Jagannatha et al. (2016)

India

RCT

PEDro=5

N=38

Population: TBI; Hypertonic Saline (HTS, n=18): Mean Age=27 yr; Gender: Male=16, Female=2; Mean Time Post Injury=6.1 hr; Median GCS=4. Mannitol (MAN, n=20): Mean Age=31 yr; Gender: Male=18, Female=2; Mean Time Post Injury=6.7 hr; Median GCS=5.

Intervention: Participants were randomized to receive HTS (3%) or MAN (20%). Outcomes were assessed daily for 6 days.

Outcome Measures: Intracranial Pressure (ICP), Mean Arterial Pressure (MAP), Heart Rate (HR), Blood Glucose, Fluid Balance, Serum Osmolality, Serum Sodium.

1.       There was no significant difference between groups in reduction in ICP (p=0.135).

2.       Blood Glucose significantly decreased over 6 d in the HTS group (p=0.003).

3.       There was no significant difference in Blood Glucose over 6 d in the MAN group (p=0.36).

4.       There was no significant difference in HR, MAP, Fluid Balance, Serum Osmolality, or Serum Na+ (all p>0.05) for both MAN and HTS groups over 6 days.

Jagannatha et al. 2018

India

Post-Hoc Analysis

N= 38

Population: TBI; Hypertonic Saline (HTS, n=18): Mean Age=27 yr; Gender: Male=16, Female=2; Mean Time Post Injury=6.1 hr; Median GCS=4. Mannitol (MAN, n=20): Mean Age=31 yr; Gender: Male=18, Female=2; Mean Time Post Injury=6.7 hr; Median GCS=5.

Intervention: A post-hoc analysis of the study conducted by Jagannatha et al. (2016), focusing on comparing urinary sodium and urine osmolarity in the HTS and Mannitol groups.

Outcome Measures: Urinary Sodium, Urinary Osmolarity.

1.       Urinary sodium excretion was significantly higher in the HTS group compared to the Mannitol group (p=0.02)

2.       Urinary Osmolarity was not different between groups (=0.63)

Cottenceau et al. (2011)

Israel

RCT

PEDro=6

N=47

Population: TBI; Hypertonic Saline (HTS, n=22): Mean Age=42.7 yr; Median GCS=5. Mannitol (MAN, n=25): Mean Age=36.1 yr; Median GCS=7.

Intervention: Participants were randomized to receive HTS (7.5%, 2 mL/kg) or MAN (20%, 4 mL/kg). Outcomes were assessed at baseline, 30 min, 120 min, and 6 mo.

Outcome Measures: Intracranial Pressure (ICP), Mean Arterial Pressure (MAP), Cerebral Perfusion Pressure (CPP), Global Cerebral Blood Flow Oxygen (CBF), Arterial Jugular Difference for Oxygen Content (AVDO₂), Global Cerebral Metabolic Rate of Oxygen (CMRO₂).

1.       The HTS group had significantly greater CBF when compared to the MAN group (p=0.0087) over time.

2.       There was no significant difference between groups over time in ICP, MAP, CPP, AVDO₂, or CMRO₂ (all p>0.05).

Battison et al.

(2005)

UK

RCT Crossover

PEDro=5

N=9

Population: TBI=6, SAH=3.

Intervention: Participants received intravenous infusions of 20% mannitol (200 mL), a solution of 7.5% hypertonic saline (100mL) and 6% dextran-70 (HSD) over 5 min in a randomized order. Outcomes were assessed before and after treatment.

Outcome Measure: Intracranial Pressure (ICP).

1.       Both mannitol and HSD were effective in reducing ICP.

2.       HSD caused a significantly greater decrease in median ICP than mannitol (13 mmHg versus 7.5 mmHg, p=0.044).

3.       HSD had a longer duration of effect than mannitol (p=0.044).

Harutjunyan et al. (2005)

Germany

RCT

PEDro=5

N=40

Population: TBI; Hypertonic Saline group (HTS; n=17): Mean Age=47 yr; Gender: Male=9, Female=8; Mean GCS=6. Mannitol group (MAN; n=15): Mean Age=47 yr; Gender: Male=8, Female=7; Mean GCS=5.8.

Intervention: Patients at risk of increased ICP were randomized to receive either 7.2% hypertonic saline or 15% mannitol. Treatment was stopped when ICP was <15 mmHg.

Outcome Measures: Intracranial Pressure (ICP),  Cerebral Perfusion Pressure (CPP), Heart Rate (HR), Mean Arterial Pressure (MAP).

1.       There was no significant difference over time or between groups for HR (all p>0.05).

2.       There was no significant difference in MAP between groups (p>0.05).

3.       There was a significant reduction in ICP over time for both the HTS and MAN groups (all p<0.0001), however, there was no significant difference between groups (p>0.05).

