Critical Illness
Conditions
Brief summary
The purpose of the study is 1) to determine whether administration of intravenous zinc to critically ill children is safe, and 2) to determine an appropriate dose of zinc supplementation.
Detailed description
Our recently published studies in children with septic shock demonstrated that pediatric septic shock is characterized by large scale repression of genes that either directly depend on normal zinc homeostasis or directly participate in zinc homeostasis. Functional validation studies demonstrated that nonsurvivors of pediatric septic shock have abnormally low serum zinc concentrations. A follow-up pilot study in a general population of critically ill children demonstrated that the presence of low plasma zinc concentrations is a prevalent problem in critically ill children. In addition, low plasma zinc concentrations correlate inversely with indices of inflammation and directly with the number of organ failures. These preliminary data, coupled with the expected safety of zinc supplementation, provided the rationale for a double blinded, prospective, placebo-controlled trial of zinc supplementation in critically ill children, with the two primary study endpoints to assess efficacy being highly clinically relevant: reduction of the lymphopenia rate and improvement of glucose homeostasis. Although the proposal was well-received, the primary concern precluding funding of this trial were lack of safety and dosing data for intravenous zinc. We have therefore developed a proposal for a Phase I/II study of safety and pharmacokinetics to address these concerns. It is anticipated that data generated through this proposal will provide the necessary preliminary data to re-submit our application for an interventional efficacy trial of zinc supplementation in critically ill children
Interventions
DRUGZinc sulfate
Zinc sulfate 200 mcg/ml in Normal Saline
Sponsors
Children's Hospital Medical Center, Cincinnati
UCSF Benioff Children's Hospital Oakland
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Days to 10 Years
Healthy volunteers
No
Inclusion criteria
* Admission to pediatric intensive care unit * Age between 1 month and 10 years * Pediatric Risk of Mortality III score \> 5, OR presence of at least 1 new organ failure * Anticipated pediatric intensive care unit length of stay \> 3 days * Ability of parent or legal guardian to provide informed consent
Exclusion criteria
* Known zinc deficiency * Pre-existing bone marrow failure * New or existing diagnosis of diabetes mellitus * Limitation of care orders in place * New diagnosis of brain injury, encephalopathy * Clinical contraindication for zinc supplementation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| New Fever | 7 days | Because of reports of fever in patients wiht zinc overdoses, we monitored patients for new fever while on supplementation |
| Plasma Zinc Concentration Over Time | 7 days | Plasma Zinc levels were measured daily during the seven day study period in each group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucose Homeostasis | 7 days | Patients were assigned a score based on glucose range to take into account the degree of hyperglycemia as well as the need for insulin over the course of the 7 day study period. This score is an ordinal scale ranging from 1 to 5, with a score of 1 indicating no hyperglycemia, and 5 indicating severe hyperglycemia despite insulin administration. |
Countries
United States
Participant flow
Pre-assignment details
One patient was enrolled but withdrawn by PI due to insufficient intravenous access to obtain study labs
Participants by arm
| Arm | Count |
|---|---|
| Control Group No intervention | 6 |
| Low Dose Group 250 mcg/kg/day supplemental IV zinc sulfate divided every 8 hours for 7 days
Zinc sulfate: Zinc sulfate 200 mcg/ml in Normal Saline | 6 |
| Medium Dose Group 500 mcg/kg/day supplemental IV zinc sulfate q8 hours for 7 days
Zinc sulfate: Zinc sulfate 200 mcg/ml in Normal Saline | 6 |
| High Dose Group 750 mcg/kg/day supplemental IV zinc sulfate q8 hrs for 7 days
Zinc sulfate: Zinc sulfate 200 mcg/ml in Normal Saline | 6 |
| Total | 24 |
Baseline characteristics
| Characteristic | Control Group | Low Dose Group | Medium Dose Group | High Dose Group | Total |
|---|---|---|---|---|---|
| Age, Continuous | 1.5 years | 1.8 years | 5.3 years | 2.6 years | 1.9 years |
| Number of patients with >= 2 organs failed | 3 participants | 3 participants | 4 participants | 3 participants | 13 participants |
| Pediatric Index of Mortality (PIM) | 3.4 percentage mortality risk | 6.0 percentage mortality risk | 7.0 percentage mortality risk | 5.2 percentage mortality risk | 5.9 percentage mortality risk |
| Pediatric Logistic Organ Dysfunction (PELOD ) | 11 units on a scale | 11 units on a scale | 20 units on a scale | 21 units on a scale | 11 units on a scale |
| Pediatric Risk of Mortality (PRISM) III | 12 units on a scale | 8 units on a scale | 12 units on a scale | 9 units on a scale | 9 units on a scale |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 4 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 6 | 1 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
New Fever
Because of reports of fever in patients wiht zinc overdoses, we monitored patients for new fever while on supplementation
Time frame: 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control Group | New Fever | 0 participants |
| Low Dose Group | New Fever | 2 participants |
| Medium Dose Group | New Fever | 1 participants |
| High Dose Group | New Fever | 0 participants |
Comparison: Chi square analysis comparing number of participants with new fever in each groupp-value: 0.24Chi-squared
Primary
Plasma Zinc Concentration Over Time
Plasma Zinc levels were measured daily during the seven day study period in each group.
