Introduction:

Pain is the fifth vital sign. Postoperative pain in patients after craniotomy is common during recovery, and its incidence has been reported between 24%¹ and 40%.²Acute postoperative pain in patients after craniotomy often does not get attention and is therefore underdiagnosed and undertreated. Compounding this problem is the traditional belief that neurosurgical pain is inconsequential and even dangerous to treat. Postoperative pain may lead to hypertension, tachycardia, myocardial ischemia, myocardial infarction, and delayed recovery.^3-4In patients with decreased intracranial compliance, increased sympathetic activity will increase cerebral blood flow, cerebral oxygen consumption and intracranial pressure,. Thus, improving postoperative analgesia in patients undergoing craniotomy would be of great benefit.

The ideal analgesic for use in patients following craniotomy should have a good analgesic effect with no deleterious effects on the cardiovascular or respiratory systems. It should not affect the central nervous system, CPP, ICP, conscious level or pupils. It should have a high therapeutic index and should have no active or epileptogenic metabolites. It should be excreted by both the liver and kidney, and not have altered pharmokinetics when severe organ failure is present. It should not alter the clotting cascade or platelet function and should not provoke nausea or vomiting.⁵

Opioids remain the main agent for providing postoperative analgesia. However, the use of opioids is associated with an increased incidence of postoperative complications, such as oversedation, respiratory depression (which may cause raised ICP due to carbon dioxide retention) and postoperative nausea and vomiting (PONV). Recent data suggest that the extensive use of opioids may be associated with hyperalgesia and allodynia.⁶ Opioids have had a limited role in the analgesic management of patients who have undergone major intracranial surgery because of concern that opioids will affect the postoperative neurological examination. Therefore, there is a continuous search for adjuvant therapies to reduce opioid doses and their related adverse effects, in order to improve recovery.

Dexmedetomidine is an alpha 2-adrenergic agonist that provides sedation, anxiolysis and analgesia with much less respiratory depression than other sedatives. Systemic administration of dexmedetomidine has been reported to enhance the analgesic effect of opioids and reduce opioids requirement in the perioperative period. Many RCTs have been conducted on Intravenous dexmedetomidine for pain management but very few are done on neurosurgery patients.^7-8Alpha-2 adrenergic receptors act on the locus ceruleus area, inhibiting nociceptive neurotransmission through the posterior horn of the spinal cord.⁹Alpha-2 adrenergic receptors also act on the presynaptic  membrane, inhibiting the release of norepinephrine, which in turn induces hyperpolarization and inhibits the pain signals to the brain.^10,11 Moreover,  dexmedetomidine promotes the release of acetylcholine from spinal interneurons; the resulting increased synthesis and release of nitric oxide could be involved in the regulation of analgesia.¹²

Lignocaine is a widely available and commonly used local anaesthetic. Lignocaine infusion has been described as having analgesic, anti-hyperalgesic, and anti-inflammatory properties. Systemic effect of lignocaine occurs predominantly in damaged and dysfunctional nerves, where it prevents depolarization of the neuronal membranes. Many studies have demonstrated decrease in systemic inflammatory markers in patients receiving lignocaine perioperatively^13-16 Perioperative intravenous lignocaine infusion has been reported to reduce postoperative pain in patients after abdominal surgery, thoracic and breast surgeries, cardiac surgeries & hip replacement; however, very few studies have examined lignocaine’s effect on acute postoperative pain after neurosurgery.^17-18

Objectives

1.    To determine effect of intraoperative lignocaine or dexmedetomidine infusion on intraoperative hemodynamic, opioid requirement &acute post-operative pain relief in patients undergoing craniotomy.

2.    To compare i.v lignocaine with i.v dexmedetomidine infusion for acute post-operative pain relief in patients undergoing craniotomy.

Hypothesis

Intraoperative infusion of lignocaine or dexmedetomidine would improve postoperative analgesia in patients following elective craniotomy surgery in a randomized controlled trial.

Methods

Study settings

The study will be conducted in the Neurosurgery Operation Theatre & PACU, Institute of Neurosciences, Kolkata. Participants will be recruited from the in-patient department of Institute Of Neurosciences, Kolkata who are posted for undergoing elective craniotomy surgery.

Study design

This study is designed as a randomized, prospective, monocentric, double blind and parallel group clinical trial.

Study duration

The study will be initiated from August 2018. The first patient will be recruited after formal approval from Ethics Committee, I-NK. The study will be continued till December 2018. Within January 2019 the study team will lock the data, analyze and prepare the draft report for this study. 

