<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03773276</url>
  </required_header>
  <id_info>
    <org_study_id>R.18.11.323 - 2018/11/05</org_study_id>
    <nct_id>NCT03773276</nct_id>
  </id_info>
  <brief_title>Norepinephrine Boluses in Liver Transplantation</brief_title>
  <official_title>Norepinephrine Boluses for Prevention of Postreperfusion Syndrome in Living Donor Liver Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mansoura University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mansoura University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      We study the efficacy of Norepinephrine boluses on prevention of postreperfusion syndrome&#xD;
      during living donor liver transplantation.&#xD;
&#xD;
      NE and Post-reperfusion:&#xD;
&#xD;
      On portal vein declamping, we will start rapid 500 ml 4% albumin infusion or packed RBCs&#xD;
      (according to the anhepatic hemoglobin level 5 min before declamping) through 14 Gauge&#xD;
      peripheral venous cannula in all patients.&#xD;
&#xD;
      NE boluses technique; We will inject NE boluses in the C.V.P port of the pulmonary artery&#xD;
      catheter with 5 ml saline flushing after each. After reperfusion, we will start bolus&#xD;
      noradrenaline 20 µg if mean arterial blood pressure (mABP) decreases by 10 % or more of the&#xD;
      basal reading (immediately before portal vein declamping after ensuring withholding of the&#xD;
      surgical manipulation). Additional NE boluses will be given as follow;&#xD;
&#xD;
        -  If mABP rises to 65 mmHg (lowest target level), we will hold NE boluses.&#xD;
&#xD;
        -  If mABP remains constant or begins to rise but did not reach 65 mmHg, we will give 20 µg&#xD;
           after 10 seconds from the previous bolus&#xD;
&#xD;
        -  If mABP continues to drop, we will add 10 µg to the previous dose after 10 seconds and&#xD;
           can be repeated.&#xD;
&#xD;
        -  If mABP remains below 65 mmHg more than 1 minute, we will give the scheduled bolus NE&#xD;
           with adding 10 µg adrenaline boluses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Anesthesia technique:&#xD;
&#xD;
      On admission to the pre-anesthetic room, patients will receive intravenous pantoprazole&#xD;
      sodium 40 mg, midazolam 0.02 mg/kg and the prophylactic antibiotics.&#xD;
&#xD;
      In the operating room, we apply standard monitors in the form of pulse oximetry, non-invasive&#xD;
      blood pressure, and electrocardiography. Induction of anesthesia will be fentanyl 2 µg/kg,&#xD;
      propofol 1-2 mg/kg, and rocuronium bromide 0.8 -1 mg/kg.&#xD;
&#xD;
      After tracheal intubation, we will insert an arterial catheter in the radial artery of the&#xD;
      non-dominant hand after performing modified Allen's test. Then, we will insert five port&#xD;
      pulmonary artery catheter for continuous cardiac output monitoring (the equipment).&#xD;
&#xD;
      Anesthesia will be maintained by sevoflurane in 40% oxygen with infusion of fentanyl 0.5-1&#xD;
      µg/kg/h and rocuronium bromide 200-400 µg /kg/h. We adopt goal directed fluid replacement&#xD;
      protocol keeping the target mABP of 65 mmHg using norepinephrine in fluid non-responders with&#xD;
      low SVR (German medical association 2009). Crystalloids will be Ringer's Acetate and the&#xD;
      colloid will be albumin 4% in Ringer Acetate solution.&#xD;
&#xD;
      We will keep the intraoperative and the two-day postoperative glucose between 110 and 180&#xD;
      mg/dl by intravenous insulin infusion or glucose 10% or 25% boluses as appropriate. We&#xD;
      monitor UO hourly in the intraoperative and ICU periods and only administer frusemide to&#xD;
      prevent volume overload.&#xD;
&#xD;
      Surgical technique:&#xD;
&#xD;
      The donor surgical team will excise the right liver lobe (without inclusion of the middle&#xD;
      hepatic vein). They will flush the graft with 3-4 liters of cold&#xD;
      histidine-tryptophan-ketoglutarate (HTK) (Custodial, Bensheim, Germany) via antegrade&#xD;
      flushing of the portal vein to get completely clear fluid without flushing via the hepatic&#xD;
      artery. Both recipient and donor operations will be synchronized to minimize graft&#xD;
      preservation time.&#xD;
&#xD;
      The right hepatic vein will be unclamped then the portal vein and the graft preservative&#xD;
      contents will be washed into the systemic circulation by the portal blood.&#xD;
&#xD;
      NE and Post-reperfusion:&#xD;
&#xD;
      On portal vein declamping, we will start rapid 500 ml 4% albumin infusion or packed RBCs&#xD;
      (according to the anhepatic hemoglobin level 5 min before declamping) through 14 Gauge&#xD;
      peripheral venous cannula in all patients.&#xD;
&#xD;
      NE boluses technique; We will inject NE boluses in the C.V.P port of the pulmonary artery&#xD;
      catheter with 5 ml saline flushing after each. After reperfusion, we will start bolus&#xD;
      noradrenaline 20 µg if mean arterial blood pressure (mABP) decreases by 10 % or more of the&#xD;
      basal reading (immediately before portal vein declamping after ensuring withholding of the&#xD;
      surgical manipulation). Additional NE boluses will be given as follow;&#xD;
&#xD;
