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SETTING Seahorse Paediatric Intensive Care Unit (PICU), Bristol Royal Hospital for

Children (BRCH) FOR STAFF All medical and nursing staff PATIENTS Patients on PICU ___________________________________________________________________________

Index 1. Definitions 2. Age-specific values 3. Stepwise approach to treatment 4. General considerations 5. Investigations for underlying immunodeficiency 6. Underlying immune dysregulation and sepsis mimics 7. Peri/post-mortem investigations

Definitions

In adults, sepsis is defined as ‘life threatening organ dysfunction caused by a dysregulated host response to an infection’1. The definition of paediatric sepsis is under review, but the current definitions2, 3 are outlined below.

Systemic Inflammatory Response Syndrome (SIRS) – At least 2 of the following criteria, one of which must be abnormal temperature or white cell count:

• Core temperature >38.5oC or <36oC • Tachypnoea • Tachycardia or bradycardia • Abnormal White Cell Count

Infection – Proven or suspected infection caused by any pathogen, or a clinical syndrome associated with a high probability of infection

Sepsis – SIRS in the presence of infection

Severe Sepsis – Sepsis plus one of the following: • Cardiovascular dysfunction • Acute respiratory distress syndrome • Two or more organ dysfunction

Septic Shock – Sepsis and cardiovascular organ dysfunction, defined as hypotension or need for a vasoactive drug, or two of the following:

• Metabolic acidosis with base excess >5mMol/L • Raised lactate • Urine output <0.5ml/kg/hr • Prolonged capillary refill time >5 seconds • Core to peripheral temperature gap >3oC

Clinical Guideline SEPTIC SHOCK IN CHILDREN: MANAGEMENT ON PICU

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Of note, the SIRS criteria are non-specific (fever with associated tachycardia is common in children with mild viral illness) and do not reliably discriminate children with infections on a more severe trajectory or with a higher risk of mortality.

The Australia and New Zealand Intensive Care Society (ANZIC) Paediatric Study group have developed a Paediatric Sepsis score to more accurately identify children at high risk of sepsis mortality, based on information available within the first hour of PICU admission4 (see Appendix Table 3).

Age-specific values Table 1: Age-specific values agreed upon and later reviewed by the International Paediatric Sepsis Consensus Conference 20052,3

Age Tachycardia (Heart rate)

Bradycardia (Heart rate)

Tachypnoea (Respiratory rate)

Abnormal White Cell Count

Systolic Hypotension (<5th Percentile)

0 – 7 days >180 <100 >50 >34 <59

1 wk. – 1 mo. >180 <100 >40 >19.5 or <5 <79

1 mo. – 1 yr. >180 <90 >34 >17.5 or <5 <75

2 – 5 yrs. >140 - >22 >15.5 or <6 <74

6 – 12 yrs. >130 - >18 >13.5 or <4.5 <83

13 – 18 yrs. >110 - >14 >11 or <4.5 <90

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Stepwise approach to treatment

*See Steroids section below for advice on risk factors for adrenocortical insufficiency and Hydrocortisone dosing

**European Society of Paediatric and Neonatal Intensive Care (ESPNIC) definition. See Vasoactive medications section for advice on calculating the Vasoactive-inotrope score.

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General considerations • Haemodynamic monitoring

Advanced haemodynamic monitoring is recommended to help differentiate between ‘cold’ and ‘warm’ shock and to guide ongoing fluid, inotrope and vasopressor support5, 6. This should include invasive mean arterial blood pressure (MAP) and central venous pressure (CVP) monitoring, and serial assessment of lactate levels and central venous saturations (ScvO2 - as a surrogate for mixed venous saturations (SvO2)). Echocardiography should be performed and use of oesophageal ultrasound doppler to monitor cardiac output should be considered. Table 2 provides normal ranges for advanced haemodynamic monitoring. Whilst there is no evidence for specific haemodynamic goals5, it is appropriate to target the age-appropriate normal range for the heart rate and MAP, and ScvO2>70%, or no greater than 30% below arterial saturations in children with cyanotic heart disease. A cardiac index (CI) of 3.5-5.5L/min/m2 should be aimed for. Fluid responsiveness should be continually assessed; this is defined as an increase in stroke volume ≥10% in response to a fluid bolus. Serial examination should include assessment of pulse volume, central capillary refill time, urine output and mental status to evaluate response to resuscitation. Signs of fluid overload, including hepatomegaly and chest crepitations should be monitored for.

