Hypotension
Conditions
Keywords
children, sodium nitroprusside, controlled hypotension, dose-response, pharmacokinetics, pharmacodynamics, safety, efficacy
Brief summary
Sodium nitroprusside (SNP) has been approved for control of blood pressure in adults, yet there are no controlled studies in children. The purpose of this study is to determine the efficacy and safety of sodium nitroprusside in children who will be having surgery, and who require blood pressure lowering in order to decrease the amount of blood loss during their surgery.
Detailed description
The trial is a multicenter randomized, double-blind, parallel group, dose-ranging, effect-controlled study examining the effects of sodium nitroprusside in pediatric subjects requiring relative hypotension during a surgical or medical procedure. The goal is to establish the starting and maximum infusion rates that afford optimum blood pressure control in children and a safe dosing regimen in children. The objective is to describe the relationship between the infusion rate of nitroprusside and changes in blood pressure. The specific aims of this trial are: 1. To define the onset and offset of blood pressure lowering effects of nitroprusside to obtain adequate instructions for dose titration in the pediatric population. 2. To construct a dose-response model that defines the relationship between nitroprusside infusion rate and changes in blood pressure in pediatric subjects. 3. To assess the safety of nitroprusside administration in pediatric subjects requiring controlled reduction of blood pressure.
Interventions
DRUGNitroprusside
Study drug was infused via a dedicated peripheral intravenous catheter or via a dedicated lumen of a multi-orifice central venous catheter. Infusion pumps capable of reliable delivery at low infusion rates (to 0.1 mL/hr) were used.Study drug was dispensed to the sites in 2 mL vials containing 25 mg/mL of sodium nitroprusside. The pharmacist prepared and dispensed the study drug, and supplied blinded study drug for each subject according to a randomization assignment generated by the IVRS (Interactive Voice Response System).
Sponsors
Stanford University
Duke University
The Emmes Company, LLC
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 17 Years
Healthy volunteers
No
Inclusion criteria
Study subjects must meet all of the following criteria: * Subject is less than 17 years of age * Neonates must be full-term gestation and have a body weight of at least 2.5 kg * Subject requires pharmacologically-induced hypotension for acute blood pressure management for surgery or other invasive procedure, e.g., cerebral artery embolization * Duration of the subject's controlled hypotension is expected to be ≥ 2 hours * Subject requires general anesthesia with endotracheal intubation * Subject requires placement of intra-arterial line during the surgical or medical procedure * The subject's parent or legal guardian gives permission (informed consent) and subject gives assent when appropriate.
Exclusion criteria
Subjects will be excluded if any of the following criteria exist: * Subject has a known allergy to SNP * Subject has a known mitochondrial cytopathy with a disorder of oxidative phosphorylation or of respiratory chain enzymes * Subject has a contraindication to vasodilator therapy for control of blood pressure during surgery or procedures * Subject has participated in other clinical trials for investigational drugs and/or devices within 30 days prior to enrollment * Subject has any serious medical condition which, in the opinion of the investigator, is likely to interfere with study procedures * Subject is moribund (death likely to occur within 48 hours) * Subject has a positive result for the urine or serum human chorionic gonadotropin (HCG) test administered at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Approximately 30 minutes | From the Baseline MAP until the end of the blinded phase; scheduled for 30 min |
| Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | 30 days | Treatment-emergent AEs (TEAEs) were defined as an AE experienced by the patient that was either first observed after the initiation of study drug (blinded or open-label) or represented an exacerbation (usually in severity) of a pre existing condition observed prior to treatment. Subjects will be followed for 30 days after discontinuation of study drug. The occurrence of Serious Adverse Events (SAEs) will be monitored for 30 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 25 minutes | Change From Baseline in MAP (mmHg) After 20 and 25 Minutes Double-Blind Infusion (Overall) for ITT Efficacy Evaluable Population. |
| Infusion Rate of Sodium Nitroprusside That Reduces MAP to a Predetermined Clinically Meaningful Target Value +/- 10%; | Up to the end of open label treatment (Approximately 120 minutes) | Infusion rate of sodium nitroprusside at which a predetermined clinically meaningful target value (+/- 10%) of MAP was achieved during study drug administration |
| Number of Participants Who Reach Target MAP; | To the end of open label treatment (approximately 120 minutes) | Blinded Study Drug Administration Period: Started with study drug administration following stabilization of anesthesia. Patients were administered a blinded dose of SNP for up to 30 mins. This period ended at the start of open-label study drug infusion or at the completion of the blinded infusion if no open-label study drug was given. The follow-up period immediately followed for those patients not receiving open-label infusion. Blinded Treatment Phase II - gap between the end of blinded study drug infusion and the start of open-label study drug infusion Open-label treatment phase began with the start of open-label study drug infusion and was at least 90 mins in duration. SNP was initiated at a dose deemed appropriate by the investigator and was gradually adjusted to reach a target MAP based on clinical presentation and needs of the patient. Target MAP was not to be \< 50 mmHg (40 mmHg for patients \< 30 days of age). This period ended at the completion of open-label infusion. |
Countries
United States
Participant flow
Recruitment details
206 participants were randomized to be dosed with one of 4 differed SNP infusion rates.