        -  If mABP rises to 65 mmHg (lowest target level), we will hold NE boluses.&#xD;
&#xD;
        -  If mABP remains constant or begins to rise but did not reach 65 mmHg, we will give 20 µg&#xD;
           after 10 seconds from the previous bolus&#xD;
&#xD;
        -  If mABP continues to drop, we will add 10 µg to the previous dose after 10 seconds and&#xD;
           can be repeated.&#xD;
&#xD;
        -  If mABP remains below 65 mmHg more than 1 minute, we will give the scheduled bolus NE&#xD;
           with adding 20 µg adrenaline boluses.&#xD;
&#xD;
      Immunosuppression:&#xD;
&#xD;
      All patients will receive intravenous 0.5 gm methylprednisolone at the start of the warm&#xD;
      ischemia. After hepatic artery anastomosis and declamping, we will administer 500 mg&#xD;
      mycophenolate mofetil through the nasogastric tube and i.v. 20 mg basiliximab.&#xD;
&#xD;
      In the ICU, patients will receive oral tacrolimus starting the day after the operation&#xD;
      (adjusting the dose targeting serum level of 5-10 ng/ml) and mycophenolate mofetil 500 mg 4&#xD;
      days after.&#xD;
&#xD;
      In the ICU:&#xD;
&#xD;
      We adopt early ICU tracheal extubation once the patient is hemodynamically stable and pH &gt;&#xD;
      7.3 with adequate consciousness and muscle power (guided by neuromuscular monitoring).&#xD;
&#xD;
      We will keep the pulmonary artery catheter in place for hemodynamic monitoring in case of&#xD;
      instability and will exchange it by central venous catheter after 48 hours postoperatively.&#xD;
&#xD;
      Data collection and Monitoring:&#xD;
&#xD;
      1- Preoperative data:&#xD;
&#xD;
        1. Age, sex, weight, height, BSA, MELD score and Child-Pugh classification&#xD;
&#xD;
        2. Medical co-morbidities: hypertension, cardiac diseases, Diabetes Mellitus&#xD;
&#xD;
        3. Cause of the end stage liver disease (ESLD), and the donor age and gender&#xD;
&#xD;
        4. Liver tests: serum albumin, bilirubin, INR, AST, ALT&#xD;
&#xD;
        5. S.Cr&#xD;
&#xD;
        6. C-reactive protein We will collect the preoperative data 24 hours before the operation.&#xD;
&#xD;
      2- Intra-operative and Post-operative data: The primary outcome will be the incidence of PRS.&#xD;
      We will record the lowest mABP, the duration of hypotension (below 20% from the basal value&#xD;
      or below 65 mmHg). We will record significant arrhythmias, ischemia (ST depression more than&#xD;
      1mV in lead II) during reperfusion and NE boluses. We will report the need and duration of&#xD;
      pre-reperfusion and post-reperfusion NE infusions.&#xD;
&#xD;
      We will record the intraoperative CI, SVI, mABP, mPAP, PAOP, SVR, PVR, and serum Na, K,&#xD;
      ionized Ca and Cl at six times;&#xD;
&#xD;
        -  immediately before skin incision,&#xD;
&#xD;
        -  at the beginning of the anhepatic (portal vein clamping),&#xD;
&#xD;
        -  5 minutes before portal reperfusion,&#xD;
&#xD;
        -  5 min after portal unclamping,&#xD;
&#xD;
        -  5 min after hepatic arterial declamping and&#xD;
&#xD;
        -  at the time of skin closure. The incidence of the AKI defined as 50% increase in the&#xD;
           S.Cr or 0.3 mg/dl increase from the baseline S.Cr in the early 48 post¬operative hours.&#xD;
           In the postoperative period, S.Cr will be measured at arrival to ICU, 1st, 2nd, 7th,&#xD;
           28th and at three-month postoperative with measuring of the 24 hour-urine output in the&#xD;
           first 2 days.&#xD;
&#xD;
      We will stage AKI as follow: stage 1 when S.Cr = 1.5-1.9 times baseline or &gt; 0.3 mg/dl&#xD;
      increase from the baseline, stage 2 when S.Cr = 2-2.9 times baseline and stage 3 when S.Cr =&#xD;
      3 times baseline or increase to &gt; 4 mg/dl or initiation of renal replacement therapy.&#xD;
&#xD;
      We will record warm ischemia, cold ischemia, the total ischemia and the operative times. We&#xD;
      will mention the blood transfusions (before and after reperfusion), UO in the anhepatic phase&#xD;
      and the total intraoperative amounts.&#xD;
&#xD;
      Laboratory assessment of the graft function will include pH, serum lactate, INR, AST, ALT,&#xD;
      GGT, albumin and bilirubin at the 1st, 2nd and 7th days postoperatively. We will report early&#xD;
      postoperative surgical complications (7 days) especially vascular insufficiency of the graft&#xD;
      detected by the ultrasound Doppler evaluation.&#xD;
&#xD;
      In case of persistent graft dysfunction, graft rejection and ischemia- reperfusion injury&#xD;
      will be diagnosed and graded by histopathological examination of liver biopsy performed by&#xD;
      consultant liver pathologist.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 17, 2018</start_date>
  <completion_date type="Actual">August 28, 2020</completion_date>
  <primary_completion_date type="Actual">April 18, 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>This is a feasibility (efficacy and safety) trial that tests the Norepinephrine boluses for the prevention of postreperfusion syndrome during liver transplantation operation.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of postreperfusion syndrome</measure>
    <time_frame>5 minutes after reperfusion</time_frame>
