This document summarizes a study on the efficacy and safety of using highly concentrated hypertonic saline (HTS) to treat traumatic brain injury (TBI) related refractory intracranial hypertension. The study found that 30% HTS was effective at reducing intracranial pressure in both single and repeated doses without significantly affecting physiological, biochemical, or hematological parameters. The authors concluded that 30% HTS is an effective and safe method for managing refractory intracranial hypertension in TBI patients. However, further research is needed to determine if HTS treatment improves clinical outcomes when used with other therapies.

1. Efficacy and Safety of Highly
Concentrated Hypertonic Saline in the
Treatment of Traumatic Brain
Injury Related Refractory Intracranial
Hypertension
Dr. Emmet Major
Coppel Prize 2013

2. Hyperosmolar Therapy
Mannitol
Hypertonic Saline

3. Documeted & Theoretical Advantages of HTS
over Mannitol
1. Higher reflection coeffcient results in HTS being more
osmotically effective (pathologies with intact BBB)
2. Does not rely on osmotic diuresis (i.e. only increases
serum osmolality directly with no diuretic component)
3. Use of HTS may avoid documeted adverse effects of
mannitol use, including rebound ICP elevation,
intravascular volume depletion with reduced CPP, and
renal failure
4. HTS allows clinicians to employ a “low-volume
resuscitation” strategy in the haemorhagically shocked
trauma patient

4. Benefits of high - v - low concentration HTS
• Low-volume resuscitation strategy (30%
HTS has an osmolarity 10.33 mOsm/ml)
• Convenience, ease and rapidity of
administration

5. Safety concerns over use of HTS
•
Osmotic demyelination syndrome/central pontine
myelinolysis
•
•
•
•
•
•
•
Rebound oedema and increases in ICP
Excessive increases in serum osmolality
Electrolyte disturbance
Non-anion gap hyperchloraemic acidosis
Volume overload
Coagulopathy
Thrombophlebitis and tissue necrosis

6. Patients
Age
Mechanism
Pathology
ICP Monitor
Concurrent ICP Controlling Measures
Patient 1
43
Fall down stairs
Subdural haemmorhage
Traumatic SAH
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Mannitol
Patient 2
44
Road traffic collision
Subdural haemmorhage
Diffuse axonal injury
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Patient 3
21
Assault
Subdural haemmorhage
Intraparenchymal contusions
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Patient 4
44
Road traffic collision
Subdural haemmorhage
Intraparenchymal contusions
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Mannitol
External Ventricular Drain
Patient 5
23
Road traffic collision
Subdural haemmorhage
Diffuse axonal injury
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
External Ventricular Drain
Thipentone
Patient 6
23
Fall down stairs
Extradural haemmorhage
Subdural haemmorhage
Intraparenchymal contusion
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Patient 7
37
Assault
Subdural haemmorhage
Intraparenchymal contusions
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Mannitol
Patient 8
37
Road traffic collision
Subdural haemmorhage
Traumatic SAH
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Mannitol
Thiopentone
Decompressive Craniectomy
Patient 9
54
Fall from height
Subdural haemmorhage
Traumatic SAH
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Mannitol
External Ventricular Drain
Patient 10
16
Object falling from height to
head
Subdural haemmorhage
Intraparenchymal contusions
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Patient 11
16
Road traffic collision
Diffuse axonal injury
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Patient 12
31
Road traffic collision
Subdural haemmorhage
Diffuse axonal injury
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Mannitol
External Ventricular Drain
Decompressive Craniectomy
Patient 13
41
Fall from height
Subdural haemmorhage
Intraparenchymal contusions
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Patient 14
33
Assault
Subdural haemmorhage
Intraparenchymal contusions
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam
Mannitol
Thiopentone
Decompressive Craniectomy
Patient 15
51
Road traffic collision
Diffuse axonal injury
Yes
Intubated & Ventilated
Propofol/Fentanyl/Midazolam

7. Dynamic Physiological Measurements &
Laboratory Investigations
Study designed to assess:
(i) Efficacy of 30% HTS
(ii) Safety of 30% HTS
Laboratory Investigations
- Arterial Blood Gad
Physiological
Parameters
ICP
MAP
CPP
Pulse
↓
pCO2
hourly8
Laboratory Investigations
- Biochemistry
2 Hours Pre HTS
HCO3
2 Hours Post HTS
BE
4 Hours Post HTS
Sodium
Inopressor
Requirements
Potassium
Time
Na
6 Hours Pre HTS
4 Hours Post HTS
ClUrea
20 Hours Post HTS
Laboratory Investigations
- Coagulation
PT
10 Hours Post HTS
Creatinine
Time
pH
Baseline
1 Hour Post HTS
Hours Post HTS
K
2 Main Cohorts:
(i) Single Dose 30% HTS
(ii) Repeated Dose 30% HTS (> 8 hours apart)
APTT
Time
10 Hours Pre HTS
10 Hours Post HTS
20 Hours Post HTS

8. Statistical Analysis
• Data are reported as mean ± SD unless
otherwise stated.
• Changes in physiological, biochemical and
haematological parameters following HTS
administration were assessed using oneway repeated measures ANOVA with posttest Bonferroni’s multiple comparison test.
•
P<0.05 was considered statistically
significant.

