What does the evidence say about the effect of continuous infusion of hypertonic saline versus standard care on 6-Month neurological outcomes in patients with traumatic brain injury?

Comment by InpharmD Researcher

Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care, as determined by the Brain Trauma Foundation, did not result in a significantly better neurological status at 6 months.

Background

According to the Brain Trauma Foundation Guidelines on Traumatic Brain Injury (TBI) management, while hyperosmolar therapy may lower intracranial pressure, there is insufficient evidence about effects on clinical outcomes to support a specific recommendation, or to support use of any specific hyperosmolar agent, for patients with severe traumatic brain injury. [1]

References:

1. Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017 Jan 1;80(1):6-15. doi: 10.1227/NEU.0000000000001432. PMID: 27654000.
Relevant Prescribing Information

Hypertonic saline refers to to any saline solution with a concentration of sodium chloride (NaCl) higher than physiologic (0.9%). Commonly used preparations include 2%, 3%, 5%, 7%, and 23% NaCl.

Hypertonic saline is indicated as an off-label use for treating intracranial pressure due to traumatic brain injury. It is indicated for refractory intracranial hypertension due to various etiologies such as, subarachnoid hemorrhage, trauma, and neoplasm.

The optimal dose has not been established; due to insufficient evidence, the Brain Trauma Foundation guidelines do not make specific recommendations on the use of hypertonic saline for the treatment of traumatic intracranial hypertension. Hypertonic saline 23.4% bolus infusions may be administered to treat acute intracranial pressure (ICP) elevations.

Hypertonic saline is contraindicated in patients who have hypersensitivity to sodium chloride or any component of the formulation; hypertonic uterus, hypernatremia, fluid retention.

Warnings and precautions associated with hypertonic saline include extravasation, hemolysis, hyponatremia, and sodium toxicity. Hypertonic saline should be used cautiously in patients with cirrhosis, edema, heart failure, hypertension, and renal impairment.

The injection should be stored at room temperature, and protected from heat. It should not be frozen. It should only be used in clear solutions. [1]

References:

1. Sodium Chloride. Lexi-Drugs. Hudson, OH: Lexicomp, 2015. http://online.lexi.com/. Updated June 24, 2021. Accessed June 24, 2021.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What does the evidence say about the effect of continuous infusion of hypertonic saline versus standard care on 6-Month neurological outcomes in patients with traumatic brain injury?

Please see Table 1 for your response.

 

Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury

The COBI Trial

Design

Investigator-initiated, multicenter, parallel-group, open-label, randomized clinical trial with blinded adjudication of the primary outcome

(conducted in France)

Objective

To determine whether continuous infusion of hypertonic saline solution improves neurological outcome at 6 months in patients with traumatic brain injury.

Study Groups

Continuous infusion of 20% hypertonic saline solution plus standard care (n= 185)

Standard care alone (n= 185)

Inclusion Criteria

Patients aged 18 to 80 years, admitted to the intensive care unit (ICU) with moderate to severe traumatic brain injury (TBI) with traumatic abnormal brain computed tomography findings

Exclusion Criteria

Pregnancy, dependence on daily activity before trauma, cervical spinal cord injury, imminent death or fixed dilated pupils with a score of 3 on the Glasgow Coma Scale, and fluid retention

Methods

Traumatic brain injury was defined as the association of a Glasgow Coma Scale score of 12 or lower (considering the worst score before sedation during the first 24 hours).

Patients were randomized in a 1:1 ratio to receive 20% hypertonic saline solution plus standard care or standard care alone.

Within 24 hours of trauma, a 1-hour bolus infusion was injected into patients in the intervention group. Continuous infusion of 20% hypertonic saline solution was administered at a dose of 0.5-1 g/h of NaCl, and continued for a minimum of 48 hours as long as the patient was considered at risk of intracranial hypertension.

Sodium levels were monitored every eight hours for dose adjustments and hypernatremia was defined as Na+>155 mmol/L.

The Brain Trauma Foundation guidelines were used for standard treatment. Isotonic crystalloid solutions were used as maintenance fluids and first-line resuscitation fluids in case of low blood pressure. Other treatments included hyperosmolar therapy (200-250 mOsm of mannitol or hypertonic saline), cerebrospinal fluid drainage, ventilation therapy, or depressive craniectomy. Continuous hyperosmolar therapy was allowed in the control group as rescue therapy for intracranial hypertension refractory to other therapies

Duration

Randomization: November 2017 to February 2020

Follow-up: 6 months

Outcome Measures

The primary outcome was Extended Glasgow Outcome Scale (GOS-E) score (range, 1-8, with lower scores indicating worse functional outcome) at six months.

Secondary outcomes included good neurological outcomes, posttraumatic amnesia outcomes, Short-Form 36 (SF-36) scores, independence, and return home monitored at three months and six months.

Good neurological outcomes were defined as upper moderate disability to upper good recovery (Extended Glasgow Outcome Scale score of 6-8).

