Efficacy and Safety of Highly Concentrated Hypertonic Saline in the Treatment of Traumatic BrainInjury Related Refractory Intracranial Hypertension

Dr. Emmet MajorCoppel Prize 2013

Hyperosmolar Therapy

Mannitol Hypertonic Saline

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

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

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

Patients Age Mechanism Pathology ICP Monitor Concurrent ICP Controlling Measures

Patient 1 43 Fall down stairs Subdural haemmorhageTraumatic SAH

Yes Intubated & VentilatedPropofol/Fentanyl/MidazolamMannitol

Patient 2 44 Road traffic collision Subdural haemmorhageDiffuse axonal injury

Yes Intubated & VentilatedPropofol/Fentanyl/Midazolam

Patient 3 21 Assault Subdural haemmorhageIntraparenchymal contusions

Yes Intubated & VentilatedPropofol/Fentanyl/Midazolam

Patient 4 44 Road traffic collision Subdural haemmorhageIntraparenchymal contusions

Yes Intubated & VentilatedPropofol/Fentanyl/MidazolamMannitolExternal Ventricular Drain

Patient 5 23 Road traffic collision Subdural haemmorhageDiffuse axonal injury

Yes Intubated & VentilatedPropofol/Fentanyl/MidazolamExternal Ventricular DrainThipentone

Patient 6 23 Fall down stairs Extradural haemmorhageSubdural haemmorhageIntraparenchymal contusion

Yes Intubated & VentilatedPropofol/Fentanyl/Midazolam

Patient 7 37 Assault Subdural haemmorhageIntraparenchymal contusions

Yes Intubated & VentilatedPropofol/Fentanyl/MidazolamMannitol

Patient 8 37 Road traffic collision Subdural haemmorhageTraumatic SAH

Yes Intubated & VentilatedPropofol/Fentanyl/MidazolamMannitolThiopentoneDecompressive Craniectomy

Patient 9 54 Fall from height Subdural haemmorhageTraumatic SAH

Yes Intubated & VentilatedPropofol/Fentanyl/MidazolamMannitolExternal Ventricular Drain

Patient 10 16 Object falling from height to head

Subdural haemmorhageIntraparenchymal contusions

Yes Intubated & VentilatedPropofol/Fentanyl/Midazolam

Patient 11 16 Road traffic collision Diffuse axonal injury Yes Intubated & VentilatedPropofol/Fentanyl/Midazolam

Patient 12 31 Road traffic collision Subdural haemmorhageDiffuse axonal injury

Yes Intubated & VentilatedPropofol/Fentanyl/MidazolamMannitolExternal Ventricular DrainDecompressive Craniectomy

Patient 13 41 Fall from height Subdural haemmorhageIntraparenchymal contusions

Yes Intubated & VentilatedPropofol/Fentanyl/Midazolam

Patient 14 33 Assault Subdural haemmorhageIntraparenchymal contusions

Yes Intubated & VentilatedPropofol/Fentanyl/MidazolamMannitolThiopentoneDecompressive Craniectomy

Patient 15 51 Road traffic collision Diffuse axonal injury Yes Intubated & VentilatedPropofol/Fentanyl/Midazolam

Dynamic Physiological Measurements & Laboratory Investigations

Physiological Parameters

ICP Baseline 1 Hour Post HTS

↓hourly8

Hours Post HTS

MAP

CPP

Pulse

Inopressor Requirements

Laboratory Investigations - Biochemistry

Time

Na

6 Hours Pre HTS

4 Hours Post HTS

10 Hours Post HTS

20 Hours Post HTS

K

Cl-

Urea

Creatinine

Laboratory Investigations - Arterial Blood Gad

Time

pH

2 Hours Pre HTS

2 Hours Post HTS

4 Hours Post HTS

pCO2

HCO3

BE

Sodium

Potassium

Laboratory Investigations - Coagulation

Time

PT 10 Hours Pre HTS10 Hours Post HTS20 Hours Post HTSAPTT

2 Main Cohorts:(i) Single Dose 30% HTS(ii) Repeated Dose 30% HTS (> 8 hours apart)

Study designed to assess:(i) Efficacy of 30% HTS(ii) Safety of 30% HTS

Statistical Analysis

•Data are reported as mean ± SD unless otherwise stated.

•Changes in physiological, biochemical and haematological parameters following HTS administration were assessed using one-way repeated measures ANOVA with post-test Bonferroni’s multiple comparison test.

• P<0.05 was considered statistically significant.

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

Noradrenaline(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 < 0.001Data vs. baseline values(i.e. time = 0 min).

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

Noradrenaline(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 < 0.001Data vs. baseline values(i.e. time = 0 min).

HTS - Efficacy - Repeated DoseTime 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

MAP (mmHg) 90.67 ± 8.07 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

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

Noradrenaline(µg/kg/min)

0.287 ± .142 0.271 ± .183 0.234 ± .163 0.250 ± .206 0.26 ± .228 0.267 ± .248 0.275 ± .257 0.296 ± .284 0.283 ± .286 0.9679

* P < 0.05† P < 0.01‡ P < 0.001Data vs. baseline values(i.e. time = 0 min).

HTS - Efficacy - Repeated DoseTime 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

MAP (mmHg) 90.67 ± 8.07 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

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

Noradrenaline(µg/kg/min)

0.287 ± .142 0.271 ± .183 0.234 ± .163 0.250 ± .206 0.26 ± .228 0.267 ± .248 0.275 ± .257 0.296 ± .284 0.283 ± .286 0.9679

* P < 0.05† P < 0.01‡ P < 0.001Data vs. baseline values(i.e. time = 0 min).

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.

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.

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