Pre-assignment details
Of the 206 randomized participants, 3 discontinued pre-operatively and 203 participants completed the study and no patients discontinued the study post operative. Participants counted as completing the study may have stopped the blinded study drug period early but continued on to the open-label study drug period and follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| 0.3 mcg/kg/Min Infusion rate scheduled to be titrated during the blinded phase to 0.3 mcg/kg/min | 50 |
| 1 mcg/kg/Min Infusion rate scheduled to be titrated during the blinded phase to 1 mcg/kg/min | 49 |
| 2 mcg/kg/Min Infusion rate scheduled to be titrated during the blinded phase to 2 mcg/kg/min | 53 |
| 3 mcg/kg/Min Infusion rate scheduled to be titrated during the blinded phase to 3 mcg/kg/min | 51 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study - Randomized to be Dosed | Discontinued pre-operatively | 1 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | 0.3 mcg/kg/Min | 1 mcg/kg/Min | 2 mcg/kg/Min | 3 mcg/kg/Min | Total |
|---|---|---|---|---|---|
| Age, Customized | 110.30 Months STANDARD_DEVIATION 75.424 | 114.74 Months STANDARD_DEVIATION 71.479 | 114.21 Months STANDARD_DEVIATION 73.864 | 111.30 Months STANDARD_DEVIATION 76.429 | 112.64 Months STANDARD_DEVIATION 73.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 11 Participants | 12 Participants | 13 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 38 Participants | 41 Participants | 38 Participants | 156 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 14 Participants | 21 Participants | 20 Participants | 19 Participants | 74 Participants |
| Sex: Female, Male Male | 36 Participants | 28 Participants | 33 Participants | 32 Participants | 129 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 | 50 / 50 | 49 / 49 | 53 / 53 | 51 / 51 |
| serious Total, serious adverse events | 24 / 50 | 22 / 49 | 18 / 53 | 20 / 51 |
Outcome results
Primary
Change in Mean Arterial Pressure (MAP) From the Baseline MAP
From the Baseline MAP until the end of the blinded phase; scheduled for 30 min
Time frame: Approximately 30 minutes
Population: Change from Baseline in MAP across the Sodium Nitroprusside (SNP) dose groups by mean at Baseline, 30 mins (LOCF), and change from Baseline for the ITT Efficacy Evaluable Population consisted of randomized and treated patients who had a pre-treatment Baseline MAP and a second MAP determined within 30 mins of study drug infusion at the starting dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.3 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | 30 Minutes LOCF(last observation carried forward) | 65.3 mm Hg | Standard Deviation 13.3 |
| 0.3 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Baseline Observed | 76.3 mm Hg | Standard Deviation 11.37 |
| 0.3 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Change from Baseline | -11.0 mm Hg | Standard Deviation 15.68 |
| 1 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Baseline Observed | 76.9 mm Hg | Standard Deviation 14.5 |
| 1 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Change from Baseline | -17.0 mm Hg | Standard Deviation 12.88 |
| 1 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | 30 Minutes LOCF(last observation carried forward) | 59.9 mm Hg | Standard Deviation 15.43 |
| 2 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Baseline Observed | 73.5 mm Hg | Standard Deviation 11.5 |
| 2 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | 30 Minutes LOCF(last observation carried forward) | 53.5 mm Hg | Standard Deviation 12.09 |
| 2 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Change from Baseline | -20.0 mm Hg | Standard Deviation 15.95 |
| 3 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Change from Baseline | -16.6 mm Hg | Standard Deviation 18.63 |
| 3 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Baseline Observed | 76.3 mm Hg | Standard Deviation 12.06 |
| 3 mcg/kg/Min | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | 30 Minutes LOCF(last observation carried forward) | 59.6 mm Hg | Standard Deviation 17.82 |
| Total | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | 30 Minutes LOCF(last observation carried forward) | 59.5 mm Hg | Standard Deviation 15.28 |
| Total | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Baseline Observed | 75.7 mm Hg | Standard Deviation 12.37 |
| Total | Change in Mean Arterial Pressure (MAP) From the Baseline MAP | Change from Baseline | -16.2 mm Hg | Standard Deviation 16.16 |
Comparison: Paired t-test used to test the null hypothesis of no change in MAP from baseline.p-value: <0.00195% CI: [-18.44, -13.97]t-test, 2 sided
p-value: <0.00195% CI: [-15.45, -6.55]t-test, 2 sided
p-value: <0.00195% CI: [-20.7, -13.3]t-test, 2 sided
p-value: <0.00195% CI: [-24.38, -15.58]t-test, 2 sided
p-value: <0.00195% CI: [-21.87, -11.39]t-test, 2 sided
Primary
Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population