9. HTS - Efficacy - Single Dose
Time
Time 0
1 Hour
2 Hours
3 Hours
4 Hours
5 Hours
6 Hours
7 Hours
8 Hours
p-Value
(ANOVA)
ICP (mmHg)
28.78 ± 5.31
18.44 ± 6.17 ‡
18.56 ± 6.04 ‡
19.0 ± 3.91 ‡
19.25 ± 6.27 †
17.71 ± 3.40 ‡
18.63 ± 4.37 †
18.75 ± 4.10 ‡
20.13 ± 7.04
0.0004
CPP (mmHg)
70.22 ± 13.72
76.67 ± 9.03
73.89 ± 7.22
70.11 ± 13.37
72.13 ±11.03
81.13 ± 4.49
76.0 ± 11.3
75.13 ±12.05
76.5 ± 10.80
0.0605
MAP (mmHg) 97.33 ± 10.51
95.11 ± 9.31
92.44 ± 4.25
89.0 ± 11.47
91.25 ± 7.54
98.25 ± 4.40
94.25 ± 9.02
93.38 ± 9.41
96.75 ± 10.29
0.4286
Pulse
75.44 ± 19.95
74.89 ± 19.51
73.56 ± 19.22
74.56 ± 19.34
73.63 ± 17.38
70.88 ± 15.69
72.75 ± 19.96
72.13 ± 18.44
74.25 ± 23.90
0.9984
Noradrenalin
e
(µg/kg/min)
0.334 ± .385
0.306 ± .395
0.291 ± .400
0.289 ± .400
0.133 ± .135
0.178 ± .163
0.175 ± .162
0.185 ± .167
0.207 ± .171
0.6723
* P < 0.05
† P < 0.01
‡ P < 0.001
Data vs. baseline values
(i.e. time = 0 min).

10. HTS - Efficacy - Single Dose
Time
Time 0
1 Hour
2 Hours
3 Hours
4 Hours
5 Hours
6 Hours
7 Hours
8 Hours
p-Value
(ANOVA)
ICP (mmHg)
28.78 ± 5.31
18.44 ± 6.17 ‡
18.56 ± 6.04 ‡
19.0 ± 3.91 ‡
19.25 ± 6.27 †
17.71 ± 3.40 ‡
18.63 ± 4.37 †
18.75 ± 4.10 ‡
20.13 ± 7.04
0.0004
CPP (mmHg)
70.22 ± 13.72
76.67 ± 9.03
73.89 ± 7.22
70.11 ± 13.37
72.13 ±11.03
81.13 ± 4.49
76.0 ± 11.3
75.13 ±12.05
76.5 ± 10.80
0.0605
MAP (mmHg) 97.33 ± 10.51
95.11 ± 9.31
92.44 ± 4.25
89.0 ± 11.47
91.25 ± 7.54
98.25 ± 4.40
94.25 ± 9.02
93.38 ± 9.41
96.75 ± 10.29
0.4286
Pulse
75.44 ± 19.95
74.89 ± 19.51
73.56 ± 19.22
74.56 ± 19.34
73.63 ± 17.38
70.88 ± 15.69
72.75 ± 19.96
72.13 ± 18.44
74.25 ± 23.90
0.9984
Noradrenalin
e
(µg/kg/min)
0.334 ± .385
0.306 ± .395
0.291 ± .400
0.289 ± .400
0.133 ± .135
0.178 ± .163
0.175 ± .162
0.185 ± .167
0.207 ± .171
0.6723
* P < 0.05
† P < 0.01
‡ P < 0.001
Data vs. baseline values
(i.e. time = 0 min).

