Supplemental Perioperative Intravenous Crystalloids for Postoperative Nausea and Vomiting in Children Undergoing Oncological Surgery
Condition: Nausea and Vomiting, Postoperative
MeSH terms: Nausea; Vomiting; Postoperative Nausea and Vomiting
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Postoperative nausea and vomiting (PONV) is a common complication in the paediatric
      population and is a source of significant morbidity. The incidence of PONV in children is
      alarmingly high, as it is estimated to be between 33.2% to 82% depending on patient risk
      factors. Even with the administration of prophylactic antiemetic medications, the risk of
      PONV can still be approximately 30%. Various independent risk factors have been implicated in
      the development of paediatric PONV. The following risk factors were identified: a duration of
      surgery 30 minutes or longer, age 3 years or older, strabismus, adenoidectomy, and
      tonsillectomy surgeries, a history of PONV in the child or immediate relatives (parents or
      siblings), use of volatile anaesthetic, use of opioids, increased postoperative pain,
      prolonged preoperative fast, and state of dehydration Significant improvement in patient
      satisfaction can be achieved if the incidence of PONV is decreased. Although not usually
      life-threatening, PONV may lead to complications commonly associated with vomiting, including
      dehydration, electrolyte imbalance, and aspiration of gastric contents. In some surgical
      cases, PONV has also led to wound complications, oesophageal rupture, subcutaneous emphysema,
      pneumomediastinum, and bilateral pneumothorax. PONV typically describes nausea, vomiting, or
      retching that can occur starting in the post-anaesthesia care unit (PACU) and continuing
      through the 24 hours following surgery. PONV occurs twice as often in children than in adults
      and can lead to longer PACU stays, delays in hospital discharge and subsequent unplanned
      readmissions, which ultimately lead to significant financial burden on the patients.

      A variety of antiemetic regimens are recommended for the prevention and treatment of PONV in
      children, including pharmacotherapy with dexamethasone, 5HT-3 receptor antagonists,
      butyrophenones, prokinetics, anticholinergics and antihistamines.

      Hydration is yet another important factor in the development of PONV in paediatric patients.
      Administration of intravenous dextrose-containing solutions may also prevent PONV.
      Investigation of the effect of perioperative intravenous crystalloid administration on PONV
      was initially motivated by the results of observational studies suggesting that perioperative
      volume status influenced postoperative complication rates. This work showed that PONV was
      among the most prevalent events after surgery and motivated subsequent inquiry into the
      relationship between perioperative volume resuscitation and PONV .

      Multiple reviews have explained the complex physiology of nausea and vomiting. Briefly, the
      vomiting centre, located in the lateral reticular formation of the medulla, co-ordinates
      efferent activity to the respiratory, gastrointestinal, and abdominal musculature to produce
      vomiting. This centre receives afferent stimuli from a variety of sites: the pharynx,
      gastrointestinal tract chemo- and stretch receptors, the brain (including vestibular
      information from cranial nerve VIII), aortic baroreceptors, and the chemoreceptor trigger
      zone. The chemoreceptor trigger zone is a neural centre physiologically outside of the
      blood-brain barrier, which provides afferent information to the vomiting centre in response
      to noxious stimuli in the blood.

      Patients particularly paediatrics typically present for surgery with a fluid deficit
      secondary to fasting, bleeding, bowel preparation, and other causes of dehydration. It has
      been proposed that brainstem, vestibular, and intestinal hypoperfusion, with concomitant
      ischaemia, may mediate nausea and vomiting. Supplemental intravenous crystalloids could serve
      to mitigate this effect; however, no proven explanation for the putative role of volume
      status in this model exists. Hypovolemia has been associated with a rise in postoperative
      morbidity and mortality ranging from PONV to other complications such as organ dysfunction .
      Hypovolemia from overnight fasting without adequate fluid replacement can cause adverse
      effects postoperatively . Intravenous crystalloids are widely administered before, during,
      and after procedures requiring general anaesthesia. They are inexpensive and have relatively
      few adverse effects. A prior systematic review has suggested that supplemental intravenous
      crystalloids may be effective in preventing PONV . However, studies of supplemental
      perioperative intravenous crystalloids were noted to vary widely on the specific volumes
      administered.

      Despite evidence-based, multimodal prophylactic regimens, PONV remains a prevalent clinical
      problem . The use of pharmacologic agents alone reduces the risk of PONV but increases the
      risk of side effects. Intravenous crystalloids are an attractive treatment modality. Many
      different intravenous fluid interventions have been tested in a wide variety of surgical and
      anaesthetic contexts.
    

Detailed description: 
      The aim of this study is to test the hypothesis that intraoperative supplemental intravenous
      crystalloid fluid administration will reduce the incidence of postoperative nausea and
      vomiting in paediatric patients undergoing oncological surgical procedures under general
      anaesthesia.

