Nepal paediatric society clinical guidance for management of sepsis and septic shock in the paediatric intensive care units in Nepal

Justification: Sepsis is a major cause of morbidity and mortality in Nepal. There is a lack of standardisation in the management of severe sepsis and septic shock. Additionally, international guidelines may not be completely applicable to resource limited countries like Nepal. Objective: Create a collaborative standardised protocol for management of severe sepsis and septic shock for Nepal based on evidence and local resources. Process / Methods: Paediatricians representing various paediatric intensive care units all over Nepal gathered to discuss clinical practice and delivery of care of sepsis and septic shock under the aegis of Nepal Paediatric Society. After three meetings and several iterations a standardised protocol and algorithm was developed by modifying the existing Surviving Sepsis Guidelines to suit local experience and resources. Recommendations: Paediatric sepsis and septic shock definitions and management in the early hours of presentation are outlined in text and flow diagram format to simplify and standardise delivery of care to children in the paediatric intensive care setting. These are guidelines and may need to be modified as necessary depending on the resources availability and lack thereof. It is recommended to analyse data moving forward and revise every few years in the advent of additional data.


INTRODUCTION
Paediatric critical care is a relatively new field in Nepal, with around 25 stand-alone paediatric intensive care units (PICU). 1 A report from 2016 stated that there are less than 100 PICU beds available for critically ill children in Nepal with over 60% concentrated in and around the capital city. 2 The report describes the lack of trained critical care manpower, including nurses and physicians; and insufficient equipment, laboratory, and radiology services. Ongoing training in paediatric critical care is also inadequate. Additionally, even within Nepal significant disparities exist: majority of the nation is rural with difficult terrain and transportation, and further lack of resources and income exist. Access to health care, let alone sophisticated monitoring and management, is not feasible. 1 Appropriate transport of the critically ill child is almost non-existent in regions outside a few major cities, and even in these cities it is not well established. There is increased variability in critical health care delivery, including sepsis management, which, in several instances is not based on evidence and standard of care. 2 This impacts the morbidity and mortality of critically ill children. Additionally, international sepsis protocols are geared toward high resource nations with differing epidemiology, skills, resources, and practices and may lack relevance to countries like Nepal. 3

PURPOSE
The primary objective of this clinical guidance document is to put forth consensus definitions and create a standardised protocol for severe sepsis and septic shock that is 4 : 1. Collaborative among paediatricians working in various PICUs in Nepal 2. Feasible in view of the monitoring and management resources available 3. Adapted from Surviving Sepsis Guidelines This guidance is mainly for management in the PICU and high dependency unit (HDU). However, it is targeted towards all physicians and healthcare workers managing children in inpatient, emergency, urgent care settings all over Nepal. In facilities that lack PICUs or HDUs this document should guide early management of sepsis and septic shock prior to transport to a higher level of care.

METHODOLOGY Supporting organisation, selection of panel members and procedure
This clinical guideline has been prepared under the aegis of Nepal Paediatric Society. Hospitals all over Nepal were screened to identify those with PICUs. At least one paediatrician from each of the PICUs were invited to attend seminars to discuss and prepare the document. International guidelines and recommendations were reviewed. After successive iterations, the final document was agreed upon by the panel.

References used for discussions
This clinical guideline for sepsis and septic shock for Nepal was prepared by reviewing and adapting from standardised guidelines, viz., American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Paediatric and Neonatal Septic Shock 2017 5 and Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children 2020. 4 Other documents that were referenced were World Health Organisations publications on sepsis. 6,7 Additionally, since several recommendations in these international guidelines may not be feasible in the context of locally available resources, experience of paediatricians working in PICUs across Nepal was taken into consideration, and existing 'septic shock management protocols' of different hospitals were also reviewed.

CLINICAL GUIDELINE (APPENDIX 1) Definitions
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis in adults as life-threatening organ dysfunction caused by dysregulated host response to infection; and septic shock as a subset of sepsis with profound circulatory, cellular and metabolic abnormalities associated with a greater risk of mortality. 8 However, this definition lacks practicality in identifying and managing children with sepsis at the bedside in resource limited regions, including Nepal. 9 For the purposes of this document and ease of identifying septic shock in children the panel came to a consensus to define septic shock as: suspected or confirmed infection with "Triad of fever or hypothermia, tachycardia, and signs of decreased tissue perfusion. The latter is defined as cold extremities, weak pulse volume, and prolonged capillary refill 7 plus change in mental status [irritability, inappropriate crying, drowsiness, confusion, poor interaction with parents, lethargy, or becoming unarousable] and decrease in urine output, with or without low blood pressure" (Table  1).

Early Recognition
The panel recommends all facilities including PICU, HDU, inpatient wards, emergency rooms, and urgent care facilities to establish tools for early recognition of septic shock and deterioration in patient status. Such tools can be an objective evaluation of patient to assess for severity of illness and deterioration in status. Nursing staff can be taught to use such tools at dedicated intervals and alert physicians if a certain score is used. The Monaghan Paediatric Early Warning Signs (PEWS) 10,11 is a widely used and validated tool which may have high feasibility in resource limited regions since this tool is based entirely on physiologic parameters, including behaviour, cardiologic status, and respiratory status, and has no requirement for laboratory data.