11. HTS - Efficacy - Repeated Dose
Time
Time 0
1 Hour
2 Hours
3 Hours
4 Hours
5 Hours
6 Hours
7 Hours
8 Hours
p-Value
(ANOVA
)
ICP (mmHg)
33. 0 ± 5.83
16.17 ± 4.88 †
16.33 ± 8.48 †
18.33 ± 7.47 †
15.67 ±7.66 †
16.83 ± 8.28 *
17.50 ± 8.62 *
18.67 ± 11.36 *
15.17 ± 8.01 †
0.0003
CPP (mmHg)
58.0 ± 6.48
76.33 ± 7.42 ‡
74.0 ± 8.46 †
72.50 ± 13.92
68.50 ± 5.50
69.67 ±12.80
74.83 ± 12.42
*
72.67 ± 3.27
71.0 ± 11.78
0.0121
90.50 ± 10.60
89.50 ± 9.91
90.83 ± 9.37
83.67 ± 7.50
86.17 ± 11.97
92.83 ± 11.65
95.0 ± 11.10
86.67 ± 13.82
0.0887
MAP (mmHg) 90.67 ± 8.07
Pulse
75.67 ± 11.04 80.17 ± 13.59
76.17 ± 11.07
81.67 ± 19.81
79.50 ± 13.66
79.33 ± 18.40
82.0 ± 24.58
80.33 ± 30.14
75.50 ± 19.21
0.8212
Noradrenalin
e
(µg/kg/min)
0.287 ± .142
0.234 ± .163
0.250 ± .206
0.26 ± .228
0.267 ± .248
0.275 ± .257
0.296 ± .284
0.283 ± .286
0.9679
0.271 ± .183
* P < 0.05
† P < 0.01
‡ P < 0.001
Data vs. baseline values
(i.e. time = 0 min).

12. HTS - Efficacy - Repeated Dose
Time
Time 0
1 Hour
1 Hour
3 Hours
4 Hours
5 Hours
6 Hours
7 Hours
8 Hours
p-Value
(ANOVA
)
ICP (mmHg)
33. 0 ± 5.83
16.17 ± 4.88 †
16.33 ± 8.48 †
18.33 ± 7.47 †
15.67 ±7.66 †
16.83 ± 8.28 *
17.50 ± 8.62 *
18.67 ± 11.36
*
15.17 ± 8.01 †
0.0003
CPP (mmHg)
58.0 ± 6.48
76.33 ± 7.42 ‡
74.0 ± 8.46 †
72.50 ± 13.92
68.50 ± 5.50
69.67 ±12.80
74.83 ± 12.42 *
72.67 ± 3.27
71.0 ± 11.78
0.0121
90.50 ± 10.60
89.50 ± 9.91
90.83 ± 9.37
83.67 ± 7.50
86.17 ± 11.97
92.83 ± 11.65
95.0 ± 11.10
86.67 ± 13.82
0.0887
MAP (mmHg) 90.67 ± 8.07
Pulse
75.67 ± 11.04 80.17 ± 13.59
76.17 ± 11.07
81.67 ± 19.81
79.50 ± 13.66
79.33 ± 18.40
82.0 ± 24.58
80.33 ± 30.14
75.50 ± 19.21
0.8212
Noradrenalin
e
(µg/kg/min)
0.287 ± .142
0.234 ± .163
0.250 ± .206
0.26 ± .228
0.267 ± .248
0.275 ± .257
0.296 ± .284
0.283 ± .286
0.9679
0.271 ± .183
* P < 0.05
† P < 0.01
‡ P < 0.001
Data vs. baseline values
(i.e. time = 0 min).

13. HTS - Safety
Changes in biochemical, acid-base status and haematological parameters in response to single and repeat administration of
30% HTS. Data are presented as means ± SD. Nil significant.

14. Conclusions
• 30% HTS is effective and safe in the
management of refractory intracranial
hypertension in patients with traumatic
brain injury.
• Whether this, in concomitant association
with other therapeutic tools, translates into
improved clinical outcomes requires
further study.