Intervention

Subjects fulfilling the selection criteria will be randomized to one of the two equal size parallel arms of the study.

•         Group A: (LIGNO) patient will receive i.v bolus infusion of inj. lignocaine (2%) 1.5 mg/kg made in 20 ml saline over 10 min before induction of anesthesia. Intra-operatively continuous IV infusion of lignocaine 1.5 mg/kg in 20ml saline every hour until skin closurewill be administered to the patient.

•         Group B: (DEXMED)patient will receive i.v bolus infusion of inj. dexmedetomidine 1 µg/kg made to 20 ml with normal saline over 10 minutes before induction of anesthesia. Intra-operatively continuous IV infusion of dexmedetomidine 0.4µg/kg in 20 ml saline every hour until skin closure will be administered to the patient.

Blinding

The two groups will receive any one of the drug which will be prepared in 20ml syringe. They will be completely identical from all aspect except the medicine in the syringe. Group A will receive inj lignocaine 1.5mg/kg bolus diluted in 20 ml NS over 10 minutes, followed by an infusion of 1.5mg/kg diluted in 20ml NS every hour. Group B will receive inj dexmedetomidine 1mcg/kg diluted in 20ml NS over 10 min followed by 0.4mcg/kg diluted in 20ml NS every hour. Syringes will be prepared by an anaesthesiologist not involved in the study andwill be labelled as STUDY DRUG (20ml/hr infusion). The drug will not be revealed to the investigators/ study team members except in protocol defined special situations. The observer will not be allowed to know the treatment allocation.

Standard treatment

Both the groups will continue to receive standard preoperative, intraoperative & postoperative anaesthesia care from the Neuroanesthesia team.

On the day before the surgery during the pre-anesthesia consultation patient will be thoroughly evaluated regarding fitness for general anesthesia. Any preoperative medical problems will be noted. All baseline investigations (complete blood count, renal & liver function test, serum electrolytes, chest x ray, ECG, Coagulation profile) and any other relevant investigations, if required, will be checked. Preop diagnosis & surgery planned will be noted. Written valid informed consent will be taken from the patient and the NRS scores will be explained (0 as no pain and 10 as worst imaginable pain) by an anaesthesiologist.

Procedure in the operation room:

Patient will be taken on the operating table after checking the starvation status for 6 hours. Pulse oximeter, ECG and non-invasive BP monitors will be connected. Baseline parameters like heart rate, blood pressure and oxygen saturation will be checked and noted. IV access will be secured. Intra-arterial cannula will be inserted percutaneously into a peripheral artery following local anaesthetic infiltration. Antisialogogue will be administered.

Anaesthesia will be induced using inj fentanyl (2mcg/kg), inj propofol (2mg/kg) slowly. After confirming ventilation muscle relaxant (rocuronium 0.6 mg/kg) will be administered. Patient will be ventilated with 100% O₂ till adequate muscle relaxation is obtained. Laryngoscopy and endotracheal intubation will be performed using a curved blade and endotracheal tube of appropriate size. Correct insertion of the tube will be confirmed by auscultation and Capnography reading of EtCO_2.After tracheal intubation, mechanical ventilation will be performed with a tidal volume of 8 to 10mL/kg, respiratory rate of 12 to 15/minute, inspiration and expirationratioof1:2, fraction of inhaled oxygen of 50%, and flow rate of fresh gas of 1 to 2 L/minute to maintain normocapnia (PaCO₂between 35 and 45 mm Hg).

Anaesthesia will be maintained on o2+air+sevoflurane+ cisatracurium (2mcg/kg/min) infusion. For analgesia all patients will receive inj fentanyl 2mcg/kg before induction, 1mcg/kg to attenuate potent stress responses induced by noxious stimuli at certain time points during surgery, including scalp incision and skull drilling. Inj paracetamol (15mg/kg) will be given before skin closure. Crystalloid infusion and/or colloid infusion will be used as needed to treat intravascular volume depletion. Fluid input and output will be closely monitored. Blood loss will be noted and blood replacement therapy will be given as required.

The vital signs including mean arterial blood pressure (MAP) & heart rate (HR) will be continually monitored and recorded at different intraoperative time (points, including baseline, induction, 1, 2, and 3 hours after administration of lignocaine, skull fixation, skin incision, dura opening, tumor resection, dura suturing, skin suturing, end of surgery, spontaneous breathing recovery, and extubation.