4.       There was a significant increase in CCP over time for both the HTS and MAN groups (all p<0.0001); with the HTS group significantly higher than the MAN group (p<0.05).

Vialet et al. (2003)

France

RCT

PEDro=7

N=20

Population: TBI;. Hypertonic Saline (HTS, n=10): Mean Age=35 yr; Gender: Male=5, Female=5; Mean GCS=4.7. Mannitol (MAN, n=10): Mean Age=31 yr; Gender: Male=4, Female=6; Mean GCS=6.0.

Intervention: Participants were randomized to receive intravenous infusions of 7.5% HTS or 20% MAN.  Infused volume was the same for both medications: 2 ml/kg of body weight in 20min. Outcomes were assessed over a mean of 7 days.

Outcome Measures: Intracranial Pressure (ICP), Cerebral Perfusion Pressure (CPP), Glasgow Outcome Scale (GOS), Mortality.

1.       HTS had significantly fewer mean episodes of ICP>25 mmHg per day (6.9 versus 14.6, p<0.01) and shorter mean daily duration of these episodes (67 min versus 131 min, p<0.01) than MAN.

2.       There was no significant difference between HTS and MAN in mean episodes of CPP<70 mmHg (4.0 versus 3.1, p>0.05) or mean daily duration of these episodes (58 min versus 62 min, p>0.05).

3.       Failure of treatment was significantly greater in MAN than HTS (70% versus 10%, p=0.01).

4.       There was no significant difference between HTS and MAN in poor GOS (60% versus 50%, p>0.05) or mortality (40% versus 50%, p>0.05).

Mangat et al. (2015)

USA

Case Control

N=1238

Population: TBI; Hypertonic Saline (HTS, n=45): Mean Age=38.37 yr; Mean GCS=5.46. Mannitol (MAN, n=477): Mean Age=36.13 yr; Mean GCS=4.75. Hypertonic Saline & Mannitol (HTS+MAN; n=137): Mean Age=31.42 yr; Mean GCS=4.82. Control (n=589): Mean Age=42.63 yr; Mean GCS=4.96.

Intervention: Patients who received HTS, MAN, or neither (control) were retrospectively analyzed.

Outcome Measures: Intracranial Pressure (ICP) Length of Stay (LOS), Mortality.

1.       There was no significant difference in total number of ICP recording days between the HTS and MAN groups (p=0.09).

2.       The cumulative and daily ICP burdens were significantly lower in patients who received HTS compared to patients who received MAN (p=0.003 and p=0.001, respectively).

3.       LOS was significantly lower in the HTS compared to MAN with a 1:1 match (p=0.004); however, this became insignificant with a 1:2 match (p=0.06).

4.       There was no significant difference between HTS and MAN in mortality rate (p=0.53).

Tang et al. (2015)

Taiwan

Pre-Post

N=21

Population: TBI=8, Stroke=10, Tumor=3; Mean Age=52.05 yr; Gender: Male=12, Female=9; Mean GCS=10.6.

Intervention: Participants received 1 g/kg of 20% mannitol.

Outcome Measures: Intracranial Pressure (ICP), Pressure Reactivity Index (PRx), Cerebral Perfusion Pressure (CPP), Cerebrovascular Pressure Reactivity (CVPR).

1.       At baseline, ICP was significantly correlated with PRx (p=0.0044).

2.      There was a significant decrease in ICP after mannitol (p=0.036).

3.      Low baseline CPP was the only significant association with the improvement of CVPR after mannitol (p=0.039).

Colton et al. (2014b)

USA

Case Series

N=117

Population: TBI; Mean Age=40.0 yr; Gender: Male=93, Female=24; Median GCS=6.

Intervention: Participants were included in retrospective analysis after having received one of the following ICP therapies: hypertonic saline (HTS), mannitol, propofol, fentanyl, and barbiturates.

Outcome Measure: Intracranial Pressure (ICP).

1.       Treatment with HTS resulted in the largest ICP decrease of the treatments examined.

2.       Propofol and fentanyl escalations resulted in smaller but significant ICP reductions.

3.       Mannitol resulted in statistically insignificant reductions in the first hr but rebounded by the second hr.

Diringer et al. (2012)

USA

Pre-Post

N=6

Population: TBI; Mean Age=30.2 yr; Gender: Male=5, Female=1; Median GCS=6.

Intervention: Participants received 1 g/kg of 20% mannitol.

Outcome Measures: Intracranial Pressure (ICP), Cerebral Blood Volume (CBV), Blood Pressure (BP), Cerebral Blood Flow (CBF), Cerebral Metabolic Rate for Oxygen (CMRO2), Oxygen Content.