    <description>PRS defined as 30% drop in the mABP when compared to the mABP just before portal declamping sustained for 1 min within the first 5 min after portal unclamping</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Arrhythmia</measure>
    <time_frame>During and 5 minutes after norepinephrine boluses</time_frame>
    <description>if significant and persistent (or needed treatment or intervention)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ischemia</measure>
    <time_frame>During and 5 minutes after norepinephrine boluses</time_frame>
    <description>ST depression more than 1mV in lead II</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Liver graft function</measure>
    <time_frame>After 2 days postoperative</time_frame>
    <description>By pH, serum lactate mmol/l, INR, AST u/ml, ALT u/ml, albumin gm/dl and bilirubin ml/dl as a composite outcome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute kidney injury</measure>
    <time_frame>within the first 2 days postoperative</time_frame>
    <description>50% increase in the S.Cr or 0.3 mg/dl increase from the baseline S.Cr in the early 48 post¬operative hours</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month survival</measure>
    <time_frame>90 days after surgery</time_frame>
    <description>survival within 3 months after liver transplantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>one-year survival</measure>
    <time_frame>one year after transplantation</time_frame>
    <description>survival for one year post-transplantation as a dichotomous outcome</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Living Donor Liver Transplantation</condition>
  <condition>Norepinephrine Bolus</condition>
  <condition>Postperfusion Syndrome</condition>
  <arm_group>
    <arm_group_label>Norepinephrine boluses</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single arm study</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Norepinephrine boluses</intervention_name>
    <description>On portal vein declamping, We will inject NE boluses in the C.V.P port of the pulmonary artery catheter with 5 ml saline flushing after each. After reperfusion, we will start bolus noradrenaline 20 µg if mean arterial blood pressure (mABP) decreases by 10 % or more of the basal reading (immediately before portal vein declamping after ensuring withholding of the surgical manipulation). Additional NE boluses will be given as follow;&#xD;
If mABP rises to 65 mmHg (lowest target level), we will hold NE boluses.&#xD;
If mABP remains constant or begins to rise but did not reach 65 mmHg, we will give 20 µg after 10 seconds from the previous bolus&#xD;
If mABP continues to drop, we will add 10 µg to the previous dose after 10 seconds and can be repeated.&#xD;
If mABP remains below 65 mmHg more than 1 minute, we will give the scheduled bolus NE with adding 10 µg adrenaline boluses.</description>
    <arm_group_label>Norepinephrine boluses</arm_group_label>
    <other_name>Noradrenaline boluses</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All patients subjected to living donor liver transplantation with right lobe liver&#xD;
             graft.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Acute fulminant hepatitis&#xD;
&#xD;
          2. Chronic hypertension&#xD;
&#xD;
          3. Moderate to severe valvular heart disease&#xD;
&#xD;
          4. Chronic kidney disease (CKD) and Hepatorenal syndrome (HRS)&#xD;
&#xD;
          5. Preoperative S.Cr elevation &gt; 1.4 mg/kg or dialysis recently before surgery&#xD;
&#xD;
          6. Long standing diabetes mellitus (&gt; 10 years on insulin)&#xD;
&#xD;
          7. Moderate and sever Porto-pulmonary hypertension&#xD;
&#xD;
          8. Moderate and sever Hepato-pulmonary syndrome (HPS)&#xD;
&#xD;
          9. Contraindications to pulmonary artery catheter insertion&#xD;
&#xD;
         10. Budd Chiari syndrome&#xD;
&#xD;
         11. Re-transplantation&#xD;
&#xD;
         12. Massive blood transfusion (more than 5 units of blood before portal clamping)&#xD;
&#xD;
         13. Graft/weight ratio &gt; 1.4 and &lt; 0.8&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Amr M Yassen, Professor</last_name>
    <role>Study Director</role>
    <affiliation>Mansoura University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mansoura University, Gastrointestinal Surgery Center, Liver Transplantation</name>
      <address>
        <city>Mansoura</city>
        <state>Dakahlia</state>
        <zip>35516</zip>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 9, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 12, 2018</study_first_posted>
  <last_update_submitted>December 20, 2022</last_update_submitted>
  <last_update_submitted_qc>December 20, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Norepinephrine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>We will make anonymized individual data available to researchers at appropriate requests. We may make them available as a supplement along with the published manuscript if the journal supports this option.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03773276
org study id: R.18.11.323 - 2018/11/05
nct id: NCT03773276
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
We study the efficacy of Norepinephrine boluses on prevention of postreperfusion syndrome
      during living donor liver transplantation.

