ME et al. Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome. Pediatrics 2003;112:793-9
(6)Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001;345:1368-77
(7)Carcillo JA, Davis AL, Zartisky A. Role of early fluid resusciation in pediatric septic shock. JAMA Sep 1991; 266(9):1242-5
(8)Kobayashi L, Constantini TW, Coimbra R. Hypovolemic shock resuscitation. Surg Clin North Am. Dec 2012; 92(6):1403-23
(9)Akech S, Ledermann H, Maitland K. Choice of fluids for resusciation in children with severe infection and shock: systematic review. BMJ 2010;341:c4416
(10)Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO et al. Mortality after fluid bolus in African children with severe infection. NEJM 2011;364:2483-95
(11)Meyer S, McGuire W, Gottschling S, Shamdeen GM, Cortner L. The role of vasopressin and terlipressin in catecholamine-resistant shock and cardio-circulatory arrest in children: Review of the literature. Wein Med Wochenschr 2011;161:192-203
(12)Lin JC, Cacillo JA> Increased glucose/glucose infusion rate ratio predicts anion gap acidosis in pediatric sepsis. Critical Care Medicine 2004;32(Suppl 20):A5
(13)Broner CW, Stidham GL, Westenkirchner DF, Watson DC. A prospective randomized, double-blind comparison of calcium chloride and calcium gluconate therapies for hypocalcemia in critically ill children. J Pediatr. Dec 1990; 117(6):986-9
(14)Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Critical Care Medicine. Aug 1995;23(8):1430-9
(15)Markovitz BP, Goodman DM, Watson S, Bertoch D, Zimmerman J. A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: What is the role of steroids. Pediatric Crti Care Med 2005;6:270-4
(16)Pizzaro CF, Troster EJ, Damini D, Carcillo JA. Absolute and relative adrenal insufficiency in children with septic shock. Critical Care Medicine. Apr 2005;33(4):855-9
(17)de Oliveira CF, de Oliveira DSF, Gottschal AFC, Moura JDG, Costa GA, Ventura AC et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Medicine 2008;34:1065-75
(18)Jones AE, ShapiroNI, Trzeciak S, Arnold RC, Claremont HA, Kline JA et al. Lactate clearance vs central venous oxygen saturation as goals of early sepss therapy: a randomized clinical trial. JAMA 2010;3030:739-46
(19)Lacroix J, Hebert PC. Transfusion strategies for patients in paediatric intensive care units. NEJM 2007;356:1609-19
(20)Foland JA, Fortenberry JD, Warsaw BL, Pettignano R, Merritt RK, Heard ML et al. Fluid overload before continuous hemofiltration and survival in critically ill children: A retrospective analysis. Critical Care Medicine 2004;32:1771-6
(21)Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. Intensive Care Medicine 2008;34:17-61