Time frame: 7 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control Group | Plasma Zinc Concentration Over Time | Day 6 | 56.8 mcg/dL | Standard Deviation 7.3 |
| Control Group | Plasma Zinc Concentration Over Time | Day 7 | 58.7 mcg/dL | Standard Deviation 4.9 |
| Control Group | Plasma Zinc Concentration Over Time | Day 3 | 60.3 mcg/dL | Standard Deviation 10.7 |
| Control Group | Plasma Zinc Concentration Over Time | Day 2 | 63.0 mcg/dL | Standard Deviation 10.1 |
| Control Group | Plasma Zinc Concentration Over Time | Day 1 | 51.2 mcg/dL | Standard Deviation 14.8 |
| Control Group | Plasma Zinc Concentration Over Time | Day 5 | 57.3 mcg/dL | Standard Deviation 5.1 |
| Control Group | Plasma Zinc Concentration Over Time | Day 4 | 59.5 mcg/dL | Standard Deviation 4.3 |
| Low Dose Group | Plasma Zinc Concentration Over Time | Day 1 | 36.4 mcg/dL | Standard Deviation 8.8 |
| Low Dose Group | Plasma Zinc Concentration Over Time | Day 7 | 67.1 mcg/dL | Standard Deviation 12.2 |
| Low Dose Group | Plasma Zinc Concentration Over Time | Day 5 | 58.9 mcg/dL | Standard Deviation 12.9 |
| Low Dose Group | Plasma Zinc Concentration Over Time | Day 2 | 42.1 mcg/dL | Standard Deviation 15.4 |
| Low Dose Group | Plasma Zinc Concentration Over Time | Day 4 | 54.4 mcg/dL | Standard Deviation 17.6 |
| Low Dose Group | Plasma Zinc Concentration Over Time | Day 3 | 47.4 mcg/dL | Standard Deviation 17.8 |
| Low Dose Group | Plasma Zinc Concentration Over Time | Day 6 | 62.6 mcg/dL | Standard Deviation 15.7 |
| Medium Dose Group | Plasma Zinc Concentration Over Time | Day 7 | 67.6 mcg/dL | Standard Deviation 10.8 |
| Medium Dose Group | Plasma Zinc Concentration Over Time | Day 1 | 37.7 mcg/dL | Standard Deviation 25.2 |
| Medium Dose Group | Plasma Zinc Concentration Over Time | Day 2 | 46.3 mcg/dL | Standard Deviation 29.1 |
| Medium Dose Group | Plasma Zinc Concentration Over Time | Day 3 | 52.3 mcg/dL | Standard Deviation 10.9 |
| Medium Dose Group | Plasma Zinc Concentration Over Time | Day 4 | 63.3 mcg/dL | Standard Deviation 18.9 |
| Medium Dose Group | Plasma Zinc Concentration Over Time | Day 5 | 66.8 mcg/dL | Standard Deviation 20 |
| Medium Dose Group | Plasma Zinc Concentration Over Time | Day 6 | 66.0 mcg/dL | Standard Deviation 16.8 |
| High Dose Group | Plasma Zinc Concentration Over Time | Day 4 | 101.9 mcg/dL | Standard Deviation 33.4 |
| High Dose Group | Plasma Zinc Concentration Over Time | Day 3 | 68.2 mcg/dL | Standard Deviation 33.4 |
| High Dose Group | Plasma Zinc Concentration Over Time | Day 7 | 93.3 mcg/dL | Standard Deviation 8.7 |
| High Dose Group | Plasma Zinc Concentration Over Time | Day 6 | 114.0 mcg/dL | Standard Deviation 43.7 |