      NE and Post-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.

      NE boluses technique; We will inject NE boluses in the C.V.P port of the pulmonary artery
      catheter with 5 ml saline flushing after each. After reperfusion, we will start bolus
      noradrenaline 20 µg if mean arterial blood pressure (mABP) decreases by 10 % or more of the
      basal reading (immediately before portal vein declamping after ensuring withholding of the
      surgical manipulation). Additional NE boluses will be given as follow;

        -  If mABP rises to 65 mmHg (lowest target level), we will hold NE boluses.

        -  If mABP remains constant or begins to rise but did not reach 65 mmHg, we will give 20 µg
           after 10 seconds from the previous bolus

        -  If mABP continues to drop, we will add 10 µg to the previous dose after 10 seconds and
           can be repeated.

        -  If mABP remains below 65 mmHg more than 1 minute, we will give the scheduled bolus NE
           with adding 10 µg adrenaline boluses.
Anesthesia technique:

      On admission to the pre-anesthetic room, patients will receive intravenous pantoprazole
      sodium 40 mg, midazolam 0.02 mg/kg and the prophylactic antibiotics.

      In the operating room, we apply standard monitors in the form of pulse oximetry, non-invasive
      blood pressure, and electrocardiography. Induction of anesthesia will be fentanyl 2 µg/kg,
      propofol 1-2 mg/kg, and rocuronium bromide 0.8 -1 mg/kg.