      Outcomes:

      Primary outcomes:

      We will analyse the risk of PONV occurring at different postoperative time points
      postoperatively (i.e., early, late). The early postoperative period will be defined as the
      period within six hours after surgery, while the late postoperative period will be defined as
      the time nearest to 24 hours after surgery. PON was defined as an unpleasant sensation
      associated with the urge to vomit. POV was defined as an attempted expulsion of gastric
      contents (vomiting or retching). PONV was defined as any nausea, vomiting, or both.

      Secondary outcomes:

        1. Risk of requiring antiemetic rescue medication during the postoperative period.
           Antiemetic rescue medication was defined as any additional intervention provided for the
           treatment of established PON, POV, or PON.

        2. Risk of suffering a serious adverse event (any of: admission to high-dependency unit,
           postoperative cardiac or respiratory complication, or death).

        3. To comprehensively determine the predictors of PONV as the dependant variable with age,
           gender, weight, operative time, treatment group, pain, fever, and preoperative
           chemotherapy as independent variables.

      Patients and methods

      This double-blind, prospective randomized controlled trial will be conducted in Borg Al-Arab
      Children's Cancer Centre, Alexandria University Hospitals in Borg Al-Arab, Alexandria, Egypt.
      After obtaining ethical committee approval and informed consent, we will study 100 patients,
      aged 3-13 years, with a diagnosis of malignancy, undergoing surgery. Parents will be given
      the option to give their children clear fluids up to 4 hours prior their arrival to the
      operating room. Screened participants will be excluded if:

        1. They personally had a history of PONV or motion sickness;

        2. A sibling or parent or both, had a history of PONV.

        3. They received antiemetic medication in the 24 hours preceding surgery.

        4. Their BMI exceeded 30 kg/m2.

        5. They had a history of cardiovascular or renal disease.

        6. Developmental delay or mental retardation, or both.

        7. They significant intraoperative blood loss (> 30% blood volume loss).

        8. They had a history of cardiorespiratory disease.

        9. They had a history of renal or hepatic diseases.

      Patients will be prospectively and randomly assigned to one of the four groups (25 in each
      group). Random sequence generation and allocation concealment will be done using
      Computer-generated randomization. Supplemental crystalloid administration started after
      induction of anaesthesia (intraoperatively), in addition to standard fluid management.
      Patients will be divided into 4 groups:

        1. Group A: intraoperative infusion of 15 mL/kg/hour Ringer's lactate.

        2. Group B: intraoperative infusion of 10 mL/kg/hour Ringer's lactate.

        3. Group C: intraoperative infusion of 6 mL/kg/hour Ringer's lactate.

        4. Group D: standard fluid management alone.

      Perioperative management:

      All children will be given midazolam at 0.5 mg/kg orally for sedation 30 min in preoperative
      holding area. Anaesthesia will induced with sevoflurane in oxygen. After induction a
      peripheral IV cannula will be inserted for intravenous access; none of the patients will
      receive any prophylactic antiemetic drugs. Anaesthesia will be maintained with endotracheal
      tube (ETT), and controlled ventilation using atracurium, sevoflurane, and oxygen. Anaesthesia
      will be supplemented with fentanyl 1 µg/kg during induction and a suitable regional analgesia
      technique for surgery. Monitoring will include electrocardiogram, blood pressure, endtidal
      CO2, temperature and pulse oximetry. The ETT Will be removed at the conclusion of surgery
      under a deep plane of anaesthesia.

      Postoperative care will be standardized. Rescue antiemetics will be administered to patients
      if they were severely nauseated or vomited on more than one occasion using ondansetron 1-2 mg
      i.v., analgesia will be given to children complaining of pain using a pain scale monitoring
      for toddlers and young children. This will be consisted of oral analgesia (paracetamol).
      Perioperatively, the study investigators and postanesthesia care unit (PACU) nurses will be
      blinded to the allocation of the groups and the amount of fluid the subjects received.
    

Intervention name(s): Ringer's Lactate; Ringer's Lactate; Ringer's Lactate; normal Saline
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): infusion of 15 mL/kg/hour Ringer's lactate intraoperative; infusion of 10 mL/kg/hour Ringer's lactate intraoperative .; infusion of 6 mL/kg/hour Ringer's lactate intraoperative .; standard fluid management: 4 ml for 1st 10 kg, 2 ml for the next 10 kg , 1 ml rest of body weight
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be prospectively and randomly assigned to one of the four groups (25 in each group). Random sequence generation and allocation concealment will be done using Computer-generated randomization. Supplemental crystalloid administration started after induction of anaesthesia (intraoperatively), in addition to standard fluid management. Patients will be divided into 4 groups:
Group A: intraoperative infusion of 15 mL/kg/hour Ringer's lactate.
Group B: intraoperative infusion of 10 mL/kg/hour Ringer's lactate.
Group C: intraoperative infusion of 6 mL/kg/hour Ringer's lactate.
Group D: standard fluid management alone.
Masking: Single (Participant)
Primary purpose: Prevention
Keywords: Postoperative nausea and vomiting, oncological surgery