Neonatal septic shock Pathophysiology and treatment

Dr . Bharathi B

The big picture …..

• 4 million neonatal deaths worldwide

• 36% due to sepsis .

• Worse in resource limited settings

• One half of VLBW babies die within first seven days of life

• Exposure of the developing brain to infl mediators secondary to sepsis leads to cerebral palsy

Definitions of the sepsis continuum

• Infection• Sepsis• Severe sepsis• Septic shock• SIRS

Definition contd…Consensus definition Suggested modific for preterm

SIRS

The presence of at least 2 of the following , one of which must be abnormal temperature or leucocyte count

•Core temp > 38.5 ° c or < 36 °C•Tachycardia – mean HR > 2SD above normal for age or Bradycardia – HR < 10 th centile for age•Mean resp rate > 2 SD above age or mech ventilation for an acute process •Leucocyte count elevated or depressed for age or > 10 % immature neutrophils

SIRS

The presence of at least 2 of the following , one of which must be abnormal temperature or leucocyte count

•Core temp >38.0 ° c or < 36 °C•Tachycardia – mean HR > 2SD above normal for age or Bradycardia – HR < 10 th centile for age•Mean resp rate > 2 SD above age or mech ventilation for an acute process •Leucocyte count elevated or depressed for age or > 20 % immature to total neutrophil ratio or CRP > 10mg/dl

Wynn et al , Clin Perinatol 2010 June

Definition contd………InfectionA suspected or proven ( culture , tissue stain , PCR ) infection caused by any pathogen OR A clinical syndrome associated with high probability of infection.

SepsisSIRS in the presence of or as a result of suspected or proven infection

Severe SepsisSepsis plus one of the following : cardiovascular organ dysfunction or ARDS or 2 or more other organ dysfunction

Septic shockSepsis and cardiovascular dysfunction

Wynn et al , Clin Perinatol 2010 June

Organ dysfunctionConsensus definitions of organ dysfunction25 Suggested modifications for premature infants

    Cardiovascular dysfunction     Cardiovascular dysfunction

Despite administration of isotonic intravenous fluid bolus >40 mL/kgin 1 hr

Despite administration of isotonic intravenous fluid bolus >40 mL/kg in1 hr (>10ml/kg in infants less than 32 weeks)1

• Decrease in BP (hypotension) <5th percentile for age or systolic BP>2 SD below normal for age

• Decrease in BP (hypotension) <5th percentile for age or systolic BP>2 SD below normal for age or MAP < 30mm Hg with poor capillaryrefill time (>4 seconds)2

    OR     OR

• Need for vasoactive drug to maintain BP in normal range(dopamine >5 mcg/kg/min or dobutamine, epinephrine, ornorepinephrine at any dose)

• Need for vasoactive drug to maintain BP in normal range (dopamine>5 mcg/kg/min or dobutamine, or epinephrine at any dose)3

    OR     OR

• Two of the following: • Two of the following:

-Unexplained metabolic acidosis: base deficit >5.0 mEq/L -Unexplained metabolic acidosis: base deficit >5.0 mEq/L

-Increased arterial lactate >2 times upper limit of normal -Increased arterial lactate >2 times upper limit of normal

-Oliguria: urine output <0.5 mL/kg/hr -Oliguria: urine output <0.5 mL/kg/hr

-Prolonged capillary refill: >5 secs -Prolonged capillary refill: >4 sec4

-Core to peripheral temperature gap >3°C -Simultaneous measurement of core and peripheral temperature notcommon in premature neonates

Pathophysiology of Sepsis: A Disease of The Microcirculation

• “Lethal Triad”

Systemic Inflammation

Coagulation Impaired Fibrinolysis

Agents

• Bacteria – Gram positive

Gram negative

• Viral• Fungal

Pathophysiology – Molecular and cellular events

Wynn et al , Clin Perinatol 2010 June

Molecular and cellular events – contd …

Wynn et al , Clin Perinatol 2010 June

Pathophysiology of events in sepsis

Wynn et al , Clin Perinatol 2010 June

Septic shock – Hemodynamics and other organ effects – Peculiarities in

newborn• Hemodynamic responses are less well

characterized in neonates• Factors that contribute to developmental

differences in hemodynamics include 1 Altered struc .& func. of cardiomyocytes2 Transition from fetal to neonatal circ.3. PDA 4. PPHN

• Wynn et al , Clin Perinatol 2010 June

Hemodynamics contd…

• Blood pressure = Q × PVR • Low BP usually due to low Q , as PVR will be

high• If Q normal and PVR is high there may

hypertension .

Silveria et al , Rev Bras Ter Intensiva 2010 ; 22(3):280-290

Vitals vary with day of life & gest. age

Silveria et al , Rev Bras Ter Intensiva 2010 ; 22(3):280-290

Silveria et al , Rev Bras Ter Intensiva 2010 ; 22(3):280-290

And BP fluctuation is not permissible ..