      After tracheal intubation, we will insert an arterial catheter in the radial artery of the
      non-dominant hand after performing modified Allen's test. Then, we will insert five port
      pulmonary artery catheter for continuous cardiac output monitoring (the equipment).

      Anesthesia will be maintained by sevoflurane in 40% oxygen with infusion of fentanyl 0.5-1
      µg/kg/h and rocuronium bromide 200-400 µg /kg/h. We adopt goal directed fluid replacement
      protocol keeping the target mABP of 65 mmHg using norepinephrine in fluid non-responders with
      low SVR (German medical association 2009). Crystalloids will be Ringer's Acetate and the
      colloid will be albumin 4% in Ringer Acetate solution.

      We will keep the intraoperative and the two-day postoperative glucose between 110 and 180
      mg/dl by intravenous insulin infusion or glucose 10% or 25% boluses as appropriate. We
      monitor UO hourly in the intraoperative and ICU periods and only administer frusemide to
      prevent volume overload.

      Surgical technique:

      The donor surgical team will excise the right liver lobe (without inclusion of the middle
      hepatic vein). They will flush the graft with 3-4 liters of cold
      histidine-tryptophan-ketoglutarate (HTK) (Custodial, Bensheim, Germany) via antegrade
      flushing of the portal vein to get completely clear fluid without flushing via the hepatic
      artery. Both recipient and donor operations will be synchronized to minimize graft
      preservation time.

      The right hepatic vein will be unclamped then the portal vein and the graft preservative
      contents will be washed into the systemic circulation by the portal blood.

      NE and Post-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.

      NE boluses technique; We will inject NE boluses in the C.V.P port of the pulmonary artery
      catheter with 5 ml saline flushing after each. After reperfusion, we will start bolus
      noradrenaline 20 µg if mean arterial blood pressure (mABP) decreases by 10 % or more of the
      basal reading (immediately before portal vein declamping after ensuring withholding of the
      surgical manipulation). Additional NE boluses will be given as follow;

        -  If mABP rises to 65 mmHg (lowest target level), we will hold NE boluses.

        -  If mABP remains constant or begins to rise but did not reach 65 mmHg, we will give 20 µg
           after 10 seconds from the previous bolus

        -  If mABP continues to drop, we will add 10 µg to the previous dose after 10 seconds and
           can be repeated.

        -  If mABP remains below 65 mmHg more than 1 minute, we will give the scheduled bolus NE
           with adding 20 µg adrenaline boluses.

      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) and mycophenolate mofetil 500 mg 4
      days after.

      In the ICU:

      We adopt early ICU tracheal extubation once the patient is hemodynamically stable and pH >
      7.3 with adequate consciousness and muscle power (guided by neuromuscular monitoring).

      We will keep the pulmonary artery catheter in place for hemodynamic monitoring in case of
      instability and will exchange it by central venous catheter after 48 hours postoperatively.

      Data collection and Monitoring:

      1- Preoperative data:

        1. Age, sex, weight, height, BSA, MELD score and Child-Pugh classification

        2. Medical co-morbidities: hypertension, cardiac diseases, Diabetes Mellitus

        3. Cause of the end stage liver disease (ESLD), and the donor age and gender

        4. Liver tests: serum albumin, bilirubin, INR, AST, ALT

        5. S.Cr

        6. C-reactive protein We will collect the preoperative data 24 hours before the operation.

      2- Intra-operative and Post-operative data: The primary outcome will be the incidence of PRS.
      We will record the lowest mABP, the duration of hypotension (below 20% from the basal value
      or below 65 mmHg). We will record significant arrhythmias, ischemia (ST depression more than
      1mV in lead II) during reperfusion and NE boluses. We will report the need and duration of
      pre-reperfusion and post-reperfusion NE infusions.

