Simma et al.

(1998)

Switzerland

RCT

PEDro=6

N=32

Population: TBI; Lactated Ringer’s Solution Group (LRS, n=17): Mean Age=7.3yr; Gender: Male=9, Female=8; Time Post Injury=<3 d; Mean GCS=5.8. Hypertonic Saline Group (HTS, n=15): Mean Age=7.3yr; Gender: Male=7, Female=8; Time Post Injury=<3d; Mean GCS=5.5.

Intervention: Patients were randomly assigned to receive either LRS or HTS in addition to standard care over a period of 72 hr. Data was collected every 4 hr.

Outcome Measure: Intracranial Pressure (ICP) , Cerebral Perfusion Pressure (CPP) , Serum Sodium Concentration, Length of Stay (LOS), Respiratory Distress Syndrome Rates, Complication Rates.

1.        There was an inverse relationship between ICP and serum sodium concentration for both the LRS group (p<0.030) and the HS group (p<0.001) in the first 8hr of treatment. However, beyond this time point, only the hypertonic saline group maintained this significant relationship.

2.        Correlations between CPP levels and serum sodium concentration only became significant for the HS patients after 8hr of treatment (p=0.002).

3.        The LRS patients experienced a significantly longer LOS (p=0.040). LRS patients also experienced a greater frequency of respiratory distress syndrome, and more than two complications compared with the HS group; however, these did not reach statistical significance (p=0.100, p=0.090 respectively).

(1992)

USA

RCT

PEDro=6

N=18

Population: TBI; Mean Age=8.3 yr; Mean Time Post Injury=22.0 hr; Mean GSC=5.8.

Intervention: Each patient received one saline bolus of 3% and 0.9% saline in a blinded, randomized crossover fashion. Doses ranged between 6.5-10 mL/kg in each patient. Intracranial pressure (ICP) was monitored for 2 hr post-administration.

Outcome Measure: ICP, Central Venous Pressure (CVP), Renal Function.

1.        Administration of 0.9% saline did not result in a change in ICP (p=0.320).

2.        When participants received 3% saline, there was a significant within group difference in ICP from baseline to average ICP during the 2hr (p=0.003); serum sodium levels increased.

3.        Significant difference in ICP between normal saline (0.9%) and 3% saline were noted post-intervention (p=0.002).

4.        No significant change in CVP or renal function were seen within either group.

(2017a)

Greece

Case Series

N=29

Population: TBI; Mean Age=8.9 yr; Gender: Male=15, Female=14; Median GCS=6.

Intervention: Patients with severe TBI who received hyperosmolar therapy (7.5% hypertonic saline) as a result of failure to lower ICP< 20 mmHg with standard therapy, were retrospectively reviewed.

Outcome Measure: Intracranial Pressure (ICP), Cerebral Perfusion Pressure (CPP), Serum Sodium, Glasgow Outcome Scale Extended (GOSE), Adverse Effects.

1.       Before receiving hypertonic saline, all patients first received therapy with mannitol.

2.       Hypertonic saline dose started at 5 ml/kg/h and was adjusted accordingly thereafter (mean dose=3 ml/kg/h). Infusion was terminated when ICP fell below 20 mmHg.

3.       Hypertonic saline was associated with significant reduction in ICP and CPP elevation at 30, 60 and 120 min post-infusion (all p<0.001).

4.       Serum sodium was significantly elevated 120 min post-infusion (Median=142 mmol/L to 149 mmol/L; p<0.001).

5.       One third of patients had severe neurological impairment (GOSE=3-4) at 6 mo post injury.

6.       Five patients did not survive, 3 patients developed severe hypernatremia, 2 had acute respiratory distress syndrome and 1 patient developed an acute kidney injury.

(2016)

USA

Case Control

N=236

Population: Severe TBI; Early Hypotension-No Treatment (n=5): Mean Age=5.8yr; Gender: Male=3, Female=2. Early Hypotension-Treatment (n=55): Mean Age=10.6yr; Gender: Male=34, Female=21. No Early Hypotension (n=174): Mean Age=7.4yr; Gender: Male=125, Female=49.

Intervention: Patient medical records were examined to compare outcomes of patients treated for early hypotension and those who received no hypotension treatment.

Outcome Measure: In-hospital Mortality, Glasgow Outcome Scale (GOS).