Table 2: Normal ranges for advanced haemodynamic monitoring5

Variable Formula Normal range Units

Cardiac Index (CI) CI = cardiac output/body surface area

3.5 – 5.5 L/min/m2

Stroke Index (SI) SI = CI/heart rate 30 – 60 mL/m2

Systemic vascular resistance index (SVRI)

SVRI = 80 x (mean arterial pressure – central venous pressure)/CI

800 – 1600 Dyne-s/cm5/m2

Flow Time Corrected (FTc)

FTc = flow time/√cycle time

330 – 360 m/sec

• Refractory shock There is no universally agreed definition of refractory septic shock, but the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) have developed and validated a definition (see Stepwise approach to treatment flowsheet), which is strongly predictive of need for extracorporeal membrane oxygenation (ECMO) or death7.

• Intubation and ventilation Intubation and ventilation should be strongly considered in all children with fluid-refractory catecholamine-resistant septic shock, even in the absence of respiratory failure. Early invasive mechanical ventilation can help to mitigate the high metabolic demand from septic shock in addition to providing cardiovascular support; increased intra-thoracic pressure reduces left ventricular afterload, which is particularly helpful in patients with low cardiac output and high systemic vascular resistance.

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Extreme caution should be exercised to avoid worsening hypotension or precipitating cardiac arrest during induction of anaesthesia prior to intubation. Strategies should include pre-oxygenation, use of induction agents with a favourable haemodynamic profile (e.g. Ketamine and Fentanyl, avoiding Propofol and gaseous induction) at reduced doses and ongoing volume resuscitation throughout. An inotrope infusion should be running, and cardiac arrest drugs should be available.

For children with sepsis-induced acute respiratory distress syndrome (ARDS) who are responding to initial resuscitation, a trial of non-invasive ventilation can be considered as an alternative to intubation and ventilation. Patients requiring mechanical ventilation should be ventilated with a protective ventilatory strategy from the outset.

Acute Respiratory Distress Syndrome Guideline

• Vasoactive medications Dilute adrenaline can be initiated through peripheral venous access to avoid delays in therapy whilst central access is established. Whilst the stepwise approach above provides a framework for choice of vasoactive medicines, the haemodynamic state of children with septic shock is dynamic and close monitoring is required to guide ongoing vasoactive treatment.

The vasoactive-inotropic score (VIS) can be calculated using the following formula:

VIS = Dopamine dose (micrograms/kg/min) + Dobutamine dose (micrograms/kg/min) + 100 x Adrenaline dose (micrograms/kg/min) + 100 x Noradrenaline dose (micrograms/kg/min) + 10,000 x Vasopressin dose (units/kg/min) + 10 x Milrinone dose (micrograms/kg/min)

• Antimicrobials and source control

Antibiotics should be given as soon as possible, within 1 hour of identification of septic shock and ideally after blood cultures have been taken. For sepsis without a clear focus, empirical broad-spectrum antibiotics should be commenced as directed by the PICU antimicrobial guideline.

Antibiotic Guideline

If a pre-existing antibiotic plan exists, this should be followed. If any of the following features apply, discuss urgently with Microbiology: - Already on antibiotics - Any contra-indication to the antibiotics recommended in the guideline (allergy,

interactions, toxicity) - Known to be colonised with resistant organisms or previously treated for an infection with

a resistant organism (e.g. MRSA, VRE, ESBL) - Possible neurosurgical shunt infection - Known or suspected asplenism

Antiviral therapy should be initiated as early as possible if septic shock of viral origin is suspected. IV Aciclovir should be commenced if encephalitis is suspected and in neonates with septic shock. During influenza season, empirical treatment with Oseltamivir and testing for H1N1 infection is recommended in at risk patients presenting with septic shock.

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If systemic fungal infection is suspected, a beta D-glucan assay should be sent in addition to blood cultures and anti-fungals should be commenced, as per the PICU antimicrobial guideline. Table 4 in the Appendix summarises the suggested microbiology investigations in septic shock.

If intravascular lines are presumed to be the source of sepsis, these should ideally be removed once alternative vascular access has been established. If an infection amenable to source control is identified (e.g. abscess, septic arthritis, empyema, necrotising fasciitis or infected prosthetic material), this should be urgently discussed with the relevant surgical specialty. If Toxic Shock Syndrome (TSS) is suspected, refer to the TSS guideline.

