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 - Journal club. JAMA. 2021;325(20):2056-2066. doi:10.1001/jama.2021.5561

1. BY: KHALED GHANAYIM
DEPARTMENT OF INTERNAL MEDICINE G’, AFULA HAEMEK

2. OVERVIEW
• Epidemiology
• Pathophysiology
• Study design
• Results
• Limitations
• Discussion
• Take home message

3. EPIDEMIOLOGY
• Each year 19 million people suffer from traumatic brain injury (TBI)
• Mortality rates have decreased over the years
• However almost 8 million lives are affected with incomplete recovery
• Almost one third of patients with TBI die in hospital
• Another third suffer severe neurological damage

4. PATHOPHYSIOLOGY
• Traumatic brain injury (TBI) causes accumulation of fluid in the skull (edema)
• Vasogenic edema being the most prominent
• Results are increased intra cranial pressure (ICP) -> reduced cerebral perfusion pressure
(CCP)
• Hypertonic solutions theorized mechanism of action:
• Rheological effect – reducing blood viscosity thus causing plasma expansion in turn increasing
oxygen delivery. In response, cerebral vasoconstriction occurs due to autoregulation, and cerebral
blood volume is decreased
• Osmotic gradient through BBB
• Osmotic diuretic causing free water loss and increased blood osmolarity -> dehydrating effect

5. METHODS
• Multicenter
• Parallel group
• Open-label
• Randomized clinical trial
• Blinded adjudication
• Conducted in 9 different ICUs in France
• Consent from first of kin as soon as possible
• If regained consciousness, consent was taken from patient up to 6 months after trial

6. METHODS - DESIGN
Inclusion Exclusion
• Age: 18-80
• Moderate to sever TBI
- GCS 12 or lower
- Abnormal CT findings
(extradural hematoma, subdural
hematoma, subarachnoid hemorrhage,
brain contusion, brain hematoma, brain
edema, or skull fracture)
• Pregnancy
• Dependance in ADL prior to admission
• Cervical spinal cord injury
• Imminent death or fixed dilated pupils
• Score of 3 on the GCS
• Fluid retention (ascites or pulmonary edema)

7. TBI SEVERITY CLASSIFICATION

9. METHODS - PROTOCOL
• After randomization 1-hour bolus infusion was injected
• Continuous infusion afterwards (0.5-1 g/h of NaCl)
• Serum Na was monitored every 8 hours
• Infusion continued for a minimum of 48 hours
• After intervention cessation, Na levels were monitored for 48 hours
• During monitoring, a 1-hour bolus infusion (5 g) was injected if:
o Na levels < 140 mmol/L
o Levels decreased more than 12 mmol/L per day

10. OUTCOMES
Primary:
Extended Glasgow Outcome Scale (GOS-E) score at 6 months after the trauma event
Secondary:
o Mortality at 6 months
o GOS-E score at 3 months
o Duration of posttraumatic amnesia evaluated
at ICU discharge, 3 and 6 months
o Autonomy in ADL at 3 and 6 months (Katz
Index)
o Quality of life survey at 3 and 6 months
o Place of residence at 3 and 6 months
o Na levels and blood osmolarity every 8 hours
and daily
o Intracranial pressure every 8 hours if available

11. GOS-E SCORE
1:
Patient
deceased
2:
vegetative
state:
inability to
obey
commands or
speak
3:
lower end of
severe
disability:
dependence
on others
for care
4:
upper end of
severe
disability:
partial
independence
at home
5:
lower end of
moderate
disability:
inability
to work
6:
upper end of
moderate
disability:
reduced work
capacity
7:
lower end of
good recovery:
ability to
resume
previous
activities with
some injury-
related
problems
8:
upper end of
good
recovery:
absence of
trauma-
related
problems

12. RESULTS

13. RESULTS - POPULATION
• 370 patients randomized
• 11 people did not complete the follow-up
• Mean days of continuous infusion – 2.7 (SD 1.3) days
• Median age: 46 and 43 in intervention and control groups respectively.
• Males compromised 78.8% of intervention and 80% of control groups
• No difference in other characteristics: TBI degree, GCS, Pupillary response, Marshall CT
classification or interventions prior to randomization.

14. RESULTS – PRIMARY ENDPOINT
No significant difference in the 6-month GOS-E score distribution

15. RESULTS – SECONDARY OUTCOMES

16. RESULTS – ADVERSE EVENTS

17. RESULTS – ADVERSE EVENTS

18. RESULTS – ADVERSE EVENTS

19. RESULTS – ADVERSE EVENTS

20. RESULTS – ADVERSE EVENTS

21. RESULTS – ADVERSE EVENTS

22. DISCUSSION
• Continuous infusion of 20% saline did not improve primary outcome at 6 months
• No significant change in secondary outcomes including mortality
• Adverse events numerically higher in intervention, but not significant
• Intervention yielded lower ICH for the first 2 days, but showed a rebound effect 4 days onward
• Lower incidence of adverse events may be due to dose adjustment prior

23. LIMITATIONS
• Many patients (almost half) received bolus of hypertonic solution prior to randomization
• Inclusion of moderate TBI with severe TBI may have hindered the power of the study
• Not double blinded
• Therapeutic intensity not measured
• Small study population
• Prevention approach rather than curative

24. TAKE HOME MESSAGE
• Continuous infusion of 20% HTS did not yield better neurological results at 6 months
• No significant difference in secondary outcomes
• Adverse events were similar
• Further studies are required and a better pathophysiological understanding

25. THANK YOU FOR LISTENING!