Intravenous Access
As soon as the patient arrives to the facility, intravenous (IV) access needs to be attempted. At least two large bore catheters are required. If three attempts are unsuccessful, intraosseus (IO) catheter may be placed and used with the decision to retry to place IV at a subsequent time.

Monitoring
Monitoring and reassessment are key in avoiding deterioration and complications of therapy, and evaluation of response (improvement) to therapy.
Reassessment is recommended after every intervention, large or small. This will detect the status of the patient upon which further intervention can be done. Frequently, assessment and monitoring may be required on a continuous basis.   ii. Invasive Endotracheal intubation and invasive ventilation depend on the level of shock and resource availability. a. In a facility where there is a lack of trained manpower and resources, intubation may be even more detrimental to the patient. In such a situation endotracheal intubation is only recommended in the event of impending respiratory arrest and immediate transport to a higher centre is essential. 4

Guidance for Management of Sepsis and Septic Shock; Basnet S et al.
Lung protective ventilation with high positive end expiratory pressure (PEEP), low tidal volume, and low supplemental oxygen (FiO2) is recommended for invasive mechanical ventilation. Avoiding auto PEEP and maintaining plateau pressure below 30 cm H2O can further protect lungs. It is recommended to accept mild hypoxemia and hypercarbia if necessary. Prone positioning can help with oxygenation.

Fluids
i. Maintenance fluid: Children presenting with sepsis including suspected or confirmed infection and hypothermia or hyperthermia but are normotensive may be administered maintenance IV fluid. 4 Avoid fluid boluses. 7 Careful monitoring of signs of decreased cardiac output and hypotension is essential.
Type of fluid: Normal saline (NS) or lactated ringers (LR). Add dextrose if serum glucose is below 150 mg/dL.
ii. Fluid bolus: Children presenting in shock (Table 1) should be administered fluid bolus. 4,7 Type and amount of fluid: 10 -20 ml/kg aliquots of normal saline or lactated ringers are administered up to 40 -60 ml/kg over the first two hours. Careful reassessment of cardiac output / perfusion is necessary after every bolus. Fluid is discontinued immediately if signs of fluid overload develop. Particular monitoring and slow fluid infusion (10 -15 ml/kg in one hour) are required in children admitted with severe malnutrition and shock. 7

Blood products
i. Cross matched packed red blood cells (PRBC), 10 ml/kg may be administered in children with haemoglobin of less than 6 g/dL after two fluid boluses and still hypotensive 3,7 but have no signs of fluid overload (Table 3). Slow blood transfusion is recommended in haemodynamically stable patients only if haemoglobin falls below 4 g/dL. 3,7 ii. Platelets transfusion of 10 ml/kg is only recommended when the level falls below 10 -20,000/mm 3 if patient is not bleeding, or below 50,000 if patient shows some evidence of bleeding.
iii. Fresh frozen plasma (FFP) is not routinely administered in children with septic shock without evidence of bleeding.

Vasoactive Medications
i. If more fluid (after a total of 40 -60 ml/kg) does not improve the perfusion status of the patient or signs of fluid overload and pulmonary edema develop, vasoactive medications need to be initiated.
ii v. Inodilators such as dobutamine or milrinone may need to be added only if blood pressure is high normal yet other signs of decreased perfusion persist.

Corticosteroids
IV hydrocortisone (1 -2 mg/kg every six hours) may be administered if hypotension and decreased perfusion persist even after adequate fluid and vasopressor / inotropic therapy. It should not be initiated until these therapies have been maximised.

Calcium, glucose, antipyretics
Maintain normal serum calcium. Calcium r e p l a c e m e n t w i t h c a l c i u m g l u c o n a t e i s recommended if ionised serum calcium is low. Dextrose is added to maintenance fluid once serum glucose is 150 mg/dL (7.8 mmol/L) or lower. Paracetamol is administered for oral or rectal temperature over 101 • F.

Nutrition
Nutrition needs to be provided to the patient via oral or gastric / postpyloric feeding tube. Feeding should be started as early as possible, once patient is hemodynamically stable.

Fluid overload
Fluid overload needs to be avoided with judicious use of fluid boluses and careful monitoring and reassessments. However, if it does develop post resuscitation, diuretics may be used to remove excess fluid. Furosemide bolus or infusion started at low dose and titrated up based on urine output will decrease extra body water.

CONCLUSIONS
This clinical guidance for management of sepsis and septic shock in children in Nepal is a consensus document, keeping in view the resources available, created by paediatricians working in various PICUs in the country and based / adapted from the Surviving Sepsis Campaign 2020. This is an attempt to decrease variability in critical care delivery and standardise care by providing a guide to providers. Use and efficacy of this guideline will b e m o n i t o r e d a f t e r d i s s e m i n a t i o n a n d implementation.