Treatment-emergent AEs (TEAEs) were defined as an AE experienced by the patient that was either first observed after the initiation of study drug (blinded or open-label) or represented an exacerbation (usually in severity) of a pre existing condition observed prior to treatment. Subjects will be followed for 30 days after discontinuation of study drug. The occurrence of Serious Adverse Events (SAEs) will be monitored for 30 days.
Time frame: 30 days
Population: ITT Safety Population consisted of all consented and randomized patients who received any amount of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with SEVERE TEAE | 23 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with probably related TEAE | 29 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TEAE | 50 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with Probably NOT related TEAE | 1 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MILD TEAE | 8 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with NOT related TEAE | 8 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of Deaths | 0 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N with TEAE leading to study drug withdrawal | 19 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with possibly related TEAE | 12 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MODERATE TEAE | 19 participants |
| 0.3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TESAE | 5 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MODERATE TEAE | 19 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with probably related TEAE | 32 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with SEVERE TEAE | 20 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TESAE | 4 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TEAE | 49 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with NOT related TEAE | 6 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N with TEAE leading to study drug withdrawal | 18 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of Deaths | 0 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with Probably NOT related TEAE | 5 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MILD TEAE | 10 participants |
| 1 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with possibly related TEAE | 6 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with SEVERE TEAE | 26 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TEAE | 53 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TESAE | 5 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N with TEAE leading to study drug withdrawal | 13 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MILD TEAE | 7 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MODERATE TEAE | 20 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with probably related TEAE | 40 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with possibly related TEAE | 2 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with Probably NOT related TEAE | 0 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with NOT related TEAE | 11 participants |
| 2 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of Deaths | 0 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MILD TEAE | 8 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TEAE | 51 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TESAE | 4 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of Deaths | 0 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with NOT related TEAE | 3 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N with TEAE leading to study drug withdrawal | 16 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with SEVERE TEAE | 28 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with possibly related TEAE | 9 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with Probably NOT related TEAE | 3 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MODERATE TEAE | 15 participants |
| 3 mcg/kg/Min | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with probably related TEAE | 36 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TEAE | 203 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with probably related TEAE | 137 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MILD TEAE | 33 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with possibly related TEAE | 29 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N with TEAE leading to study drug withdrawal | 66 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of Deaths | 0 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with Probably NOT related TEAE | 9 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with at least one TESAE | 18 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with NOT related TEAE | 28 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with SEVERE TEAE | 97 participants |
| Total | Overall Summary of Tolerability/Adverse Events (AEs) for ITT Safety Population | N of participants with MODERATE TEAE | 73 participants |
Secondary
Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion;
Change From Baseline in MAP (mmHg) After 20 and 25 Minutes Double-Blind Infusion (Overall) for ITT Efficacy Evaluable Population.