Silveria et al , Rev Bras Ter Intensiva 2010 ; 22(3):280-290

Other peculiar contributaries in the newborn

• Neonates are in a hypercoagulable state with increased microcirculation endothelial thrombomodulin receptors and reduced anticoagulants – promotes DIC

• Prone to bleeding – reduced coag factors & platelet function

• Limited innate immunity• Diagnosis is primarily clinical

Silveria et al , Rev Bras Ter Intensiva 2010 ; 22(3):280-290

Multi organ dysfunction

• Poor cardiac output , microcirculatory failure & microthrombi lead to compromised perfusion of kidney , liver , gut , CNS

• Recent studies suggest – MODS is due to decreases oxygen utilisation and mitochondrial dysfunction rather than impaired oxygen delivery

Silveria et al , Rev Bras Ter Intensiva 2010 ; 22(3):280-290

Other organs involved

• Pulmonary – ARDS , surfactant deficiency, pulmonary edema , pneumonia , PPHN

• Endocrine – adrenal insufficiency , altered thyroid function

• Hematologic – Lymphocte loss , thrombocytopenia , neutropenia

• Metabolic & nutrition - impaired growth & energy failure

Silveria et al , Rev Bras Ter Intensiva 2010 ; 22(3):280-290

Treatment of septic shock

• A . Initial resuscitation• B . Antibiotics & source control• C Fluid resuscitation• D . Inotropes /Vasopressors/ Vasodilators• E . ECMO• F . Corticosteroids• G . Activated protein C• H Blood products• I Mechanical Ventilation• J. Glycemic control• K . Diuretics & RRT• L. DVT / stress ulcer prophylaxis / nutrition

Initial resuscitation

• Established guidelines only for adults , children and term neonates

• No guidelines for preterms• Airway – Initially high flow nasal oxygen ,

Nasopharyngeal CPAP or NIV• Airway – intubation if apneic or severe

distress• Timely restoration of adequate circulation

Clinical Definitions to guide treatment

Therapeutic end points…. Within 1st 6 hours……….

• Term neonates• CFT < 2 sec• Normal pulses without differential between

central & peripheral pulses• Warm extremities• Urine output > 1ml/kghour• Low lactate• Mixed venous oxygen saturation > 70 %• Cardiac index 3.3 – 6 L/min/m2

Other monitoring techniques

• Functional ECHO cardiography :

Cardiac output , Peripheral vascular resistance,

Organ flow in response to volume , colloid & vasoactive medication

SVC flow > 40 ml/Kg/min• NIRS – organ perfusion

Antibiotics & source control

• Empiric antibiotics – 1 hour of diagnosis. • Choice depends on epidemic & endemic

ecologies ( H1N1, MRSA , Chloroquine resistant malaria, penicillin resistant pneumococci

• Clindamycin & anti toxin – TSS & refractory hypotension

• Early & aggressive source control

Management of hypotension & cardiovascular support

• Defn. of shock & hypotension is confounding in preterms

• Inotrope use in hypotensive preterms no shown to significantly improve outcome.

• Achieve MAP – 30 in preterms

Actions of B agonists

Circulation. 2008;118:1047-1056

Actions of a agonist

Circulation. 2008;118:1047-1056

Action of PDE Inh

Circulation. 2008;118:1047-1056

Pharmacological Management of hypotension – Inotropes and

vasopressors• Dopamine• Dobutamine• Norepinephrine• Epinephrine• Vasopressin & terlipressin• Milrinone

Inotropic and Vasopressor Drugs – action and adverse effects

Drug Clinical indication Dose range

α1 β1 β2 DA Adverse effects

Dopamine Shock (cardiogenic, vasodilatory)HFSymptomatic bradycardiaunresponsive to atropine orpacing

2 – 20 mcg/Kg/min

+++ ++++ ++ ++++ Severe hypertension (especially inpatients taking nonselective-blockers)Ventricular arrhythmiasCardiac ischemiaTissue ischemia/gangrene (high dosesor due to tissue extravasation).Severe systemic & pulmonary vasoconstriction

Circulation. 2008;118:1047-1056

Drug Clinical indication

Dose range

α1 β1 β2 DA Adverse effects

Dobutamine Low CO (decompensated HF,cardiogenic shock,sepsis-induced myocardialdysfunction)Symptomatic bradycardiaunresponsive to atropine orpacing

2 – 20 mcg/Kg/min

+ +++++ +++ - TachycardiaIncreased ventricular response rate inpatients with atrial fibrillationVentricular arrhythmiasCardiac ischemiaHypertension (especially nonselective-blocker patients)Hypotension

Circulation. 2008;118:1047-1056

Drug Clinical indication

Dose range

α1 β1 β2 DA Adverse effects

Nor-epinephrine

Shock (vasodilatory,cardiogenic)

0.1-3 mcg/kg/min

+++++

+++ ++ - ArrhythmiasBradycardiaPeripheral (digital) ischemiaHypertension (especially nonselective-blocker patients

Epinephrine Shock Cardiac arrestBronchospasm/anaphylaxisSymptomatic bradycardia orheart block

0.1-1 mcg/Kg/min

+++++

++++ +++ - Ventricular arrhythmiasSevere hypertension resulting incerebrovascular hemorrhageCardiac ischemiaSudden cardiac death

