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

Blood Transfusion Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04750070
• Other study ID #: PR-20021
• Status: Recruiting
• Phase: Phase 3
• Start date: August 17, 2021
• Est. completion date: April 2023

Study information

• Verified date: March 2022
• Source: International Centre for Diarrhoeal Disease Research, Bangladesh
• Contact: Monira Sarmin, MBBS, MCPS
• Phone: +8801718596947
• Email: drmonira[@]icddrb.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

Background:

1. 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.

2. 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.

3. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 135
• Est. completion date: April 2023
• Est. primary completion date: February 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 59 Months

Eligibility

Inclusion Criteria:

1. Children of either sex with SAM or severe underweight and diarrhea

2. Age: 1-59 months

3. Children with cerebral palsy (CP) and/or developmental dealy

4. Fluid refractory shock

Exclusion Criteria:

1. Severe anemia (hemoglobin< 5 gm/dl) who will require a blood transfusion

2. Sclerema

3. Congenital anomalies (TOF/ASD/VSD/Trisomy 21, etc.)

4. Having a rare blood group (negative blood groups)

5. A child requiring cardio-pulmonary resuscitation during screening or having gasping respiration

Related Conditions & MeSH terms

• Adrenaline
• Blood Transfusion
• Diarrhea
• Dopamine
• Hypovolemia
• Severe Acute Malnutrition
• Shock
• Shock Hypovolemic
• Shock, Septic
• Thinness

Intervention

Drug:
• Dopamine
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)
• adrenaline
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)
• Blood Transfusion
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

Locations

Country	Name	City	State
Bangladesh	Icddr,B	Dhaka

Sponsors (3)

Lead Sponsor	Collaborator
International Centre for Diarrhoeal Disease Research, Bangladesh	Muhimbili University of Health and Allied Sciences, University of British Columbia

Country where clinical trial is conducted

Bangladesh, 

References & Publications (23)

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Ahmed T, Ali M, Ullah MM, Choudhury IA, Haque ME, Salam MA, Rabbani GH, Suskind RM, Fuchs GJ. Mortality in severely malnourished children with diarrhoea and use of a standardised management protocol. Lancet. 1999 Jun 5;353(9168):1919-22. doi: 10.1016/S014 — View Citation

Chisti MJ, Pietroni MA, Smith JH, Bardhan PK, Salam MA. Predictors of death in under-five children with diarrhoea admitted to a critical care ward in an urban hospital in Bangladesh. Acta Paediatr. 2011 Dec;100(12):e275-9. doi: 10.1111/j.1651-2227.2011.02 — View Citation

Chisti MJ, Saha S, Roy CN, Salam MA. Predictors of bacteremia in infants with diarrhea and systemic inflammatory response syndrome attending an urban diarrheal treatment center in a developing country. Pediatr Crit Care Med. 2010 Jan;11(1):92-7. doi: 10.1 — View Citation

Chisti MJ, Salam MA, Bardhan PK, Faruque AS, Shahid AS, Shahunja KM, Das SK, Hossain MI, Ahmed T. Severe Sepsis in Severely Malnourished Young Bangladeshi Children with Pneumonia: A Retrospective Case Control Study. PLoS One. 2015 Oct 6;10(10):e0139966. d — View Citation

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Ramaswamy KN, Singhi S, Jayashree M, Bansal A, Nallasamy K. Double-Blind Randomized Clinical Trial Comparing Dopamine and Epinephrine in Pediatric Fluid-Refractory Hypotensive Septic Shock. Pediatr Crit Care Med. 2016 Nov;17(11):e502-e512. doi: 10.1097/PC — View Citation

Ranjit S, Aram G, Kissoon N, Ali MK, Natraj R, Shresti S, Jayakumar I, Gandhi D. Multimodal monitoring for hemodynamic categorization and management of pediatric septic shock: a pilot observational study*. Pediatr Crit Care Med. 2014 Jan;15(1):e17-26. doi — View Citation

Sarker AR, Sultana M, Mahumud RA, Ali N, Huda TM, Salim Uzzaman M, Haider S, Rahman H, Islam Z, Khan JAM, Van Der Meer R, Morton A. Economic costs of hospitalized diarrheal disease in Bangladesh: a societal perspective. Glob Health Res Policy. 2018 Jan 5; — View Citation

Sarmin M, Ahmed T, Bardhan PK, Chisti MJ. Specialist hospital study shows that septic shock and drowsiness predict mortality in children under five with diarrhoea. Acta Paediatr. 2014 Jul;103(7):e306-11. doi: 10.1111/apa.12640. Epub 2014 Apr 11. — View Citation

Sekiguchi H, Harada Y, Villarraga HR, Mankad SV, Gajic O. Focused cardiac ultrasound in the early resuscitation of severe sepsis and septic shock: a prospective pilot study. J Anesth. 2017 Aug;31(4):487-493. doi: 10.1007/s00540-017-2312-8. Epub 2017 Jan 3 — View Citation

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Sun JT. New Advances in Emergency Ultrasound Protocols for Shock. J Med Ultrasound. 2017 Oct-Dec;25(4):191-194. doi: 10.1016/j.jmu.2017.09.005. Epub 2017 Dec 6. No abstract available. — View Citation

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* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Need for mechanical ventilation	Number of children who would require mechanical ventilation	Through study completion, an average of 7 days
Secondary	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
Secondary	Length of ICU stay	Time a child stays in ICU	Through study completion, an average of 7 days
Secondary	Time-to-achieve recovery	Required times (minutes) for resuscitation of a child after randomization to a specific arms	3-4 hours
Secondary	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
Secondary	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
Secondary	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
Secondary	Length of hospital stay	Time a child stays in the hospital	variable (days to months)
Secondary	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