All patients will receive inj. ondensetron (0.1mg/kg) before extubation. At the end of surgery, endotracheal tube will be removed in a fully awake patient with spontaneous, adequate and regular respiratory rhythm capable of maintaining free airway. After extubation, the patients will be transported to the postoperative anesthesia care unit (PACU).

In PACU:

MAP and HR will be recorded at 15minute intervals in the PACU. Patients will be assessed for acute postoperative pain in the PACU at 15-minute intervals using the numeric rating scale (NRS): 0, no pain; 1 to 3, mild pain; 4 to 6, moderate pain; 7 to 10, severe pain. The NRS will be recorded till the patient is shifted out of PACU.

The secondary outcomes will be noted as follows: intraoperative consumption of propofol and fentanyl, first requirement of rescue postoperative analgesic (paracetamol, tramadol), complications including hypertension (systolic blood pressure >20% of baseline value), tachycardia (HR >100 beats/min) and PONV.

Safety reporting

Safety monitoring will be performed continuously throughout the study.

Adverse Events (AE)

‘Adverse Event’ (AE) will be defined as any untoward medical event, occurring during the study, but not necessarily causally related to it. Events with onset prior to start of study will not be considered as adverse events unless there is an increase in severity and/or frequency following institution of the medicine.

Adverse events will include any drug allergy, urtcaria, hypotension, and bradycardia intra-operatively.

Common side effects of lignocaine include:

• nausea,
• dizziness,
• numbness in places where the medicine is accidentally applied, or
• bruising, redness, itching, or swelling where the medication was injected.

Unlikely but serious side effects of lignocaine include:

• drowsiness,
• mental/mood changes,
• ringing in the ears,
• dizziness,
• vision changes,
• tremors,
• numbness,
• headache, or
• backache.

Common side effects of dexmeditomidine include:

• low or high blood pressure (hypotension or hypertension),
• slow heart rate (bradycardia),
• nausea,
• dry mouth,
• irregular heartbeat,
• fever,
• vomiting,
• low blood plasma,
• fluid buildup between lungs and chest,
• agitation,
• anemia,
• fast heart rate,
• chills,
• high blood sugar (hyperglycemia),
• low blood oxygen,
• extremely elevated body temperature (hyperthermia),
• complete or partial collapse of a lung,
• post-procedure bleeding,
• low blood calcium,
• decreased urination,
• wheezing,
• swelling of the extremities,
• acid accumulation in the body,
• fluid in the lungs.

For each individual AE the nature of the event, duration, maximum intensity, any action taken on trial medication, possible relation to study drug and finally subject outcome will be noted in the CRF.

Serious Adverse Event (SAE)

Serious Adverse Event (SAE) will be defined as an AE that was:

• Fatal
• Life threatening
• Caused persistent or significant disability or incapacity
• Causes or prolongs hospitalization
• Causes cancer
• Causes congenital anomaly
• Is an  event that is not immediately life threatening but can jeopardize health of the subject or require intervention to prevent any of the above outcomes

In the event of any SAE, details of the events will be to be noted separately and the same will be communicated to the Institutional Ethics Committee and Hospital authority at the earliest (within 24 hrs). Subsequent arrangements will be made for adequate treatment of the subjects concerned in consultation with the Ethics Committee and the hospital authorities.

Withdrawal criteria

Under the following circumstances subjects will be withdrawn from study

·         Voluntary withdrawal of informed consent

·         In the event of an AE/SAE which prevents further participation in the study, as per the discretion of the investigator

·         In the event of protocol violation----

o   Patients enrolled into study in spite of having exclusion criteria or other protocol violations

o   Use of non-permitted concomitant medications

·         Unplanned postoperative mechanical ventilation

·         Any other situation which in the opinion of the investigator was not conductive of further continuation in the study

In case of premature withdrawal the reason for withdrawal will be documented.

Statistical analysis 

The demographic, disease related variables will be presented with standard frequency for categorical and with mean (Standard Deviation)/ Median (interquartile range) for numerical variables. Standard statistical test for significance will be used to assess the difference between/ among groups. The data will be analyzed using student t test for continuous parametric variables, Mann-Whitney U test for continuous nonparametric variables and chi square test for nominal variables. A p value of < 0.05 will be taken as significant.

PROPOSED & EXPECTED OUTCOME OF PROJECT

1 .Improvement in patient care           = Yes

2 .Attainment of more knowledge        = Yes

3 .Bridging the lacunae in the knowledge = Yes

References

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