Critical Care Medicine

Septic shock in neonates and children: ACCM guidelines

Sepsis Syndrome

Also known as: Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis, Septic Shock

Related conditions: Bacteremia, Serious Bacterial Illness (SBI), Septicemia

1. Description of the problem

What every clinician needs to know

According to the National Center for Health Statistics and the Centers for Disease Control and Prevention, sepsis syndrome was the 10th leading cause of death overall in 2007. Sepsis syndrome is associated with significant morbidity and mortality, both in children and adults.

There are no specialized blood tests or clinical markers that can diagnose the sepsis syndrome. Therefore, diagnosis depends on the identification of a constellation of several clinical signs and symptoms that commonly occur in association with an infection (eg, bacteremia) or other inciting event (eg, trauma, pancreatitis, burns). The Society of Critical Care Medicine and the American College of Chest Physicians developed consensus guidelines for the diagnosis of sepsis syndrome, which have been subsequently modified for pediatrics.

Clinical features

The sepsis syndrome represents a continuum progressing from the systemic inflammatory response syndrome (SIRS) to septic shock. While SIRS is relatively common in critically ill children admitted to the pediatric intensive care unit (PICU), associated morbidity and mortality is relatively low. In contrast, septic shock is less common and is associated with significant morbidity and mortality. Septic shock is associated with 10% mortality in most epidemiologic studies and clinical trials published in critically ill children.

SIRS is defined by the presence of two or more of the following criteria:

1. Core body temperature greater than 38.5°C or less than 36°C.

2. Tachycardia, defined as a heart rate greater than 2 standard deviation (SD) mean for age, OR for children younger than 1 year of age, bradycardia, defined as a heart rate less than 10th percentile for age.

3. Tachypnea, defined as respiratory rate greater than 2 SD mean for age, or mechanical ventilation

4. Leukocytosis or leukopenia.

Sepsis is defined as SIRS + infection.

Severe sepsis is defined as sepsis plus one or more of the following:

1. Cardiovascular dysfunction.

2. Acute lung injury or acute respiratory distress syndrome.

3. Two or more other organ dysfunctions (eg, renal, hepatic, neurologic, or hematologic).

Septic shock is defined as severe sepsis plus refractory hypotension or hypoperfusion abnormalities despite adequate fluid resuscitation.

Key Management Points

1. Early recognition and diagnosis of sepsis syndrome

2. Early administration of antibiotic therapy

3. Early reversal of the shock state

4. Early end-organ support

2. Emergency Management

1. Maintain or restore airway, oxygenation, and ventilation

2. Early administration of antibiotic therapy and source control

3. Early reversal of the shock state (restore normal circulation)

The concept of a "golden hour" for the management of sepsis syndrome is now well recognized. For example, the adult Surviving Sepsis Campaign guidelines utilize a 6-hour resuscitation bundle and a 24-hour management bundle (discussed further below). The key elements in the Surviving Sepsis Campaign resuscitation bundle include

1. Measure serum lactate

2. Obtain blood cultures prior to antibiotic administration

3. Administer broad-spectrum antibiotic within 3 hours of emergency department (ED) admission and within 1 hour of non-ED admission.

4. Deliver an initial minimum of 20mL/kg crystalloid or an equivalent.

5. Administer vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) greater than 65 mmHg.

6. Maintain adequate central venous pressure (CVP) and central venous oxygen saturation (ScvO2).

While the Surviving Sepsis Campaign guidelines do not apply to critically ill children with septic shock, the American College of Critical Care Medicine (ACCM) consensus guidelines for the management of critically ill children with septic shock also emphasize the "golden hour" concept with early administration of antibiotics and reversal of the shock state, using the following therapeutic end points:

1. Capillary refill less than 2 seconds

2. Normal pulses (no differentiation between the quality of the central and distal pulses)

3. Warm extremities

4. Urine output greater than 1 mL/kg/h

5. Normal mental status

6. Normal blood pressure (for age)

7. Normal blood ionized calcium concentration

8. Normal blood glucose concentration

Additional therapeutic end points include a declining serum lactate level and/or base deficit, as well as a ScvO2 greater than 70%.

Emergency management (within the "golden hour") of critically ill children with septic shock includes

  1. Administer supplemental oxygen

  2. Establish IV/IO access

  3. Administer boluses of 20mL/kg isotonic saline or colloid, up to and over 60mL/kg until perfusion improves or hepatomegaly develops

  4. Correct hypoglycemia.

  5. Correct hypocalcemia.

  6. Administer antibiotics

The ACCM consensus guidelines for pediatric and neonatal septic shock do not provide specific recommendations on antibiotic therapy, other than the fact that antibiotics should be administered within the "golden hour" of management. The age-specific epidemiology of the causes of sepsis together with the clinically suspected focus of infection should guide the empiric choice of antibiotics. The antibiotic regimen should be reassessed within 48 to 72 hours and further guided by culture results and clinical response.