Burns: Toxic Shock syndrome and Sepsis

• Steroids If adrenocortical insufficiency is suspected in the context of septic shock (e.g. unexplained hypoglycaemia, hyponatraemia and/or hyperkalaemia, known adrenal/pituitary disorder, or recent steroid therapy), a random Cortisol level should be taken & IV Hydrocortisone should be commenced at 2-4mg/kg 6 hourly in children or 100mg/m2 daily in 3-4 divided doses in neonates, and adjusted according to response. In this context, the Endocrinology team should be involved prior to stopping steroids, as a Synacthen test may be required. Corticosteroids may be used as an adjunctive therapy in catecholamine-resistant septic shock in the absence of adrenal insufficiency, although there is no current evidence to support or refute this role. A suggested dose in this context is 1mg/kg IV Hydrocortisone 6 hourly in children and 2.5mg/kg IV Hydrocortisone 6 hourly in neonates.

• Blood products Children admitted with septic shock should have two group and save samples sent to ensure blood is available if required. A routine clotting profile and fibrinogen should be requested. For haemodynamically stabilised children with septic shock, a haemoglobin of ≥70g/l is acceptable5. A haemoglobin transfusion threshold of 90g/l is suggested in children with septic shock with high lactates and/or low central venous saturations.

A platelet transfusion threshold of 20x109/L is suggested in the absence of bleeding, in the context of sepsis. However, if the child requires procedures (including central venous line insertion) or surgery, a platelet count of ≥50x109/L should be targeted, and if ECMO is being considered, a platelet count of ≥100x109/L is appropriate. Fresh frozen plasma (FFP) is not generally recommended in children with septic shock and clotting abnormalities, unless they are actively bleeding5. However, if disseminated intravascular coagulation (DIC) is suspected, FFP and Cryoprecipitate may be required. Paediatric Transfusion Guideline

• Raised intracranial pressure Raised intracranial pressure may occur due to intracranial infection or cerebral oedema secondary to capillary leak. If suspected, Neurosurgery should be contacted urgently, appropriate imaging should be arranged, and neuroprotective measures should be instituted. A lumbar puncture should not be attempted if there are signs of raised intracranial pressure, or if the child is unstable with septic shock.

• Central access Central access should be obtained early and ideally under ultrasound guidance. Subclavian

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vein access has an increased risk of complications in patients who are at risk of being coagulopathic.

• Glucose control Glucose levels should ideally be kept within the normal range; a glucose infusion rate of 4-6mg/kg/min in children and 6-8mg/kg/min in neonates is suggested. Hypoglycaemia should be treated, and an IV Insulin infusion may be considered in persistent hyperglycaemia >10mmol/L.

• Feeds Early enteral nutrition should be commenced and increased in a stepwise fashion, unless there are specific contraindications to enteral feeding. If the child is requiring escalating doses of vasoactive support, it is reasonable to delay enteral feeding until stability is achieved and vasoactive medicines are starting to wean.

The use of parenteral nutrition during the acute phase critical illness should be avoided as is associated with poorer outcomes8. The approach to starting parenteral nutrition if there is a contraindication to the initiation of enteral nutrition should be individualised; the PICU Nutrition guideline should be used to aid this decision.

Nutrition requirement in the critically ill child: How to estimate and tailor nutrition on Seahorse PICU

• Renal replacement therapy Continuous renal replacement therapy should be used to treat or prevent fluid overload in anuric or severely oliguric children with septic shock. High volume haemofiltration should be avoided, as there is no demonstrable benefit over standard haemofiltration in the context of septic shock9.

Diuretics can be used to reverse fluid overload when shock has resolved.

• Sedation and muscle relaxants Aim for sedation alone, but muscle relaxants should be used in the context of low cardiac output state and patient-ventilator desynchrony.

• Neutropenic sepsis For children with neutropenic sepsis secondary to chemotherapy, refer to the specific guideline. Management of Infections in Paediatric Haematology and Oncology Patients Antibiotics in Febrile Neutropenia

• Intravenous immunoglobulin IVIG is not routinely recommended in septic shock5 but may be of use in children with Toxic Shock Syndrome or those with primary humoral immunodeficiencies or who are immunocompromised with known low immunoglobulin levels.

• Extracorporeal Membrane Oxygenation (ECMO) Venoarterial ECMO may be considered in children with refractory septic shock or post-cardiac arrest with successful return of spontaneous circulation in the context of sepsis. There appears to be increased survival in children who have suffered a cardiac arrest from refractory shock where venoarterial ECMO is used compared to standard therapy10.

