ONSD and Neurotoxicity in Liver Transplant
Condition: Liver Transplant; Complications
MeSH terms: Neurotoxicity Syndromes
Study type: Observational

Summary: 
      This is a diagnostic test accuracy study. The investigators measure optic nerve sheath
      diameter (ONSD) by ultrasound on the eye during living donor liver transplantation operation
      at 5 minutes after reperfusion to predict the occurrence of early tacrolimus neurotoxicity
      after liver transplantation.

      We measured the ONSD at 4 timings: (T1) Post induction and before surgical incision, (T2)
      Portal vein clamping, (T3) 5 minutes after reperfusion, and (T4) 30 min after reperfusion.
    

Detailed description: 
      Neurotoxicity is mainly associated with tacrolimus and cyclosporin, amounting to 10 - 30% for
      CS and up to 32% for tacrolimus.(2) . Sirolimus, everolimus, and mycophenolate mofetil lack
      the neurotoxicity of calcineurin inhibitors (3-4).

      Neurotoxicity mostly occurs in the early postoperative period increasing morbidity, mortality
      and hospital and intensive care stay. Neurotoxicity has variable manifestations and mainly
      affects the CNS. They are usually divided into minor manifestations as tremor, headache,
      insomnia and paraesthesia or major encephalopathy, akinetic mutism, seizures, speech
      disorders, polyneuropathy, myopathy, pseudobulbar palsy and even stroke. (2) The main
      pathogenesis of calcinurin inhibitors neurotoxicity appears to be ﬂuid extravasation
      (vasogenic edema) due to disruption of blood brain barrier, not cell destruction (cytotoxic
      edema).(5) During liver transplant operation there are changes in the intracranial pressure
      and cerebral perfusion pressure especially during reperfusion that may affect the integrity
      of blood brain barrier. (6) There are multiple methods for monitoring of intracranial
      pressure invasive or non -invasive. The invasive method remains the gold standard for
      monitoring of intracranial pressure but there is a controversy about its use in liver
      transplantation as it may be complicated by bleeding and infections (7).

      Also there are a multiple non-invasive methods for monitoring of ICP. Ultrasonographic
      measurement of the optic nerve sheath diameter (ONSD) was introduced recently as a useful
      noninvasive method for evaluating ICP. ONSD demonstrated a good correlation with the ICP
      level in many previously published studies. (8,9) Rajajee et al. found that the optimal
      cutoff of ONSD for the detection of an acutely increased ICP > 20 mm Hg was greater than 4.8
      mm. (10) We hypothesize that the absolute value or the changes of ONSD during different
      stages of living donor liver transplantation operation may predict occurrence of early
      calcinurin inhibitor neurotoxicity (CNIN).We will investigate whether the absolute value or
      changes of ONSD during different stages of living donor liver transplantation operation may
      be a predictor of early calcinurin inhibitor neurotoxicity in the first month post liver
      transplantation. This is a prospective observational cohort study that will be conducted to
      all adult patients of both sex undergoing living donor liver transplantation operation at
      Gastro-Intestinal Surgical Centre (GISC), Mansoura university Hospitals, Mansoura, Egypt over
      the period covering more than 100 consecutive cases. After Institutional review board
      approval, we will secure informed consents from all included patients during the preoperative
      visits.

      Anesthesia and surgery techniques will be done according to our center's protocol.(11)

      Reperfusion:

      On portal vein declamping, we will start rapid 500 ml 4% albumin infusion or packed RBCs
      (according to the anhepatic hemoglobin level 5 min before declamping) through 14 Gauge
      peripheral venous cannula in all patients.

      For hypotension we will give norepinephrine and for resistant hypotension we will use
      adrenaline as rescue.

      Technique of ONSD:

      Sonographic measurement of ONSD was performed with the same manner of previous studies.
      Patients were placed in the supine position with their eyes closed, and a thick gel layer was
      applied to the closed upper eyelid. The 7.5-MHz linear probe was placed on the gel without
      excessive pressure and adjusted to the proper angle for displaying the entry of the optic
      nerve into the globe. The intensity of the ultrasound was adjusted to display optimal
      contrast between the retrobulbar echogenic fat tissue and the vertical hypoechoic band. An
      ultrasound beam was focused on the retrobulbar area using the lowest possible acoustic power
      that could measure ONSD. The ONSD was measured 3 mm behind the optic disc. Measurements were
      performed in the transverse and sagittal planes of both eyes, and the ﬁnal ONSD value was
      calculated by averaging 4 measured values. (8)

      Immunosuppression:

      All patients will receive intravenous 0.5 gm methylprednisolone at the start of the warm
      ischemia. After hepatic artery anastomosis and declamping, we will administer 500 mg
      mycophenolate mofetil through the nasogastric tube and i.v. 20 mg basiliximab.

      In the ICU, patients will receive oral tacrolimus starting the day after the operation
      (adjusting the dose targeting serum level of 5-10 ng/ml) , mycophenolate mofetil 500 mg twice
      per day and basiliximab 20 mg iv 4 days after.
    

Intervention name(s): Optic nerve sheath diameter by ultrasound at 5 minutes post-reperfucion
Intervention type(s): Diagnostic Test
Intervention description(s): Patients were placed in the supine position with their eyes closed, and a thick gel layer was applied to the closed upper eyelid. The 7.5-MHz linear probe was placed on the gel without excessive pressure and adjusted to the proper angle for displaying the entry of the optic nerve into the globe. The intensity of the ultrasound was adjusted to display optimal contrast between the retrobulbar echogenic fat tissue and the vertical hypoechoic band. An ultrasound beam was focused on the retrobulbar area using the lowest possible acoustic power that could measure ONSD. The ONSD was measured 3 mm behind the optic disc. Measurements were performed in the transverse and sagittal planes of both eyes, and the ﬁnal ONSD value was calculated by average 4 measured values.
We measured the ONSD at 4 timings: (T1) Post induction and before surgical incision, (T2) Portal vein clamping, (T3) 5 minutes after reperfusion, and (T4) 30 min after reperfusion.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Adult (>= 18 years) recipients undergoing living donor liver transplantation