      We will record the intraoperative CI, SVI, mABP, mPAP, PAOP, SVR, PVR, and serum Na, K,
      ionized Ca and Cl at six times;

        -  immediately before skin incision,

        -  at the beginning of the anhepatic (portal vein clamping),

        -  5 minutes before portal reperfusion,

        -  5 min after portal unclamping,

        -  5 min after hepatic arterial declamping and

        -  at the time of skin closure. The incidence of the AKI defined as 50% increase in the
           S.Cr or 0.3 mg/dl increase from the baseline S.Cr in the early 48 post¬operative hours.
           In the postoperative period, S.Cr will be measured at arrival to ICU, 1st, 2nd, 7th,
           28th and at three-month postoperative with measuring of the 24 hour-urine output in the
           first 2 days.

      We will stage AKI as follow: stage 1 when S.Cr = 1.5-1.9 times baseline or > 0.3 mg/dl
      increase from the baseline, stage 2 when S.Cr = 2-2.9 times baseline and stage 3 when S.Cr =
      3 times baseline or increase to > 4 mg/dl or initiation of renal replacement therapy.

      We will record warm ischemia, cold ischemia, the total ischemia and the operative times. We
      will mention the blood transfusions (before and after reperfusion), UO in the anhepatic phase
      and the total intraoperative amounts.

      Laboratory assessment of the graft function will include pH, serum lactate, INR, AST, ALT,
      GGT, albumin and bilirubin at the 1st, 2nd and 7th days postoperatively. We will report early
      postoperative surgical complications (7 days) especially vascular insufficiency of the graft
      detected by the ultrasound Doppler evaluation.

      In case of persistent graft dysfunction, graft rejection and ischemia- reperfusion injury
      will be diagnosed and graded by histopathological examination of liver biopsy performed by
      consultant liver pathologist.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is a feasibility (efficacy and safety) trial that tests the Norepinephrine boluses for the prevention of postreperfusion syndrome during liver transplantation operation.
primary purpose: Prevention
masking: None (Open Label)
measure: Incidence of postreperfusion syndrome
time frame: 5 minutes after reperfusion
description: PRS defined as 30% drop in the mABP when compared to the mABP just before portal declamping sustained for 1 min within the first 5 min after portal unclamping
measure: Arrhythmia
time frame: During and 5 minutes after norepinephrine boluses
description: if significant and persistent (or needed treatment or intervention)
measure: Ischemia
time frame: During and 5 minutes after norepinephrine boluses
description: ST depression more than 1mV in lead II
measure: Liver graft function
time frame: After 2 days postoperative
description: By pH, serum lactate mmol/l, INR, AST u/ml, ALT u/ml, albumin gm/dl and bilirubin ml/dl as a composite outcome
measure: Acute kidney injury
time frame: within the first 2 days postoperative
description: 50% increase in the S.Cr or 0.3 mg/dl increase from the baseline S.Cr in the early 48 post¬operative hours
measure: 3-month survival
time frame: 90 days after surgery
description: survival within 3 months after liver transplantation
measure: one-year survival
time frame: one year after transplantation
description: survival for one year post-transplantation as a dichotomous outcome
arm group label: Norepinephrine boluses
arm group type: Experimental
description: Single arm study
intervention type: Drug
intervention name: Norepinephrine boluses
description: On portal vein declamping, We will inject NE boluses in the C.V.P port of the pulmonary artery catheter with 5 ml saline flushing after each. After reperfusion, we will start bolus noradrenaline 20 µg if mean arterial blood pressure (mABP) decreases by 10 % or more of the basal reading (immediately before portal vein declamping after ensuring withholding of the surgical manipulation). Additional NE boluses will be given as follow;
If mABP rises to 65 mmHg (lowest target level), we will hold NE boluses.
If mABP remains constant or begins to rise but did not reach 65 mmHg, we will give 20 µg after 10 seconds from the previous bolus
If mABP continues to drop, we will add 10 µg to the previous dose after 10 seconds and can be repeated.
If mABP remains below 65 mmHg more than 1 minute, we will give the scheduled bolus NE with adding 10 µg adrenaline boluses.
arm group label: Norepinephrine boluses
other name: Noradrenaline boluses
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Amr M Yassen, Professor
role: Study Director
affiliation: Mansoura University
facility: 
country: Egypt
responsible party type: Sponsor
mesh term: Syndrome
mesh term: Norepinephrine
sharing ipd: Yes
ipd description: We will make anonymized individual data available to researchers at appropriate requests. We may make them available as a supplement along with the published manuscript if the journal supports this option.