| High Dose Group | Plasma Zinc Concentration Over Time | Day 2 | 71.5 mcg/dL | Standard Deviation 34.6 |
| High Dose Group | Plasma Zinc Concentration Over Time | Day 1 | 43.4 mcg/dL | Standard Deviation 9.7 |
| High Dose Group | Plasma Zinc Concentration Over Time | Day 5 | 71.0 mcg/dL | Standard Deviation 16.9 |
Secondary
Glucose Homeostasis
Patients were assigned a score based on glucose range to take into account the degree of hyperglycemia as well as the need for insulin over the course of the 7 day study period. This score is an ordinal scale ranging from 1 to 5, with a score of 1 indicating no hyperglycemia, and 5 indicating severe hyperglycemia despite insulin administration.
Time frame: 7 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Control Group | Glucose Homeostasis | Day 1 | 4 units on a scale |
| Control Group | Glucose Homeostasis | Day 6 | 4 units on a scale |
| Control Group | Glucose Homeostasis | Day 5 | 3 units on a scale |
| Control Group | Glucose Homeostasis | Day 2 | 3.5 units on a scale |
| Control Group | Glucose Homeostasis | Day 7 | 4 units on a scale |
| Control Group | Glucose Homeostasis | Day 3 | 3.5 units on a scale |
| Control Group | Glucose Homeostasis | Day 4 | 3 units on a scale |
| Low Dose Group | Glucose Homeostasis | Day 6 | 3.5 units on a scale |
| Low Dose Group | Glucose Homeostasis | Day 4 | 4 units on a scale |
| Low Dose Group | Glucose Homeostasis | Day 3 | 3.5 units on a scale |
| Low Dose Group | Glucose Homeostasis | Day 5 | 4 units on a scale |
| Low Dose Group | Glucose Homeostasis | Day 7 | 2.5 units on a scale |
| Low Dose Group | Glucose Homeostasis | Day 2 | 3.5 units on a scale |
| Low Dose Group | Glucose Homeostasis | Day 1 | 3.5 units on a scale |
| Medium Dose Group | Glucose Homeostasis | Day 4 | 4 units on a scale |
| Medium Dose Group | Glucose Homeostasis | Day 1 | 4 units on a scale |
| Medium Dose Group | Glucose Homeostasis | Day 2 | 4 units on a scale |
| Medium Dose Group | Glucose Homeostasis | Day 3 | 4 units on a scale |
| Medium Dose Group | Glucose Homeostasis | Day 5 | 4 units on a scale |
| Medium Dose Group | Glucose Homeostasis | Day 6 | 4 units on a scale |
| Medium Dose Group | Glucose Homeostasis | Day 7 | 3 units on a scale |
| High Dose Group | Glucose Homeostasis | Day 3 | 2 units on a scale |
| High Dose Group | Glucose Homeostasis | Day 7 | 2 units on a scale |
| High Dose Group | Glucose Homeostasis | Day 6 | 3 units on a scale |
| High Dose Group | Glucose Homeostasis | Day 2 | 2.5 units on a scale |
| High Dose Group | Glucose Homeostasis | Day 1 | 2.5 units on a scale |
| High Dose Group | Glucose Homeostasis | Day 5 | 2 units on a scale |
| High Dose Group | Glucose Homeostasis | Day 4 | 2 units on a scale |