Circulation. 2008;118:1047-1056

Drug Clinical indication Dose range Action Adverse effects

Milrinone Low CO (decompensated HF,after cardiotomy

Bolus: 50 mcg/kg bolus over10 to 30 minInfusion: 0.375 to 0.75Mcg/ kg/ min (doseadjustment necessary forrenal impairment

PDE inh Ventricular arrhythmiasHypotensionCardiac ischemiaTorsade des pointes

Circulation. 2008;118:1047-1056

Drug Clinical indication

Dose range Action Adverse effects

Vasopressin Shock (vasodilatory, cardiogenic)Cardiac arrest

Infusion: 0.01 to 0.1 U/min(common fixed dose 0.04U/min)Bolus: 40-U IV bolus

V1 receptors (vascular smooth muscle)V2 receptors (renal collecting duct system

ArrhythmiasHypertensionDecreased CO (at doses 0.4 U/min)Cardiac ischemiaSevere peripheral vasoconstrictioncausing ischemia (especially skin)Splanchnic vasoconstriction

Circulation. 2008;118:1047-1056

Drug Clinical indication

Dose range Action Adverse effects

Levosimendan Decompensated HF

Loading dose: 12 to 24mcg/kg over 10 minInfusion: 0.05 to 0.2mcg / kg/ min

Calcium sensitiser

Tachycardia, enhanced AV conductionHypotension

Circulation. 2008;118:1047-1056

Guidelines for adults adaptable ???

• However no evidence for norepinephrine use in newborns

• One study – Tourneux et al concluded that“Noradrenaline was effective in increasing

systemic blood pressure. An increase in urine output and a decrease in blood lactate concentration suggest that noradrenaline may have improved cardiac function and tissue perfusion”.

What to start ? How to titrate

Other drugs

• Hydrocortisone – Improves vessel wall sensitivity , circulating catecholamines, inhibits nitric oxide synthase expression and suppresses immune response.

• Indic : fluid refractory shock , catecholamine refractory shock , proven adrenal insuff.

• Immunomodulators – IVIG , Activated protein C – no role

• Pentoxifylline – promising results in refractory shock in prematures – 5mg/Kg/hour – 6 hours- 5 days

Supportive therapies

• Blood Products and plasma therapies

Hb levels of 10g/dl during phase of shock.

Plasma therapy for DIC , TTP.

Platelet –

<10,000 or <20,000 high risk of bleed- prophylactic transfusion

If > 50,000 – transfuse if active bleeding.

Mechanical ventilation1. Target a tidal volume of 6 mL/kg predicted body weight in patients with sepsis-induced ARDS (grade 1A vs. 12 mL/kg).

2. Plateau pressures be measured in patients with ARDS and initial upper limit goal ≤30 cm H2O (grade 1B).

3. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at end expiration (atelectotrauma) (grade 1B).

4. Strategies based on higher rather than lower levels of PEEP be used for patients with sepsis- induced moderate or severeARDS (grade 2C).

5. Recruitment maneuvers be used in sepsis patients with severe refractory hypoxemia (grade 2C).

6. Prone positioning be used in sepsis-induced ARDS patients with a Pao2/Fio2 ratio ≤ 100 mm Hg in facilities that have experience with such practices (grade 2B).

•Maintain head of the bed elevated to 30-45 degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia (grade 1B).

• Noninvasive mask ventilation (NIV) be used in that minority of sepsis-induced ARDS patients in whom the benefits of NIV have been carefully considered and are thought to outweigh the risks (grade 2B).

9. That a weaning protocol be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria: a) arousable; b) hemodynamically stable (without vasopressor agents); c) no new potentially serious conditions d) low ventilatory and end-expiratory pressure requirements; and e) low Fio2 requirements which can be met safely delivered with a face mask or nasal cannula.

• If the spontaneous breathing trial is successful, consideration should be given for extubation (grade 1A).

Supportive therapies

• Strict glycemic control – 110 – 180 md/dl• Diuretics & RRT – to reverse fluid overload• DVT & stress ulcer prophylaxis – not

recommended• Nutrition – enteral preferred.

What to do………..Paediatric Severe sepsis bundleFirst hour ( resuscitation bundle)

1. Establish reliable venous access

2. Obtain blood cultures prior to antibiotics

3. Obtain serum lactate

4. Administer isotonic crystalline fluid bolus 20ml/Kg

5. Administer broad spectrum antibiotics

6.Initiate inotropes

First 6 hours ( Maintenance bundle )

1. Achieve CVP >8

2. Achieve Scvo2 >70

3. Normalization or improvement of lactate , hemodynamics

Future considerations

• X- cyton – rapid identification of organisms• Adjuvant treatment

- LPS binding proteins ( rBPI , SCD14 or anti CDI4 )- Anti infl therapies – Pentoxifylline, Nicotinic

stimulation , statins)- Synthetic host defense peptides ( rh SP-D ,

lactoferrin)- TLR antagonists

• Thank You