Whenever possible, the spectrum of antibiotics should be narrowed. Consultation with an infectious disease specialist is recommended for complex infectious problems or when sepsis occurs in immunocompromised patients.

If shock is not reversed, the next step in emergency management (still within the "golden hour") includes

  1. Begin inotrope IV/IO (preferably via a second peripheral IV or IO)

  2. Use atropine/ketamine IV/IO/IM to obtain central vascular access and airway, if necessary.

  3. Reverse cold shock by titrating dopamine and/or epinephrine. Reverse warm shock by titrating norepinephrine.

  4. Begin stress-dose hydrocortisone if catecholamine-resistant shock and if at risk for adrenal insufficiency.

3. Diagnosis

Diagnostic criteria and tests

As stated above, the early recognition and diagnosis of the sepsis syndrome depends upon the recognition of a constellation of clinical signs and symptoms in the appropriate clinical context. There are no diagnostic tests currently available to diagnose sepsis syndrome in either children or adults.

Important ancillary tests include

1. Complete blood count (CBC)

2. Serum chemistry panel (electrolytes, BUN, creatinine, glucose)

3. Arterial or venous blood gas with lactate

4. Chest x-ray

The sepsis syndrome encompasses a broad range of infections, including both gram-negative and gram-positive bacteria, rickettsial bacteria, viruses, parasites, and fungi/yeast.

Confirmatory tests

There are no special confirmatory tests for critically ill patients with sepsis syndrome.

4. Specific Treatment

The key elements in the Surviving Sepsis Campaign 24-hour maintenance bundle include

1. Administer low-dose corticosteroids for septic shock in accordance with a standardized ICU policy.

2. Administer recombinant human activated protein C (rhAPC) in accordance with a standardized ICU policy.

3. Maintain adequate glycemic control.

4. Prevent excessive inspiratory plateau pressures on mechanically ventilated patients.

Again, these Surviving Sepsis Campaign guidelines do not necessarily apply to critically ill children with septic shock. For example, rhAPC should not be used in critically ill children outside the confines of a clinical trial, based upon the results of the RESOLVE study.

Drugs and dosages

The ACCM consensus guidelines for pediatric and neonatal septic shock suggest titrating vasoactive infusions based upon the clinical scenario and response to initial treatment:

Cold shock with normal blood pressure is treated by titrating fluid therapy (including packed red blood cells [PRBC], if hemoglobin [Hgb] < 10g/dL) and epinephrine to ScvO2 greater than 70%. If ScvO2 is still less than 70%, the guidelines recommend adding a vasodilator with volume loading.

Cold shock with low blood pressure is treated by titrating fluid therapy (including PRBC, if Hgb < 10g/dL) and epinephrine to ScO2 greater than 70%. If the patient remains hypotensive, the guidelines recommend adding norepinephrine. If the ScvO2 is still less than 70%, the guidelines recommend adding inotropic support with dobutamine, milrinone, enoximone, or levosimendan.

Warm shock with low blood pressure is treated by titrating fluid therapy (including PRBC, if Hgb < 10g/dL) and norepinephrine to ScvoO2 greater than 70% If the patient remains hypotensive, the guidelines recommend adding vasopressin, terlipressin, or angiotensin. If ScvO2 is still less than 70%, the guidelines recommend adding low-dose epinephrine (0.03 to 0.3 mcg/kg/min).

Refractory cases

If catecholamine-resistant shock is present, rule out the following conditions and treat appropriately:

1. Pericardial effusion with tamponade

2. Pneumothorax

3. Intra-abdominal hypertension (Intra-abdominal pressure > 12 mmHg)

Consider the use of a pulmonary artery catheter or PICCO monitor to guide fluid, inotrope, vasopressor, vasodilator, and hormonal therapies (goal cardiac index >3.3 to <6.0 L/min/M2).

If shock persists, the use of extracorporeal circulation membrane oxygenation (ECMO) support should be strongly considered.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

The goals for the first hour ("golden hour") are to restore and maintain heart rate thresholds, capillary refill < 2 seconds, and normal blood pressure. Ongoing monitoring should include continuous electrocardiogram, pulse oximetry, intra-arterial blood pressure, core body temperature, urine output, CVP, CVP oxygen saturation. Serial glucose, calcium, and lactate should be monitored, in addition to electrolytes, BUN/creatinine, liver enzymes, CBC as clinically necessary.

