Hypotension
Conditions
Keywords
Hypotension, Low blood pressure, Neonate, Dopamine, Vasopressin, Extremely Low Birth Weight Infant
Brief summary
Low blood pressure or hypotension is a very important problem that is often seen in premature babies, especially those with low birth weight. Severe hypotension leads to significant problems including brain bleeds, developmental delays, kidney and liver problems, and other issues that can affect babies for the rest of their lives. An important aspect in the management of infants with hypotension is the decision of when to treat and with what agent. Research is being conducted to try to find the best medication to use in these situations. Dopamine is often used first, but it does not always prove to be effective, and it has several concerning side effects. This study will look at vasopressin, which has fewer side effects, as a first-line medication for low blood pressure in extremely low birth weight infants. Hypotheses and Specific Aims: This study will show superiority of vasopressin to dopamine in preterm, extremely low birth weight infants who have hypotension within the first 24 hours of life. We will specifically look at its ability to raise blood pressure values, improve clinical symptoms seen, any adverse effects, and clinical outcomes of babies being treated.
Detailed description
Hypotension in the low birth weight (LBW) and extremely low birth weight (ELBW) infant is often encountered in the postnatal adaptation phase. Severe, prolonged hypotension contributes to cellular dysfunction and cell death. Systemic hypotension affects close to half of all ELBW infants and a significant portion of LBW infants. The true definition of hypotension remains to be a question. There is a linear association between birth weight, gestational age, and mean blood pressure but blood pressure can vary significantly in the first day of life. The critical period tends to be the first 24-36 hours of life as blood pressure tends to rise significantly in the first 72 hours of life regardless of gestational age. Preterm infants suffering from hypotension have a higher incidence and increased severity of intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and long-term neurodevelopmental sequelae compared to normotensive preterm infants. Effects on other organ systems can result in renal injury, hepatic injury, and the development of necrotizing enterocolitis among other complications. An important aspect in the management of infants with hypotension is the decision of when to treat and with what agent. Dopamine is commonly used as first-line therapy, but issues with efficacy and its side effect profile have lessened its favorability over the years. Few studies compare dopamine to other agents as a first -line treatment. This study hopes to contribute to the literature information on vasopressin as a potential first-line agent for treatment of neonatal hypotension in low birth weight infants.
Interventions
DRUGDopamine
dopamine at low/medium/and high dose (5, 10, 15, and 20 mcg/kg/min) given IV as a continuous infusion, titrated up for efficacy
vasopressin at low/medium/and high dose (0.01, 0.02, 0.03, or 0.04 units/kg/hr) given IV as a continuous infusion, titrated up for efficacy
Sponsors
Thrasher Research Fund
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 24 Hours
Healthy volunteers
No
Inclusion criteria
* Infants less than 24 hours of age * Infants with birth weight of \<1001 grams and/or gestational age of \<29 weeks * Not initiated on any continuous pressor therapy prior to enrollment * Intravenous line in place * Outborn infants meeting eligibility criteria
Exclusion criteria
* Infants not meeting eligibility criteria * Infants with life-threatening congenital defects * Infants with congenital hydrops * Infants with frank hypovolemia (perinatal history consistent with decreased circulating blood volume plus clinical signs of hypovolemia) * Infants with other unresolved causes of hypotension (air leaks, lung overdistention, or metabolic abnormalities).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects in Each Group Who Have Achieved an Optimal Mean Blood Pressure Value at 24 Hours of Life | 24 hours of life | Optimal mean blood pressure (OMBP) will be defined as either a 10% increase in mean blood pressure value or a 2-3 mmHg rise in mean blood pressure value AND an improvement in tissue perfusion as demonstrated by a resolution in the specified clinical symptom (designated upon enrollment) within 4-6 hours of having reached OMBP |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acid-base Status | 96 hours or until hypotension resolved and medication completely stopped | — |
| Hyponatremia | 96 hours or until medication completely stopped | — |
| Urine Output | 96 hours or until hypotension resolved and medication completely stopped | — |
| Evidence of Ischemic Changes | 96 hours or until medication completely stopped | Physical examinations were done on at least a twice daily basis to evaluate for any ischemic lesions (especially on the limbs) of all subjects. The presence of any lesion considered to be due to ischemia would have been reported in this data. |
| Necrotizing Enterocolitis | until hospital discharge, up to 12 weeks | — |