15. References
1. Brain Trauma Foundation, Surgeons AAON, Surgeons CON, et al.: Guidelines for the
management of severe traumatic brain injury. Introduction. J.Neurotrauma 2007; 24
Suppl 1:S1–2
15. Schmoker JD, Shackford SR, Wald SL, et al.: An analysis of the relationship between
fluid and sodium administration and intracranial pressure after head injury. J.Trauma
1992; 33:476–481
2. Werner C, Engelhard K: Pathophysiology of traumatic brain injury. Br.J.Anaesth. 2007;
99:4–9
16. Zornow MH: Hypertonic saline as a safe and efficacious treatment of intracranial
hypertension. J.Neurosurg.Anesthesiol. 1996; 8:175–177
3. Brain Trauma Foundation, Surgeons AAON, Surgeons CON, et al.: Guidelines for the
management of severe traumatic brain injury. II. Hyperosmolar therapy.
J.Neurotrauma 2007; 24 Suppl 1:S14–20
17. Berger S, Schurer L, Hartl R, et al.: Reduction of post-traumatic intracranial
hypertension by hypertonic/hyperoncotic saline/dextran and hypertonic mannitol.
Neurosurgery 1995; 37:98–107; discussion 107–8
4. Ogden AT, Mayer SA, Connolly ES Jr: Hyperosmolar agents in neurosurgical practice:
the evolving role of hypertonic saline. Neurosurgery 2005; 57:207–15; discussion 207–15
18. Qureshi AI, Suarez JI: Use of hypertonic saline solutions in treatment of cerebral
edema and intracranial hypertension. Crit. Care Med. 2000; 28:3301–3313
5. Murphy N, Auzinger G, Bernel W, et al.: The effect of hypertonic sodium chloride on
intracranial pressure in patients with acute liver failure. Hepatology 2004; 39:464-470
19. Suarez JI: Hypertonic saline for cerebral edema and elevated intracranial pressure.
Cleve.Clin.J.Med. 2004; 71 Suppl 1:S9–13
6. Fenstermacher JD, Johnson JA: Filtration and reflection coefficients of the rabbit bloodbrain barrier. Am.J.Physiol. 1966; 211:341–346
20. Tollofsrud S, Tonnessen T, Skraastad O, et al.: Hypertonic saline and dextran in
normovolaemic and hypovolaemic healthy volunteers increases interstitial and
intravascular fluid volumes. Acta Anaesthesiol.Scand. 1998; 42:145–153
7. Horn P, Munch E, Vajkoczy P, et al.: Hypertonic saline solution for control of elevated
intracranial pressure in patients with exhausted response to mannitol and barbiturates.
Neurol.Res. 1999; 21:758–764
8. Schwarz S, Georgiadis D, Aschoff A, et al.: Effects of hypertonic (10%) saline in patients
with raised intracranial pressure after stroke. Stroke 2002; 33:136–140
9. Schwarz S, Schwab S, Bertram M, et al.: Effects of hypertonic saline hydroxyethyl starch
solution and mannitol in patients with increased intracranial pressure after stroke.
Stroke 1998; 29:1550–1555
10. Vialet R, Albanese J, Thomachot L, et al.: Isovolume hypertonic solutes (sodium
chloride or mannitol) in the treatment of refractory posttraumatic intracranial
hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. Crit.
Care Med. 2003; 31:1683–1687
11. Suarez JI, Qureshi AI, Bhardwaj A, et al.: Treatment of refractory intracranial
hypertension with 23.4% saline. Crit. Care Med. 1998; 26:1118–1122
12. Worthley LI, Cooper DJ, Jones N: Treatment of resistant intracranial hypertension
with hypertonic saline. Report of two cases. J.Neurosurg. 1988; 68:478–481
13. Himmelseher S: Hypertonic saline solutions for treatment of intracranial
hypertension. Curr.Opin.Anaesthesiol. 2007; 20:414–426
14. Wakai A, Roberts I, Schierhout G: Mannitol for acute traumatic brain injury. Cochrane
Database Syst.Rev. 2007; (1):CD001049
21. Mazzoni MC, Borgstrom P, Intaglietta M, et al.: Capillary narrowing in hemorrhagic
shock is rectified by hyperosmotic saline-dextran reinfusion. Circ.Shock 1990; 31:407–
418
22. Prough DS, Whitley JM, Taylor CL, et al.: Regional cerebral blood flow following
resuscitation from hemorrhagic shock with hypertonic saline. Influence of a subdural
mass. Anesthesiology 1991; 75:319–327
23. Schmoker JD, Zhuang J, Shackford SR: Hypertonic fluid resuscitation improves
cerebral oxygen delivery and reduces intracranial pressure after hemorrhagic shock.
J.Trauma 1991; 31:1607–1613
24. Shackford SR, Zhuang J, Schmoker J: Intravenous fluid tonicity: effect on intracranial
pressure, cerebral blood flow, and cerebral oxygen delivery in focal brain injury.
J.Neurosurg. 1992; 76:91–98
25. Hartl R, Ghajar J, Hochleuthner H, et al.: Hypertonic/hyperoncotic saline reliably
reduces ICP in severely head-injured patients with intracranial hypertension. Acta
Neurochir.Suppl. 1997; 70:126–129
26. White H, Cook D, Venk
atesh B: The role of hypertonic saline in neurotrauma.
Eur.J.Anaesthesiol.Suppl. 2008; 42:104–109
27. White H, Cook D, Venkatesh B: The Use of Hypertonic Saline for Treating
Intracranial Hypertension after Traumatic Brain Injury. Anaesth, Analg 2006; 102:1836–
1866
28. Ninomiya Y, Fujisawa H: A conservative test for multiple comparison based on highly
correlated test statistics. Biometrics 2007; 63:1135–1142