Time frame: 25 minutes
Population: ITT Efficacy Evaluable Population consisted of randomized and treated patients who had a pre-treatment Baseline MAP and a second MAP determined within 25 minutes of study drug infusion at the starting dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 25 mins observed (n = 39,24,15,20,98) | 69.5 mm Hg | Standard Deviation 12.15 |
| 0.3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Baseline (BL) Observed (n = 50,49,53,51,203) | 76.3 mm Hg | Standard Deviation 11.37 |
| 0.3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 25 mins (n = 39,24,15,20,98) | -6.9 mm Hg | Standard Deviation 11.8 |
| 0.3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 20 Mins Observed (n = 42,27,19,26,114) | 69.6 mm Hg | Standard Deviation 11.29 |
| 0.3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 20 mins (n = 42,27,19,26,114) | -7.5 mm Hg | Standard Deviation 14.38 |
| 1 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 25 mins observed (n = 39,24,15,20,98) | 64.4 mm Hg | Standard Deviation 10.3 |
| 1 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 20 mins (n = 42,27,19,26,114) | -10.0 mm Hg | Standard Deviation 16.37 |
| 1 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 20 Mins Observed (n = 42,27,19,26,114) | 73.2 mm Hg | Standard Deviation 15.97 |
| 1 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 25 mins (n = 39,24,15,20,98) | -18.2 mm Hg | Standard Deviation 14.69 |
| 1 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Baseline (BL) Observed (n = 50,49,53,51,203) | 76.9 mm Hg | Standard Deviation 14.5 |
| 2 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 20 mins (n = 42,27,19,26,114) | -11.1 mm Hg | Standard Deviation 16.42 |
| 2 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Baseline (BL) Observed (n = 50,49,53,51,203) | 73.5 mm Hg | Standard Deviation 11.5 |
| 2 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 20 Mins Observed (n = 42,27,19,26,114) | 62.3 mm Hg | Standard Deviation 13.58 |
| 2 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 25 mins observed (n = 39,24,15,20,98) | 60.5 mm Hg | Standard Deviation 10.53 |
| 2 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 25 mins (n = 39,24,15,20,98) | -10.2 mm Hg | Standard Deviation 13.82 |
| 3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 25 mins (n = 39,24,15,20,98) | -11.7 mm Hg | Standard Deviation 16.16 |
| 3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Baseline (BL) Observed (n = 50,49,53,51,203) | 76.3 mm Hg | Standard Deviation 12.06 |
| 3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 25 mins observed (n = 39,24,15,20,98) | 66.4 mm Hg | Standard Deviation 13.07 |
| 3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 20 mins (n = 42,27,19,26,114) | -12.5 mm Hg | Standard Deviation 14.09 |
| 3 mcg/kg/Min | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 20 Mins Observed (n = 42,27,19,26,114) | 65.8 mm Hg | Standard Deviation 12.73 |
| Total | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 20 mins (n = 42,27,19,26,114) | -9.8 mm Hg | Standard Deviation 15.08 |
| Total | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 25 mins observed (n = 39,24,15,20,98) | 66.2 mm Hg | Standard Deviation 11.94 |
| Total | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Baseline (BL) Observed (n = 50,49,53,51,203) | 75.7 mm Hg | Standard Deviation 12.37 |
| Total | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | Change from BL - 25 mins (n = 39,24,15,20,98) | -11.1 mm Hg | Standard Deviation 14.21 |
| Total | Change From Baseline MAP Nitroprusside Infusion During the Blinded Infusion; | 20 Mins Observed (n = 42,27,19,26,114) | 68.4 mm Hg | Standard Deviation 13.57 |
Secondary
Infusion Rate of Sodium Nitroprusside That Reduces MAP to a Predetermined Clinically Meaningful Target Value +/- 10%;
Infusion rate of sodium nitroprusside at which a predetermined clinically meaningful target value (+/- 10%) of MAP was achieved during study drug administration
Time frame: Up to the end of open label treatment (Approximately 120 minutes)
Population: The Analysis population included the participants in the ITT Efficacy evaluable population who achieved target MAP. ITT Efficacy Evaluable Population consisted of randomized and treated patients who had a pre-treatment Baseline MAP and a second MAP determined within 30 minutes of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 mcg/kg/Min | Infusion Rate of Sodium Nitroprusside That Reduces MAP to a Predetermined Clinically Meaningful Target Value +/- 10%; | 0.47 mcg/kg/min | Standard Deviation 0.519 |
| 1 mcg/kg/Min | Infusion Rate of Sodium Nitroprusside That Reduces MAP to a Predetermined Clinically Meaningful Target Value +/- 10%; | 0.70 mcg/kg/min | Standard Deviation 0.346 |
