All patients will undergo plain CT-scan of the brain to screen for the presence and
severity of cerebral edema in the emergency before being shifted to the L-ICU. In the L-
ICU, patients will be managed by a multidisciplinary team. Intubation and ventilation
will be undertaken for standard indications in addition to the development of grade 3
encephalopathy or evidence of cerebral edema on CT-scan. Ventilation will be managed by
fentanyl and propofol along with the use of atracurium for paralysis wherever required.
All patients will be monitored constantly for macro-hemodynamics, global tissue
perfusion, and microcirculation. The macro-hemodynamic parameters included continuous
monitoring of mean arterial pressure (MAP), heart rate and urine output per hour. The
real-time monitoring of systemic vascular resistance (SVR), stroke volume variation
(SVV), cardiac index (CI) and cardiac output (CO) will be done by a hemodynamic monitor
(FloTrac™ system 4.0, Edwards Lifesciences, California, US) wherever feasible. Global
tissue perfusion adequacy and indirect assessment of microcirculation will be done by
measurement of arterial lactate. Fluid management will be done with crystalloids, with
the use of colloids (5% albumin) in patients with severe hypoalbuminemia (serum albumin
less than 2.5gm/dl). Norepinephrine will be the primary vasopressor used to target a mean
arterial pressure of 65-70 mm of Hg. with adjunctive use of intravenous low dose
hydrocortisone and vasopressin in patients not responsive to initial therapy.
Cerebral edema: The monitoring of cerebral edema will be performed measuring the optic
nerve sheath diameter (ONSD) in both the eyes using a 7.5 MHz probe every 6-8 hours.
Apart from this, routine monitoring of pupillary size and reactions, extensor posturing
and plantar reflexes will be performed every 6-8 hrs. Transcranial doppler would be done
every 6-8 hours. Patients will receive 3% hypertonic saline as a continuous infusion,
initially started at 25ml /hr and titrated 6 hourly to between 5 and 20 mL per hour
(maximum 100 ml/hour) to achieve serum sodium levels between 145-150 mmol/L. Intravenous
20% mannitol (1 g/kg IV bolus) over 20 to 30 minutes will be administered to those
without renal failure. All patients will in addition receive intravenous N-acetylcysteine
for 5 day.Routine electroencephalogram (EEG) will be done for all patients daily to
screen for non-convulsive seizures which will be managed by intravenous levetiracetam.
Assessment of coagulation will be performed by ROTEM at baseline and subsequently as
required.
Protocol for therapeutic plasma-exchange TPE procedures will be performed using either
Spectra Optia (SPO, Terumo BCT, Lakewood, CO, USA) continuous-flow centrifugal apheresis
system or Haemonetics MCS+ (Braintree, MA, USA) intermittent flow centrifugal apheresis
system via a double-lumen central venous dialysis catheter. All patients will receive
plasma-exchange within first 12 hours of admission to the L-ICU along with a target
volume of based on the randomization group per session. The replacement fluid used will
be 90% FFP and 10% normal saline. TPE will be performed on consecutive days until the
desired response is achieved. [using our previously published protocol].
The number of sessions of TPE in each patient will be decided based on the clinical
response to SVPE. Dynamic assessment of the clinical parameters (signs of CE as assessed
by pupillary size, reaction, and optic nerve-sheath diameter), INR, lactate and arterial
ammonia will be performed at after each TPE. In patients with an improvement in INR, and
signs of CE along with a reduction in ammonia at 6 hours which was sustained at 12 and 24
hours post-TPE, subsequent sessions will be discontinued. TPE will also be discontinued
in patients who would show worsening in either clinical and/ or biochemical parameters.
In patients who will develop adverse events, the TPE procedure will be resumed or
discontinued depending on the severity of adverse event and its resolution. CRRT would be
initiated in patients who develop worsening or ammonia or cerebral edema or metabolic
complications and time to initiation of CRRT would be recorded in both groups. The time
to initiation of CRRT would be recorded in both groups after randomization.
Continuous renal replacement therapy will be administered as continuous venovenous
hemodiafiltration (CVVHDF) using Prisma and Prismaflex (Gambro) devices, with blood flows
ranging from 150-180 mL/hr and target effluent rates of 20 - 25 mL/kg/hr. Anticoagulation
was not used during dialysis. CRRT would be continued until resolution of cerebral edema
and in decrease in ammonia levels below 150 ug/dl or in those who develop adverse effects
of therapy.
Randomization will be done by taking 1:1 ratio by computer-generated sealed envelopes by
the clinical trial co-ordinator.
Intervention group : High Volume PLsma Exchange (HVPE)+ Standard Medical Treatment (SMT)
The high-volume strategy would be performed by centrifugation technique ~ 8-9 litres of
plasma would be exchanged in each patient over 6-8 hours.
Active Comparator - The Standard volume Plasma Exchange + Standard medical Treatment The
Standard volume strategy group Therapeutic Plasma Exchange would be performed varying
from 1.5- 2.5 times the plasma - volume.
