Patil 2019.

Methods	Design: parallel, 3‐armed RCT (single site) Setting: ICU in a department of neurosurgery at a teaching hospital in Indore, Madhya Pradesh, India Recruitment period: 2015‐2017 Maximum follow‐up: 1‐h observation period following the treatment goal of reduction of ICP below 15 mmHg (after a single bolus)
Participants	A total of 120 participants with isolated severe TBI due to road traffic accidents were recruited. Inclusion criteria: "After assessing the Glasgow Coma Scale (GCS), computed tomography of the head was performed to rule out the need for immediate surgery. Patients were included if they were aged 18 years, GCS 8, and had sustained elevated ICP of >20 mm Hg for more than 5 minutes" Exclusion criteria: "... imminent cranial or extracranial surgery Previous decompressive craniectomy Leakage or drainage of cerebrospinal fluid Polytrauma Oliguria, renal failure Hemoglobin <8 g/L Serum osmolality of >320 mOsm/L. The use of mannitol or HTS in the previous 6 hours." (Patil 2019 p e222) Baseline demographics Age: mean was given as 38.42 (+/‐15.5 years). The range was 18‐75 years. Gender: (F/M); not reported Severity: mean GCS at baseline reported as 6 (range 3‐8) in the HTS group; 5 (range 3‐7) in the MTL group and 5 (range 3‐6) in the combined MTL and glycerol group, BP also reported N randomized: 120 (HTS = 40; MTL = 40; MTL plus glycerol 40) N for whom ICP data analysed: not stated, but data presumed to be complete (assessments gathered across 1 h): 120 (HTS = 40; MTL = 40; MTL plus glycerol 40)
Interventions	At first‐ "Analgesia was provided to all the patients and if required sedation also provided in irritable patients (dexmedetomidine). Vasoactive support (norepinephrine) was administered in hypotensive patients. Insulin treatment was administered to maintain glycemia at <140 mg/dL. For each patient, a set of variables was collected that included demographic characteristics data, initial GCS, and timing of studied treatment. The ICP was continuously monitored by using an intracranial bolt..." When ICP exceeded 20 mm Hg for a period of > 5 min, interventions comprised a single bolus dose of one of the following: Intervention: HTS 3% (n = 40); mean dose of 1.4 mL/kg (range 0.5‐3.3); mean dose mL application 94 (range 38‐234) or Comparator 1: MTL 20% (n =40); mean dose of 2.0 mL/kg (range 0.5‐6.3); mean dose mL application 137 (range 40‐422) Comparator 2: MTL 10% plus 10% glycerol combination (n =40); mean dose of 1.7 mL/kg (range 1.6‐4); mean dose mL application 118 (range 44‐302) All treatments were "infused via the central venous line at a defined infusion rate, that is, 6 mL/minute or 120 drops/minute (osmolarity of mannitol, mannitol plus glycerol combination, and 3% HTS are almost the same, ie, 1100 mOsm/L, 1049 mOsmo/L, and 1027 mOsm/L, respectively). The infusion was stopped when ICP was reduced to <15 mm Hg, which was our treatment goal" (Patil 2019, e222).
Outcomes	ICP (goal of treatment was a reduction to ICP of < 15mm Hg). ICP was measured by the intracranial bolt. Heart rate, MAP, ICP, and calculated CPP were continuously measured up to termination of infusion. These were also measured 10 minutes after terminating infusion 30 minutes after terminating infusion 60 minutes after terminating infusion. Serum sodium level, hematocrit, serum osmolality were measured before and after treatment GCS was measured before and after the trial (at 60 min following infusion termination) The lack of data collection on adverse events is mentioned as a trial limitation.
Notes	This trial is not reported according to CONSORT/PRISMA. There is no flowchart; scant description of methods. Baseline data including lesion type, gender, are unreported. All data are reported in ranges (minimum‐maximum). Mortality is not specifically reported although GCS (after a single bolus dose) is reported. The paper states that recruitment took place 2015‐2017, but submission of the present paper was apparently made in 2016.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "All the patients were divided into 3 groups (40 in each group) using the sealed envelope method of physical randomization" (Patil 2019, p e223) Appears adequate although phrasing unusual
Allocation concealment (selection bias)	Low risk	Quote: "All the patients were divided into 3 groups (40 in each group) using the sealed envelope method of physical randomization" (.Patil 2019, p e223) Appears adequate although phrasing unusual
Blinding of participants and personnel (performance bias) participants	Low risk	Participants had severe brain injury with sustained elevated ICP of > 20 mmHg and therefore had reduced cognitive function and would be unaware of treatment status.
Blinding of participants and personnel (performance bias) Treating physicians	High risk	Agents were of different substances (or at different doses). Trial authors do not report any blinding of those administering or collecting data.
Blinding of outcome assessment (detection bias) All outcomes	High risk	We have some concerns about the lack of information on assessment of GCS, which was assessed alongside hematocrit, ICP, etc., to a maximum of 1 h, during a period of nearly constant assessment. It is not stated who undertook this, and as stated above it is unlikely staff were unaware of intervention.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete outcome data were reported (the post‐intervention data collection period lasted 60 min)
Selective reporting (reporting bias)	Unclear risk	Trial authors mention ethics approval, but not trial registration. Although most expected outcomes are present, in the absence of a published protocol or prospective trial registration, assessment of selective outcome reporting must remain as 'unclear'
Other bias	Unclear risk	Trial authors comment that they did not assess any complications associated with the placement of the subdural bolt used for measuring ICP.

BP: blood pressure; CBF: cerebral blood flow; CPP: cerebral perfusion pressure; CSF: cerebrospinal fluid; CT: computerised tomography scan; EVD: external ventricular drain(age); GCS: Glasgow Coma Scale; GOS: Glasgow Outcome Scale; HES: hydroxyethyl starch; HTS: hypertonic saline; ICP: intracranial pressure; ICU: intensive care unit; IV: intravenous; MAP/MABP: mean arterial [blood] pressure; MTL: mannitol; RCT: randomised controlled trial; SD: standard deviation; SpO2: peripheral capillary oxygen saturation; TBI: traumatic brain injury