| Heart Rate Change From Baseline | 96 hours or until hypotension completely resolved and medications stopped | Heart rate change from baseline during study drug administration |
| Presence of Patent Ductus Arteriosus (PDA) | until hospital discharge, up to 12 weeks | — |
| Grade 3 Intraventricular Hemorrhage or Worse on Head Ultrasound | Until hospital discharge, up to 15 months | — |
| Retinopathy of Prematurity Stage 3 or Higher | Until hospital discharge, up to 15 months | All subjects were followed by an ophthalmologist with initial exam at 4-6 weeks of age. The Stages describe the ophthalmoscopic findings at the junction between the vascularized and avascular retina. Each subject is followed until cleared by ophthalmology. For this outcome measure, the most severe stage of disease was used in analysis. Stage 1 is a faint demarcation line. Stage 2 is an elevated ridge. Stage 3 is extraretinal fibrovascular proliferation (neovascularization). Stage 4 is sub-total retinal detachment. Stage 5 is total retinal detachment. Stages 1 and 2 do not lead to blindness. However, they can progress to the more severe stages. |
| Presence of Bronchopulmonary Dysplasia (BPD) | 36 weeks postmenstrual age | Infants were evaluated for oxygen need at 36 weeks postmenstrual age. If they required supplemental oxygen, they were diagnosed with BPD |
| All Cause Mortality | admission to hospital discharge, up to 15 months | — |
| Ventilator Days | Until hospital discharge, up to 15 months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dopamine Treatment Dopamine treatment beginning at 5 mcg/kg/min and titrated by 5 mcg/kg/min to effect up to maximum of 20 mcg/kg/min
Dopamine: dopamine at low/medium/and high dose (5, 10, 15, and 20 mcg/kg/min) given IV as a continuous infusion, titrated up for efficacy | 10 |
| Vasopressin Treatment Arginine Vasopressin treatment beginning at 0.01 units/kg/hr and titrated up by 0.01 units/kg/hr to effect up to a maximum of 0.04 units/kg/hr
Arginine Vasopressin: vasopressin at low/medium/and high dose (0.01, 0.02, 0.03, or 0.04 units/kg/hr) given IV as a continuous infusion, titrated up for efficacy | 10 |
| Comparison Arm Infants who did not require vasopressor support for hypotension during the first 24 hours of life | 50 |
| Total | 70 |
Baseline characteristics
| Characteristic | Dopamine Treatment | Vasopressin Treatment | Comparison Arm | Total |
|---|---|---|---|---|
| Age, Continuous | 25.1 weeks STANDARD_DEVIATION 1 | 25.7 weeks STANDARD_DEVIATION 2 | 25.6 weeks STANDARD_DEVIATION 1 | 25.6 weeks STANDARD_DEVIATION 1.4 |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 28 Participants | 37 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 22 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 10 | 4 / 10 | 10 / 50 |
| other Total, other adverse events | 3 / 10 | 4 / 10 | 11 / 50 |
| serious Total, serious adverse events | 8 / 10 | 7 / 10 | 22 / 50 |
Outcome results
Primary
Number of Subjects in Each Group Who Have Achieved an Optimal Mean Blood Pressure Value at 24 Hours of Life
Optimal mean blood pressure (OMBP) will be defined as either a 10% increase in mean blood pressure value or a 2-3 mmHg rise in mean blood pressure value AND an improvement in tissue perfusion as demonstrated by a resolution in the specified clinical symptom (designated upon enrollment) within 4-6 hours of having reached OMBP
Time frame: 24 hours of life
Population: This outcome is only reportable in the two treatment groups as it evaluates the response to treatment of hypotension in those who received study drug. The comparison group infants were not hypotensive within the 24 hours and did not receive study drug, therefore, they are omitted from this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dopamine Treatment | Number of Subjects in Each Group Who Have Achieved an Optimal Mean Blood Pressure Value at 24 Hours of Life | 9 participants |
| Vasopressin Treatment | Number of Subjects in Each Group Who Have Achieved an Optimal Mean Blood Pressure Value at 24 Hours of Life | 9 participants |
Secondary
Acid-base Status
Time frame: 96 hours or until hypotension resolved and medication completely stopped
Population: Treatment groups during study drug administration. Comparison group during first 96 hours of life. For all- only arterial gases
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dopamine Treatment | Acid-base Status | 7.18 pH | Standard Deviation 0.07 |
| Vasopressin Treatment | Acid-base Status | 7.2 pH | Standard Deviation 0.07 |
| Comparison Group | Acid-base Status | 7.25 pH | Standard Deviation 0.09 |
Secondary
All Cause Mortality
Time frame: admission to hospital discharge, up to 15 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dopamine Treatment | All Cause Mortality | 2 participants |
| Vasopressin Treatment | All Cause Mortality | 4 participants |
| Comparison Group | All Cause Mortality | 10 participants |
Secondary
Evidence of Ischemic Changes
Physical examinations were done on at least a twice daily basis to evaluate for any ischemic lesions (especially on the limbs) of all subjects. The presence of any lesion considered to be due to ischemia would have been reported in this data.
