Management of Shock in Children With SAM or Severe Underweight and Diarrhea

Study Overview
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Brief Summary
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Diarrhea is one of the leading causes of under-five childhood mortality and accounts for 8% of 5.4 million global under-5 deaths. The coexistence of sepsis and hypovolemic shock in children with severe acute malnutrition (SAM) having diarrhea is common. At Dhaka hospital of icddr,b, the death rate is as high as 40% and 69% in children with severe sepsis and septic shock respectively with co-morbidities such as severe malnutrition. The conventional management of SAM children with features of severe sepsis recommended by WHO includes administration of boluses of isotonic saline followed by blood transfusion in unresponsive cases with septic shock; whereas the Surviving Sepsis Campaign (SSC) guideline recommends vasoactive support. To date, no study has evaluated systematically the effects of inotrope(s) and vasopressor or blood transfusion in children with dehydrating diarrhea (for example, in cholera) and SAM having shock and unresponsive to WHO standard fluid therapy. This randomized trial will generate evidence whether inotrope and vasopressor or blood transfusion should be selected for severely malnourished children having hypotensive shock and who failed to respond to WHO standard fluid bolus.

Detailed Description
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Background: Burden: Burden: Diarrhea is one of the leading causes of under-five childhood mortality and accounts for 8% of 5.4 million global under-5 deaths. Co-morbidity of severe acute malnutrition (SAM) and shock in children with diarrhea is associated with increased mortality. Nearly half of the patients admitted to the Intensive Care Unit (ICU) of Dhaka Hospital of icddr,b present with sepsis. Data demonstrates that about 43% of children progressed from severe sepsis to septic shock despite receiving recommended treatment. The death rate was found to be as high as 40% and 69% in children with severe sepsis and septic shock respectively with co-morbidities such as severe malnutrition. Knowledge gap: The conventional management of SAM children with features of severe sepsis recommended by WHO include administration of boluses of isotonic saline followed by blood transfusion in unresponsive cases with septic shock. However, a recent African study reported significantly higher mortality among children with features of severe sepsis when they were treated with boluses. To date, no study has evaluated systematically the effects of inotrope or vasopressor or blood transfusion in children with dehydrating diarrhea (for example, in cholera) and SAM having shock and unresponsive to WHO standard fluid therapy. Relevance: If this randomized trial signifies survival benefit from a blood transfusion, inotrope or vasopressor in the management of fluid refractory shock in children with severe acute malnutrition and cholera or other dehydrating diarrheas, then this approach would be a good candidate for implementation in the management of such children especially in developing countries Hypothesis: We hypothesize that the death rates will be significantly lower in children with SAM or severe underweight, dehydrating diarrhea and fluid refractory shock who will be treated with dopamine or adrenaline compared to blood transfusion, after treatment failure with WHO standard bolus intravenous fluid therapy. Objectives: To reduce mortality of the SAM or severely underweight children presenting with diarrhea and fluid refractory shock who will receive WHO standard fluid therapy followed by dopamine or adrenaline, compared to those receiving blood transfusion after WHO standard fluid therapy. Methods: This will be a randomized, three-arm, controlled, non-masked clinical trial in children 1- 59 months old with SAM or severely underweight and fluid refractory shock. It will compare the efficacy of WHO-recommended fluid resuscitation followed by dopamine or adrenaline administration versus WHO recommended fluid resuscitation followed by blood transfusion. After parental written informed consent, children, in addition to usual supportive care, will be allocated to the study interventions following randomization.