1.       There was a significant reduction in ICP 1hr after mannitol (21.5 mmHg to 13.7 mmHg, p<0.003).

2.      There was no significant change in CBV, BP, CBF, CMRO2 or oxygen content 1hr after mannitol (all p>0.05).

Sakellaridis et al. (2011)

Greece

Case Control

N=29

Population: TBI; Mean Age=36 yr; Mean GCS=5.4.

Intervention: Participants who received hypertonic saline (HTS) or mannitol were retrospectively analyzed.

Outcome Measures: Intracranial Pressure (ICP), Duration of effectiveness.

1.       There was no significant difference between HTS and mannitol in reducing ICP.

2.       There was no significant difference between HTS and mannitol in duration of effectiveness.

Kerwin et al. (2009)

USA

Cohort

N=22

Population: TBI; Mean Age=35.7 yr; Gender: Male=16, Female=6; Mean GCS=6.9.

Intervention: Patients received intravenous infusions of 23.4% hypertonic saline (HTS) or mannitol (15-75 g, at the discretion of the neurosurgeon).

Outcome Measure: Intracranial Pressure (ICP).

1.       Mean ICP reduction was significantly greater by HTS than mannitol (9.3mmHg versus 6.4 mmHg, p=0.0028).

2.       Patients with initial ICP>30 mmHg had a significantly greater mean ICP reduction by HTS than mannitol (12.6 mmHg versus 8 mmHg, p=0.0105).

3.       More patients responded to HTS than mannitol (93% versus 74%, p=0.002).

4.       HTS was more likely to yield an ICP reduction of >10 mmHg, while mannitol was more likely to yield a reduction of <5 mmHg.

5.       There was no significant difference between HTS and mannitol in amount of time ICP>20 mmHg (9.7 hr versus 7.4 hr, p=0.236) or duration of response (4.1 hr versus 3.8hr, p=0.854).

Oddo et al. (2009)

USA

Cohort

N=12

Population: TBI; Mean Age=36 yr; Gender: Male=9, Female=3; Mean GCS=3; Mean Time Post Injury=8 hr.

Intervention: Participants received intravenous infusions of 7.5% hypertonic saline (HTS) or 25% mannitol.

Outcome Measures: Intracranial Pressure (ICP), Mean Arterial Pressure (MAP), Cerebral Perfusion Pressure (CPP), Brain Tissue Oxygen Tension (P_btO₂), Central Venous Pressure (CVP), Cardiac Output (CO).

1.       Mean ICP was more significantly reduced (p<0.001) by HTS than mannitol after 60min (15 mmHg versus 23 mmHg) and 120min (15 mmHg versus 24 mmHg).

2.       Mean CPP was more significantly increased by HTS than mannitol after 120min (76 mmHg versus 65 mmHg, p=0.02).

3.       Mean CO was more significantly increased by HTS than mannitol after 30 min (7.5 L/min versus 5.3 L/min, p=0.003), 60 min (7.8 L/min versus 6.6 L/min, p=0.007), and 120min (7.5 L/min versus 6.1 L/min, p=0.002).

4.       Mean P_btO₂ was significantly increased by HTS (p<0.01) and decreased by mannitol (p>0.05) over time, with significant differences at 60min (37 mmHg versus 28 mmHg, p<0.05) and 120 min (41 mmHg versus 27.5 mmHg, p<0.01).

5.       There were no significant differences in MAP or CVP between groups.

Ware et al. (2005)

USA

Case Control

N=13

Population: TBI; Mean Age=42.0 yr; Gender: Male=10, Female=3; Time Post Injury<12 hr; Mean GCS=7.7.

Intervention: Participants received intravenous infusions of 23.4% hypertonic saline (HTS) and mannitol.

Outcome Measure: Intracranial Pressure (ICP).

1.       Both HTS and mannitol significantly reduced ICP (p<0.001) and there was no significant difference between them (p=0.174).

2.       Mean duration of ICP reduction by HTS was significantly longer than mannitol (96 min versus 59 min, p=0.016).

Hartl et al. (1997)

Germany

Pre-Post

N=11

Population: TBI; GCS<9.

Intervention: Patients received 30 intravenous administrations of 20% mannitol (125 mL) infused over 30 min.

Outcome Measures: Intracranial Pressure (ICP), Cerebral Perfusion Pressure (CPP).

1.       When initial ICP was <20 mmHg, neither ICP nor CPP change significantly during or after mannitol infusion.

2.       When initial ICP was >20 mmHg, there was a significant decrease in mean ICP (maximal decrease from 23 mmHg to 16 mmHg at 60min, p<0.05) and a significant increase in mean CPP (maximal increase from 68 mmHg to 80 mmHg at 120 min, p<0.05) in response to mannitol.