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However, the ECMO service at BRCH is not commissioned for this indication, and a decision to establish ECMO in these circumstances therefore requires discussion with a commissioned ECMO service. Extracorporeal Life Support

Investigations for underlying immunodeficiency Children with recurrent or severe bacterial or fungal infection, bronchiectasis or chronic ENT problems may have an underlying immune deficiency. These children should be discussed with the Infectious Diseases & Immunology team and may require further investigation, but this should be carried out in the convalescent phase of the illness, and not whilst they are acutely unwell with septic shock.

Underlying immune dysregulation and sepsis mimics Haemophagocytic Lymphohistiocytosis Children with a Haemophagocytic Lymphohistiocytosis (HLH) often present with multi-organ dysfunction that may mimic severe sepsis. HLH is a syndrome of severe, dysregulated inflammation which can lead to a cytokine storm and multi-organ failure. It should be considered in children with persistent fever, coagulopathy and thrombocytopaenia or pancytopaenia, which may be out of proportion with the degree of multi-organ dysfunction. A Ferritin >10,000 is both sensitive and specific for HLH11, as demonstrated by Figure 1. Typically, patients also have elevated triglycerides and low fibrinogen. If HLH is suspected, refer urgently to Rheumatology. Figure 1: Suggested algorithm for investigation of suspected HLH11.

PIMS-TS Paediatric Inflammatory Multi-System Syndrome – temporally associated with SARS-CoV 2 (PIMS-TS) is a newly recognised syndrome defined by evidence of inflammation (persistent fever, neutrophilia, elevated CRP) and single or multi-organ failure, with a suspected temporal association with Covid-19 infection and in the absence of any other microbial cause. The syndrome may mimic septic shock, and if suspected, should be discussed urgently with the Infectious Diseases & Immunology team. The RCPCH guidance for management of PIMS-TS can be accessed below. Paediatric Multisystem Inflammatory Syndrome Temporally Associated with Covid-19

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Peri/post-mortem investigations In some cases, children with septic shock may deteriorate rapidly and death may be inevitable. In such cases, there should be discussion with a Pathologist and the Infectious Diseases and Immunology team regarding further investigations which are required. As a minimum, the following investigations should be obtained with consent from parents:

- Peripheral blood: Plasma: 1 ml Lithium heparin for Neutrophil function tests Whole blood: 1ml EDTA for Lymphocyte subsets Discuss with the Immunology lab at Southmead (available out of hours via NBT

switchboard) prior to sending samples. - Additional samples for microscopy, culture & sensitivities (M,C&S) and viral polymerase chain

reaction (PCR) Sterile urine sample CSF sample Peripheral/central and line blood samples

- Consider skin biopsy for fibroblast culture to allow genetic screening for HLH - Request Pathologist to look for:

Anatomical clue of immunodeficiency, for example small/absent spleen, presence of larger numbers of lymph glands or total absence of lymphoid tissue

Evidence of haemophagocytosis in the spleen, liver, lymph nodes or bone marrow

If an underlying metabolic disorder is suspected, refer to the guideline below. Specimen Collection for Peri-Mortem Diagnosis of Metabolic Disorders in Children

REFERENCES 1. Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock JAMA. 2016; 315(8):801–810.

2. Goldstein B et al. International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005 Jan; 6(1):2-8.

3. Goldstein B et al. Reply: Values for Systolic blood pressure. Pediatr Crit Care Med. 2005; 6(4):500-501.

4. Schlapbach, L.J. et al. Prediction of pediatric sepsis mortality within 1 h of intensive care admission. Intensive Care Med. 2017; 43, 1085–1096.

5. Weiss SL e al. Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Pediatr Crit Care Med. 2020 Feb; 21(2):e52-e106.

6. 'Brierley J, Peters MJ. Distinct haemodynamic patterns of septic shock at presentation to pediatric intensive care. Pediatrics 2008; 122: 752-759.

7. Morin L et al. Validation of the pediatric refractory septic shock definition: post hoc analysis of a controlled trial. Ann Intensive Care. 2021 Feb 10; 11(1):32.

8. Fivez T et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med. 2016; 374: 1111-1122.

9. Joannes-Boyau O et al. High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury

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(IVOIRE study): a multicentre randomized controlled trial. Intensive Care Med. 2013 Sep; 39(9):1535-46.