Official Title
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Randomized Controlled Trial of Dopamine, Adrenaline, and Blood Transfusion for Treatment of Fluid Refractory Shock in Children With Severe Acute Malnutrition or Severe Underweight and Cholera or Other Dehydrating Diarrheas

Conditions
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Shock Hypovolemic, Shock, Septic, Blood Transfusion, Adrenaline, Dopamine

Intervention / Treatment
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* Drug: Dopamine
* Drug: adrenaline
* Drug: Blood Transfusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children of either sex with SAM or severe underweight and diarrhea Age: 1-59 months Children with cerebral palsy (CP) and/or developmental dealy Fluid refractory shock Exclusion Criteria: Severe anemia (hemoglobin< 5 gm/dl) who will require a blood transfusion Sclerema Congenital anomalies (TOF/ASD/VSD/Trisomy 21, etc.) Having a rare blood group (negative blood groups) A child requiring cardio-pulmonary resuscitation during screening or having gasping respiration

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Systematic evaluation of the effects of inotrope(s) and vasopressor or blood transfusion in children with dehydrating diarrhea (for example, in cholera) and SAM or severe underweight having shock and unresponsive to WHO standard fluid therapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dopamine arm<br>Children in the dopamine arm (Treatment plan A) will receive dopamine, 8 microgram/kg/min (increasing the dose after 15 minutes to 12 microgram/kg/min to a maximum of 15 microgram/kg/min) | Drug: Dopamine<br>* Children will receive dopamine, 8 microgram/kg.min (increasing the dose after 15 minutes to 12 microgram/kg/min to a maximum of 15 microgram/kg/min)<br>|
| Experimental: Adrenaline arm<br>Children in the adrenaline arm (Treatment plan B) will receive adrenaline, 0.1 microgram/kg/min (increasing the dose after 15 minutes to 0.2 microgram/kg.min to a maximum of 0.3 microgram/kg.min) | Drug: adrenaline<br>* Children will receive adrenaline, 0.1 microgram/kg/min (increasing the dose after 15 minutes to 0.2 microgram/kg.min to a maximum of 0.3 microgram/kg.min)<br>* Other names: Epinephrine;|
| Active Comparator: Blood transfusion arm<br>Children in the blood transfusion arm (Treatment plan C) will receive a transfusion of whole human blood in a dose of 10 mL/kg over 2-3 hours. While the blood transfusion is being arranged, IV fluid would be given @ of 3 ml per kg per hour | Drug: Blood Transfusion<br>* Children will receive a transfusion of whole human blood in a dose of 10 mL/kg over 2-3 hours. While the blood transfusion is being arranged, IV fluid would be given @ of 3 ml per kg per hour<br>* Other names: Blood;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Case fatality rate | Number of mortalities among SAM or severe underweight children presenting with diarrhea and fluid refractory shock who would receive WHO standard fluid therapy followed by dopamine or adrenaline, compared to those receiving blood transfusion after WHO standard fluid therapy | 28 days (± 3 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure rates | Number of children where we failed to achieve the goal of resuscitation after starting any one of the interventions | Through study completion, an average of 7 days | 
| Need for mechanical ventilation | Number of children who would require mechanical ventilation | Through study completion, an average of 7 days | 
| Heart failure | Number of children who developed heart failure. Heart failure will be assessed on the basis of - age-specific tachypnea, tachycardia, enlarged tender liver, pedal edema, basal crackles and/or gallop and response to furosemide (combination of findings). | Through study completion, an average of 7 days | 
| Length of ICU stay | Time a child stays in ICU | Through study completion, an average of 7 days | 
| Time-to-achieve recovery | Required times (minutes) for resuscitation of a child after randomization to a specific arms | 3-4 hours | 
| Left ventricular function of the study participants | Evaluation of left ventricular function (hyperdynamic or normal) by cardiac USG at enrollment, at time of heart failure (if any) | Through study completion, an average of 7 days | 
| Right ventricular function of the study participants | Evaluation of right ventricular function (hyperdynamic or normal) by cardiac ultrasound at enrollment, at time of heart failure (if any) | Through study completion, an average of 7 days | 
| Inferior vena cava collapsibility of the study participants | Evaluation of Inferior vena cava collapsibility by cardiac ultrasound at enrollment, at time of heart failure (if any) | Through study completion, an average of 7 days | 
| Length of hospital stay | Time a child stays in the hospital | variable (days to months) | 
| Mean arterial pressure (MAP) stabilization at 48 hours | Number of children whose MAP was stabilized at 48 hours | 48 hours from the point of inclusion in the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe acute malnutrition, Children, Shock, Cholera, Dehydrating diarrhea, Severe underweight