The subsequent ICU goals are to restore and maintain normal perfusion pressure, defined as the MAP minus the CVP for age, ScvO2 greater than 70%, and cardiac index greater than 3.3 and less than 6.0 L/min/M2.

Alternative diagnosis

Children with refractory shock not responding to the above therapeutic measures should be suspected to have one or more of the following occult conditions (treatment for each condition is listed in parentheses):

  1. Pericardial effusion with tamponade (pericardiocentesis)

  2. Pneumothorax (thoracentesis)

  3. Adrenal insufficiency (corticosteroid replacement therapy)

  4. Hypothyroidism (thyroid hormone replacement therapy)

  5. Ongoing blood loss (blood product replacement/hemostasis)

  6. Intra-abdominal hypertension/abdominal compartment syndrome (peritoneal catheter or abdominal release)

  7. Tissue necrosis (nidus removal)

  8. Inappropriate source control (remove nidus, adjust antibiotic therapy)

Follow-up

Critically ill children with sepsis syndrome should be managed in a PICU setting.

Pathophysiology

Sepsis syndrome is characterized by the triad of inflammation, coagulation, and endothelial injury.

The host inflammatory response is complex and results from a dysregulated host response to infection or other inciting event, such that the balance between pro-inflammatory mechanisms and the compensatory anti-inflammatory mechanisms largely determines the clinical phenotype. The clinical phenotype is quite heterogeneous, which means that a "one-size fits all" approach to management will not be successful.

For example, a shift in the homeostatic balance to a predominantly anti-inflammatory phenotype leads to a state of relative immune suppression, or immunoparalysis. In this scenario, the patient is unable to clear the infection and is at significantly increased risk for hospital-acquired infections. These patients may therefore benefit from immunostimulatory therapies. Conversely, a shift in balance towards a predominantly pro-inflammatory phenotype results in widespread cellular injury, multiple organ failure, and death. These patients may therefore benefit from immunosuppressive therapies.

Activation of the coagulation cascade is an essential component in the development of multiple organ dysfunction syndrome in critically ill children with sepsis syndrome. The overwhelming inflammatory response (discussed in the preceding paragraph) causes widespread activation of the coagulation cascade through release of tissue factor. Tissue factor binds to activated factor VII, which in turn activates factors IX and X. Factor X converts prothrombin to thrombin, which cleaves fibrinogen to fibrin.

Thrombin and cytokines also stimulate the release of plasminogen-activator-inhibitor (PAI)-1 from platelets and the endothelium. PAI-1 inhibits tissue plasminogen activator (tPA), which breaks down blood clots (fibrinolysis). Finally, thrombomodulin (another modulator of fibrinolysis, which activates protein C) is also impaired by inflammation and endothelial injury. Sepsis therefore results in an overall pro-coagulant, anti-fibrinolytic state.

Endothelial injury further contributes to the pathophysiology of sepsis syndrome. Endothelial activation appears to be a key mediator in both the widespread inflammation and coagulation discussed in the preceding paragraphs. Endothelial injury contributes to microcirculatory dysfunction, which impairs tissue oxygen delivery and utilization.

Epidemiology

The largest epidemiologic study involving critically ill children with the sepsis syndrome utilized a hospital discharge database and population data from seven states (representing 24% of the United States population). Based on this study, there are approximately 40,000 cases of pediatric (under 19 years of age) severe sepsis every year in the United States (incidence 0.56 cases per 1000 population per year). The incidence is highest during infancy (5.16 cases per 1000 per year) and appears to be more common in males versus females.

Hospital mortality is approximately 10%, resulting in approximately 4300 deaths per year. Most of the cases (49%) had underlying co-morbid conditions. Respiratory infections (37%) and primary bacteremia (25%) were the most common predisposing conditions. The mean length of stay was 31 days. Each case generated hospital costs of $40,600, resulting in annual healthcare expenditures of nearly $2 billion every year.

Prognosis

The prognosis for critically ill children with sepsis syndrome is generally favorable. Survival in most developed nations exceeds 80% (ie, mortality rate between 10% to 20% in most reported series). However, there is emerging data that suggests that survivors have long-term sequelae. For example, Czaja et al just published results suggesting that almost half of all pediatric patients admitted to the PICU with severe sepsis require emergency re-admission to the PICU during the first year of follow-up.

What's the evidence?

Unfortunately, there are limited prospective data from randomized, controlled clinical trials in pediatric sepsis.

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Castellanos-Ortega, A, Suberviola, B, García-Astudillo, LA, Holanda, MS, Ortiz, F, Llorca, J. "Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasi-experimental study". Crit Care Med. vol. 38. 2010. pp. 1036-43.

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