1.        Hypotension was associated with increased in-hospital mortality (23.3% versus 8.6%; p=0.010). Additionally, timely treatment of hypotension was associated with reduced in-hospital mortality when compared to non-early hypotension treatment (Adjusted relative risk=0.460).

2.        Compared to those with hypotension not treated in a timely manner, those who received timely treatment had improved GOS at discharge (Adjusted relative risk=0.540).

(2016)

USA

PCT

N=128

Population: TBI; Pre-protocol (n=99):  Mean Age=6.54yr; Gender: Male=52, Female=47; Mean GCS=5.43. Post-protocol (n=29): Mean Age=5.89yr; Gender: Male=16, Female=13; Mean GCS=5.28.

Intervention: Patients with severe TBI were retrospectively identified. Those treated before the implementation of a new treatment protocol (based on the Brain Trauma Foundation’s 2012 guidelines) were compared with those treated after the new protocol was implemented.

Outcome Measure: Protocol Adherence, Discharge Disposition, Glasgow Outcome Scale (GOS).

1.       Use of 3% hypertonic saline (HTS) over mannitol was used as a surrogate measure of protocol adherence. After protocol implementation, HTS treatment was increased (22% to 41%; p=0.040) while mannitol use administration was decreased (48% to 14%; p=0.001).

2.       Patients in the post-protocol group had more favourable discharge disposition than those in the pre-protocol group (69% versus 36%, respectively; p=0.002).

3.       GOS scores were not significantly increased after protocol implementation (p=0.124).

(2016)

Canada

Case Series

N=16

Population: TBI; Median Age=13; Gender: Male=12, Female=4; Median Time Post Injury=196 min; Median GCS=6.

Intervention: Retrospective review of patients with severe TBI, admitted to a pediatric intensive care unit (ICU), who were treated with a hyperosmolar agent.

Outcome Measure: Intracranial Pressure (ICP), Cerebral Perfusion Pressure (CPP), Serum Sodium.

1.       All patients received 3% hypertonic saline (HTS,average dose=1.8 ml/kg), and all but 3 patients received mannitol (average dose=0.6 g/kg).

2.       Both 3% HTS and mannitol were associated with a nonsignificant decrease in ICP (p=0.096 and p=0.055, respectively.)

3.       No significant changes in CPP or serum sodium were observed.

(2000)

USA

Case Series

N=10

Population: TBI; Mean Age=5.7yr; Gender: Male=8, Female=2; Mean Time Post Injury=3.2 d; Mean Time Post Injury=3.2 d; Mean GCS=4.7.

Intervention: Patients who had failed conventional therapy were treated with a continuous infusion of 3% hypertonic saline in order to achieve target serum sodium levels. Measurements were observed and recorded every 6 hr. Outcomes were assessed at 6mo follow-up.

Outcome Measure: Glasgow Outcome Scale (GOS), Intracranial Pressure (ICP), Cerebral Perfusion Pressure (CPP) , Serum Osmolarity.

1.        There was a significant decrease in ICP at 6, 12, 24, 48 and 72 hr time points compared to baseline (all p<0.01).

2.        There was a significant decrease in ICP spike frequency and a significant increase in CPP at 6, 12, 24, 48 and 72 hr (all p<0.01).

3.        A significant increase in serum osmolarity was reported at 12 hr (p<0.05) and at 24, 48 and 72 hr (all p<0.01).

4.        Although one patient died, the remaining nine reported a median GOS score of 4 at 6 mo follow-up.

(2000)

USA

Case Series

N=68

Population: TBI; Mean Age=7.8yr; Gender: Male=47, Female=21; Mean GSC=5.5.

Intervention: Children with intracranial hypertension (ICP >20 mmHg) were retrospectively analyzed. Patients were administered continuous hypertonic saline (3%) and intermittent mannitol to target serum sodium levels. Measurements were taken every 6 hr for 7 d. Mean dose of hypertonic saline was between 11-27 mL/kg per d over a 7 d period.

Outcome Measure: ICP; serum sodium, osmolarity, and creatinine levels; renal function.

1.        There were 3 patients (4%) that died of uncontrolled ICP.

2.        Within 72hr, ICP was <20 mmHg 93% of the time, 21-30 mmHg 5% of the time, and >30 mmHg 2% of the time.

3.        Patients with serum sodium levels >180 mEq/L, all had poor outcomes.

4.        Serum creatinine levels increased with increased serum concentrations of sodium (p<.001) and with serum osmolarity (p<.001).

5.        No development of renal failure or rebound of ICP.