Time frame: 96 hours or until medication completely stopped
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dopamine Treatment | Evidence of Ischemic Changes | 0 participants |
| Vasopressin Treatment | Evidence of Ischemic Changes | 0 participants |
| Comparison Group | Evidence of Ischemic Changes | 0 participants |
Secondary
Grade 3 Intraventricular Hemorrhage or Worse on Head Ultrasound
Time frame: Until hospital discharge, up to 15 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dopamine Treatment | Grade 3 Intraventricular Hemorrhage or Worse on Head Ultrasound | 3 participants |
| Vasopressin Treatment | Grade 3 Intraventricular Hemorrhage or Worse on Head Ultrasound | 3 participants |
| Comparison Group | Grade 3 Intraventricular Hemorrhage or Worse on Head Ultrasound | 6 participants |
Secondary
Heart Rate Change From Baseline
Heart rate change from baseline during study drug administration
Time frame: 96 hours or until hypotension completely resolved and medications stopped
Population: This outcome is only reportable in the two treatment groups as it evaluates the change in heart rate in those who received study drug. The comparison group infants were not hypotensive within the 24 hours and did not receive study drug, therefore, they are omitted from this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dopamine Treatment | Heart Rate Change From Baseline | 31 beats per minute | Standard Deviation 19 |
| Vasopressin Treatment | Heart Rate Change From Baseline | 0 beats per minute | Standard Deviation 10 |
Secondary
Hyponatremia
Time frame: 96 hours or until medication completely stopped
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dopamine Treatment | Hyponatremia | 3 participants |
| Vasopressin Treatment | Hyponatremia | 3 participants |
| Comparison Group | Hyponatremia | 11 participants |
Secondary
Necrotizing Enterocolitis
Time frame: until hospital discharge, up to 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dopamine Treatment | Necrotizing Enterocolitis | 0 participants |
| Vasopressin Treatment | Necrotizing Enterocolitis | 1 participants |
| Comparison Group | Necrotizing Enterocolitis | 2 participants |
Secondary
Presence of Bronchopulmonary Dysplasia (BPD)
Infants were evaluated for oxygen need at 36 weeks postmenstrual age. If they required supplemental oxygen, they were diagnosed with BPD
Time frame: 36 weeks postmenstrual age
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dopamine Treatment | Presence of Bronchopulmonary Dysplasia (BPD) | 8 participants |
| Vasopressin Treatment | Presence of Bronchopulmonary Dysplasia (BPD) | 4 participants |
| Comparison Group | Presence of Bronchopulmonary Dysplasia (BPD) | 31 participants |
Secondary
Presence of Patent Ductus Arteriosus (PDA)
Time frame: until hospital discharge, up to 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dopamine Treatment | Presence of Patent Ductus Arteriosus (PDA) | 5 participants |
| Vasopressin Treatment | Presence of Patent Ductus Arteriosus (PDA) | 6 participants |
| Comparison Group | Presence of Patent Ductus Arteriosus (PDA) | 34 participants |
Secondary
Retinopathy of Prematurity Stage 3 or Higher
All subjects were followed by an ophthalmologist with initial exam at 4-6 weeks of age. The Stages describe the ophthalmoscopic findings at the junction between the vascularized and avascular retina. Each subject is followed until cleared by ophthalmology. For this outcome measure, the most severe stage of disease was used in analysis. Stage 1 is a faint demarcation line. Stage 2 is an elevated ridge. Stage 3 is extraretinal fibrovascular proliferation (neovascularization). Stage 4 is sub-total retinal detachment. Stage 5 is total retinal detachment. Stages 1 and 2 do not lead to blindness. However, they can progress to the more severe stages.
Time frame: Until hospital discharge, up to 15 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dopamine Treatment | Retinopathy of Prematurity Stage 3 or Higher | 3 participants |
| Vasopressin Treatment | Retinopathy of Prematurity Stage 3 or Higher | 2 participants |
| Comparison Group | Retinopathy of Prematurity Stage 3 or Higher | 4 participants |
Secondary
Urine Output
Time frame: 96 hours or until hypotension resolved and medication completely stopped
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dopamine Treatment | Urine Output | 4.4 ml/kg/hr | Standard Deviation 1.4 |
| Vasopressin Treatment | Urine Output | 3.5 ml/kg/hr | Standard Deviation 1.4 |
| Comparison Group | Urine Output | 3.9 ml/kg/hr | Standard Deviation 1.4 |
Secondary
Ventilator Days
Time frame: Until hospital discharge, up to 15 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dopamine Treatment | Ventilator Days | 52 days |
| Vasopressin Treatment | Ventilator Days | 45.5 days |
| Comparison Group | Ventilator Days | 17.5 days |