| 2 mcg/kg/Min | Infusion Rate of Sodium Nitroprusside That Reduces MAP to a Predetermined Clinically Meaningful Target Value +/- 10%; | 1.21 mcg/kg/min | Standard Deviation 0.678 |
| 3 mcg/kg/Min | Infusion Rate of Sodium Nitroprusside That Reduces MAP to a Predetermined Clinically Meaningful Target Value +/- 10%; | 1.86 mcg/kg/min | Standard Deviation 0.922 |
| Total | Infusion Rate of Sodium Nitroprusside That Reduces MAP to a Predetermined Clinically Meaningful Target Value +/- 10%; | 1.07 mcg/kg/min | Standard Deviation 0.843 |
Secondary
Number of Participants Who Reach Target MAP;
Blinded Study Drug Administration Period: Started with study drug administration following stabilization of anesthesia. Patients were administered a blinded dose of SNP for up to 30 mins. This period ended at the start of open-label study drug infusion or at the completion of the blinded infusion if no open-label study drug was given. The follow-up period immediately followed for those patients not receiving open-label infusion. Blinded Treatment Phase II - gap between the end of blinded study drug infusion and the start of open-label study drug infusion Open-label treatment phase began with the start of open-label study drug infusion and was at least 90 mins in duration. SNP was initiated at a dose deemed appropriate by the investigator and was gradually adjusted to reach a target MAP based on clinical presentation and needs of the patient. Target MAP was not to be \< 50 mmHg (40 mmHg for patients \< 30 days of age). This period ended at the completion of open-label infusion.
Time frame: To the end of open label treatment (approximately 120 minutes)
Population: ITT Efficacy Evaluable Population consisted of randomized and treated patients who had a pre-treatment Baseline MAP and a second MAP determined within 30 minutes of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 0.3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Not determined | 0 participants |
| 0.3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved target MAP | 48 participants |
| 0.3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Did NOT achieve target MAP | 2 participants |
| 0.3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during Blinded Phase II | 0 participants |
| 0.3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during the blinded treatment | 35 participants |
| 0.3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during Open-label Treatment | 13 participants |
| 1 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during the blinded treatment | 36 participants |
| 1 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during Open-label Treatment | 9 participants |
| 1 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved target MAP | 49 participants |
| 1 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Did NOT achieve target MAP | 0 participants |
| 1 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Not determined | 0 participants |
| 1 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during Blinded Phase II | 4 participants |
| 2 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved target MAP | 52 participants |
| 2 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during Blinded Phase II | 8 participants |
| 2 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during Open-label Treatment | 6 participants |
| 2 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Not determined | 1 participants |
| 2 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Did NOT achieve target MAP | 0 participants |
| 2 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during the blinded treatment | 38 participants |
| 3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Did NOT achieve target MAP | 0 participants |
| 3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Not determined | 0 participants |
| 3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during Open-label Treatment | 5 participants |
| 3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during the blinded treatment | 39 participants |
| 3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved during Blinded Phase II | 7 participants |
| 3 mcg/kg/Min | Number of Participants Who Reach Target MAP; | Achieved target MAP | 51 participants |
| Total | Number of Participants Who Reach Target MAP; | Achieved during Open-label Treatment | 33 participants |
| Total | Number of Participants Who Reach Target MAP; | Achieved target MAP | 200 participants |
| Total | Number of Participants Who Reach Target MAP; | Did NOT achieve target MAP | 2 participants |
| Total | Number of Participants Who Reach Target MAP; | Achieved during the blinded treatment | 148 participants |
| Total | Number of Participants Who Reach Target MAP; | Achieved during Blinded Phase II | 19 participants |
| Total | Number of Participants Who Reach Target MAP; | Not determined | 1 participants |