10. Oberender et al. Venoarterial extracorporeal membrane oxygenation versus conventional therapy in severe pediatric septic shock. Pediatric Critical Care Medicine 2018; 19(10): 965-972.

11. Sen ES, Steward CG, Ramanan AV. Diagnosing haemophagocytic syndrome. Archives of Childhood 2017; 102:279-284.

RELATED DOCUMENTS AND PAGES

See hyperlinks to guidelines within this document. Acute Respiratory Distress Syndrome Guideline

Antibiotic Guideline

Burns: Toxic Shock syndrome and Sepsis

Paediatric Transfusion Guideline

Nutrition requirement in the critically ill child: How to estimate and tailor nutrition on Seahorse PICU

Management of Infections in Paediatric Haematology and Oncology Patients Antibiotics in Febrile Neutropenia Extracorporeal Life Support

Paediatric Multisystem Inflammatory Syndrome Temporally Associated with Covid-19 Specimen Collection for Peri-Mortem Diagnosis of Metabolic Disorders in Children

AUTHORISING BODY

Paediatric Intensive Care Governance Group.

SAFETY Nil QUERIES AND CONTACT

PICU Consultant Ext. 28018.

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Appendix Table 3: Paediatric Sepsis Score developed by the ANZIC group using variables recorded in the first hour of PICU admission to predict mortality4. The score defines 5 levels of sepsis mortality risk: 0-2 points – very low risk; 3-5 points – low risk; 6-8 points – moderate risk; 9-11 points – high risk; ≥12 points – very high risk.

System Parameter Points by severity level

0 3 5 10

Respiratory

PaO2/FiO2 ratio ≥300 100 to <300 <100

Ventilation during the 1st hour

No Yes

Circulatory

Systolic BP<5th percentile

No Yes

Cardiac arrest pre-admission

No Yes

Metabolic Lactate (mmol/l) <3.0 3.0 to <6.0 6.0 to <10.0 ≥10

Neurology Pupils Both reactive Both dilated, unresponsive

Table 4: Suggested microbiology investigations in septic shock. Further investigations may be advised by the Infectious Diseases & Immunology team, especially if risk factors such as foreign travel are present.

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Sample Investigation Container

Blood Microscopy, culture & sensitivities (M,C&S) Peripheral & line samples

Blood culture bottles

Meningococcal & Pneumococcal PCR EDTA red top - Min. 0.4ml

Herpes simplex virus (HSV) PCR EDTA red top - Min. 0.4ml

Enterovirus PCR EDTA red top - Min. 0.4ml

Streptococcal serology: - Anti-DNAse B - Antistreptolysin (ASO)

Serum gold top - Min. 0.5ml

Consider: - Adenovirus PCR - Ebstein Barr Virus (EBV) PCR - Cytomegalovirus (CMV) PCR - Parvovirus B19 PCR - Human Herpesvirus 6 (HHV-6)

EDTA red top - Min. 0.4ml

If fungal infection suspected: - Beta-D-glucan fungal antigen - Galactomannan Aspergillus antigen

2 x serum gold top - Min. 0.5ml in each

CSF From lumbar puncture if patient is stable enough or from external ventricular drain (EVD) if in-situ

M,C&S and Protein & Glucose Sterile universal container x 4

Meningococcal & Pneumococcal PCR Sterile universal container Min. 0.2ml

HSV PCR Sterile universal container Min. 0.2ml

Enterovirus PCR

Sterile universal container Min. 0.2ml

Urine M,C&S Sterile universal container

Pneumococcal urinary antigen Sterile universal container

Throat swab or nasal pharyngeal aspirate (NPA)

M,C&S Bacterial swab

Respiratory viruses PCR panel - Influenza A & B - Respiratory syncytial virus (RSV) - Human metapneumovirus (HMPV) - Adenovirus - Parainfluenza 1,2,3 &4 - Rhinovirus

Swab in viral transport medium

Coronavirus PCR Swab in viral transport medium

Endotracheal tube secretions

M,C&S Sterile universal container

Stool Enterovirus PCR Blue top universal stool container

Enteric bacterial panel (if diarrhoea) - Salmonella, Shigella, Campylobacter, E.coli 0157

Blue top universal stool container

Gastroviruses PCR (if diarrhoea +/- vomiting) - Norovirus, Adenovirus, Rotavirus, Astrovirus,

Sapovirus

Blue top universal stool container