 

Baseline characteristics

 

Characteristics

Intervention (n= 185)

Control (n= 185)

Age, median (IQR), y

46 (27-60)

43 (27-59)

Sex, No./total (%):

Male

145/184 (78.8)

148/183 (90.9)

Female

39/184 (21.2)

35/183 (19.1)

Severe TBI (GCS score <  8), No./total (%)

134/184 (72.8)

131/183 (71.6)

GCS score, median (IQR)

7 (4-9)

7 (4-9)

Motor response < 5, No./total (%)

168/184 (91.3)

164/184 (89.6)

Pupillary response, No./total (%)

Both reacting

130/184 (70.7)

123/182 (67.6)

One reacting

42/184 (22.8)

47/182 (25.8)

None reacting

12/184 (6.5)

12/182 (6.6)

Hypotension, No./total (%)c

30/184 (16.3)

27/182 (14.8)

Hypoxia, No./total (%)c

29/184 (15.8)

26/182 (14.3)

Hemoglobin level < 9.0 g/L before randomization, No./total (%)

14/184 (7.6)

15/182 (8.2)

Received bolus of hyperosmolar therapy prior to randomization, No./total (%)

103/184 (56)

101/182 (55.2)

Neurosurgery prior to randomization, No./total (%)

59/184 (32.1)

40/182 (22.0)

Intracranial pressure lobe at randomization, No./total (%)

122/184 (66.3)

128/181 (70.7)

Intracranial pressure probe during ICU stay, No./total (%)

153/184 (83.2)

163/181 (89.1)

Time from trauma event to randomization, median (IQR), h

13 (8-18)

12 (7-18)

Results

 

Primary outcome:

The adjusted common odds ratio for the GOS-E score at 6 months was 1.02 (95% CI, 0.71-1.47; P = .92)

 

Secondary outcomes:

Outcomes

Intervention (n= 185)

Control (n= 185)

Absolute difference (95% CI)

Good neurological outcomes, No./total (%)

At 3 mo

62/175 (35.4)

53/176 (30.1)

5.21 (-4.49 to 15.12)

At 6 mo

59/181 (32.6)

63/178 (35.4)­

-2.80 (-12.59 to 7.00)

Patients alive without posttraumatic amnesia, No./total (%)

At ICU discharge

32/179 (17.9)

24/179 (13.4)

4.47 (-3.04 to 11.98)

At 3 mo

56/121 (46.3)

51/130 (39.2)

7.05 (-5.17 to 19.27)

At 6 mo

78/139 (56.1)

66/142 (46.5)

9.64 (-2.00 to 21.27)

SF-36 Physical composite score, mean (SD)

At 3 mo

39.7 (10.3)

38.7 (10.3)

1.16 (-1.80 to 4.11)

At 6 mo

43.7 (10.5)

43.0 (11.1)

1.12 (-1.89 to 4.11)

SF-36 Mental composite score, mean (SD)

At 3 mo

39.8 (12.3)

41.2 (11.0)

-1.41 (-4.73 to 1.90)

At 6 mo

41.6 (11.4)

43.1 (10.7)

-1.67 (-4.80 to 1.46)

Independence, No./total (%)

At 3 mo

112/175 (64.0)

110/174 (63.2)

0.78 (-9.31 to 10.88)

At 6 mo

132/180 (72.8)

118/176 (67.1)

5.73 (-3.78 to 15.25)

Return home, No./total (%)

At 3 mo

83/179 (46.4)

76/180 (42.2)

4.15 (-6.12 to 14.41)

At 6 mo

106/181 (58.6)

103/178 (57.9)

0.70 (-9.51 to 10.90)

 

Safety

 

Adverse events

No. (%)

 

Intervention (n= 185)

Control (n= 185)

Adverse effects

120 (64.9)

113 (61.1)

Severe adverse effects

50 (27)

46 (24.9)

Central pontine myelinolysis

1 (0.5)

1 (0.5)

Metabolic tolerance:

Severe hypernatremia (> 160 mmol/L)

23 (12.4)

11 (6)

Hyponatremia (<135 mmol/L)

4 (2.2)

3 (1.6)

Hypokalemia (<3 mmol/L)

0

0

Acute Kidney Injury (KDIGO stage > 2)

4 (2.2)

8 (4.4)

Deep vein thrombosis or pulmonary embolism

11 (6)

4 (2.2)

Hospital-acquired pneumonia

83 (44.9)

75 (40.5)

Study Author Conclusions

Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurological status at 6 months.

InpharmDTM Researcher

Critique

Comparing the two treatments could lead to ethical concern, as it may be considered unethcial to withold hyperosmolar therapy in these patients. 

Additionally, while the study was multi-centered and randomized, blinding was not performed, thus accounting for a potential for bias.

Furthermore, as this trial was conducted in France, there may be differences in applicability of treatment in the U.S. 

 

 

 

References:

Roquilly A, Moyer JD, Huet O, Lasocki S, Cohen B, Dahyot-Fizelier C, Chalard K, Seguin P, Jeantrelle C, Vermeersch V, Gaillard T, Cinotti R, Demeure Dit Latte D, Mahe PJ, Vourc'h M, Martin FP, Chopin A, Lerebourg C, Flet L, Chiffoleau A, Feuillet F, Asehnoune K; Atlanrea Study Group and the Société Française d’Anesthésie Réanimation (SFAR) Research Network. Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury: The COBI Randomized Clinical Trial. JAMA. 2021 May 25;325(20):2056-2066. doi: 10.1001/jama.2021.5561. PMID: 34032829; PMCID: PMC8150692.