intravenous infusion of Lignocaine vs. dexmedetomidine given intraoperatively for reducing Acute Postoperative Pain After elective craniotomy Surgery

Completed

• Conditions: Other intraoperative and postprocedural complications and disorders of nervous system,

• Registration Number: CTRI/2018/09/015598
• Lead Sponsor: institute of neurosciences

Brief Summary

Introduction:Painis the fifth vital sign. Postoperative pain in patients after craniotomy iscommon during recovery, and its incidence has been reported between 24%1and 40%.2Acute postoperative pain in patients after craniotomy oftendoes not get attention and is therefore underdiagnosed and undertreated.Compounding this problem is the traditional belief that neurosurgical pain isinconsequential and even dangerous to treat. Postoperative pain may lead tohypertension, tachycardia, myocardial ischemia, myocardial infarction, anddelayed recovery.3-4In patients with decreased intracranialcompliance, increased sympathetic activity will increase cerebral blood flow,cerebral oxygen consumption and intracranial pressure,. Thus, improvingpostoperative analgesia in patients undergoing craniotomy would be of greatbeneï¬t.

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

Opioidsremain the main agent for providing postoperative analgesia. However, the useof opioids is associated with an increased incidence of postoperativecomplications, such as oversedation, respiratory depression (which may causeraised ICP due to carbon dioxide retention) and postoperative nausea andvomiting (PONV). Recent data suggest that the extensive use of opioids may beassociated with hyperalgesia and allodynia.6 Opioids have had alimited role in the analgesic management of patients who have undergone majorintracranial surgery because of concern that opioids will affect thepostoperative neurological examination. Therefore, there is a continuous searchfor adjuvant therapies to reduce opioid doses and their related adverseeffects, in order to improve recovery.

Dexmedetomidineis an alpha 2-adrenergic agonist that provides sedation, anxiolysis and analgesiawith much less respiratory depression than other sedatives. Systemicadministration of dexmedetomidine has been reported to enhance the analgesiceffect of opioids and reduce opioids requirement in the perioperative period.Many RCTs have been conducted on Intravenous dexmedetomidine for painmanagement but very few are done on neurosurgery patients.7-8Alpha-2adrenergic receptors act on the locus ceruleus area, inhibiting nociceptiveneurotransmission through the posterior horn of the spinal cord.9Alpha-2adrenergic receptors also act on the presynaptic  membrane, inhibiting the release ofnorepinephrine, which in turn induces hyperpolarization and inhibits the painsignals to the brain.10,11 Moreover, dexmedetomidine promotes the release of acetylcholine from spinalinterneurons; the resulting increased synthesis and release of nitric oxidecould be involved in the regulation of analgesia.12

Lignocaineis a widely available and commonly used local anaesthetic. Lignocaine infusionhas been described as having analgesic, anti-hyperalgesic, andanti-inflammatory properties. Systemic effect of lignocaine occurspredominantly in damaged and dysfunctional nerves, where it preventsdepolarization of the neuronal membranes. Many studies have demonstrated decreasein systemic inflammatory markers in patients receiving lignocaineperioperatively13-16 Perioperative intravenous lignocaine infusionhas 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 acutepostoperative pain after neurosurgery.17-18

Objectives1.    Todetermine effect of intraoperative lignocaine or dexmedetomidine infusion onintraoperative hemodynamic, opioid requirement &acute post-operative painrelief in patients undergoing craniotomy.

2.   To compare i.v lignocainewith i.v dexmedetomidine infusion for acute post-operative pain relief inpatients undergoing craniotomy.

 **Hypothesis**

Intraoperative infusion of lignocaine ordexmedetomidine would improve postoperative analgesia in patients followingelective craniotomy surgery in a randomized controlled trial.

Methods

Study settings The study will be conductedin the Neurosurgery Operation Theatre & PACU, Institute of Neurosciences,Kolkata. Participants will be recruitedfrom the in-patient department of Institute Of Neurosciences, Kolkata who areposted for undergoing elective craniotomy surgery.

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

**Studyduration** The study will be initiated from August 2018. The firstpatient will be recruited after formal approval from Ethics Committee, I-NK.The study will be continued till December 2018. Within January 2019 the studyteam will lock the data, analyze and prepare the draft report for thisstudy.

InterventionSubjects fulfilling the selection criteria will berandomized 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 madein 20 ml saline over 10 min before induction of anesthesia. Intra-operativelycontinuous IV infusion of lignocaine 1.5 mg/kg in 20ml saline every hour untilskin closurewill be administered to the patient.

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

BlindingThe two groups will receive any one of the drug whichwill be prepared in 20ml syringe. They will be completely identical from allaspect except the medicine in the syringe. Group A will receive inj lignocaine1.5mg/kg bolus diluted in 20 ml NS over 10 minutes, followed by an infusion of1.5mg/kg diluted in 20ml NS every hour. Group B will receive injdexmedetomidine 1mcg/kg diluted in 20ml NS over 10 min followed by 0.4mcg/kgdiluted in 20ml NS every hour. Syringes will be prepared by ananaesthesiologist not involved in the study andwill be labelled as STUDY DRUG(20ml/hr infusion). The drug will not be revealed to the investigators/ studyteam members except in protocol defined special situations. The observer willnot be allowed to know the treatment allocation.

Standard treatmentBoth the groups willcontinue to receive standard preoperative, intraoperative & postoperativeanaesthesia care from the Neuroanesthesia team.

On the day before thesurgery during the pre-anesthesia consultation patient will be thoroughlyevaluated regarding fitness for general anesthesia. Any preoperative medicalproblems 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, willbe checked. Preop diagnosis & surgery planned will be noted. Written validinformed consent will be taken from the patient and the NRS scores will beexplained (0 as no pain and 10 as worst imaginable pain) by ananaesthesiologist.

**Procedurein the operation room:**

Patient will be taken on theoperating table after checking the starvation status for 6 hours. Pulseoximeter, ECG and non-invasive BP monitors will be connected. Baselineparameters like heart rate, blood pressure and oxygen saturation will bechecked and noted. IV access will be secured. Intra-arterial cannula will beinserted percutaneously into a peripheral artery following local anaestheticinï¬ltration. Antisialogogue will be administered.

Anaesthesia will be inducedusing inj fentanyl (2mcg/kg), inj propofol (2mg/kg) slowly. After confirmingventilation muscle relaxant (rocuronium 0.6 mg/kg) will be administered.Patient will be ventilated with 100% O2 till adequate musclerelaxation is obtained. Laryngoscopy and endotracheal intubation will beperformed using a curved blade and endotracheal tube of appropriate size.Correct insertion of the tube will be confirmed by auscultation and Capnographyreading of EtCO2.After tracheal intubation, mechanical ventilationwill be performed with a tidal volume of 8 to 10mL/kg, respiratory rate of 12to 15/minute, inspiration and expirationratioof1:2, fraction of inhaled oxygenof 50%, and flow rate of fresh gas of 1 to 2 L/minute to maintain normocapnia(PaCO2between 35 and 45 mm Hg).

Anaesthesia will bemaintained on o2+air+sevoflurane+ cisatracurium (2mcg/kg/min) infusion. Foranalgesia all patients will receive inj fentanyl 2mcg/kg before induction, 1mcg/kgto attenuate potent stress responses induced by noxious stimuli at certain timepoints during surgery, including scalp incision and skull drilling. Injparacetamol (15mg/kg) will be given before skin closure. Crystalloid infusionand/or colloid infusion will be used as needed to treat intravascular volumedepletion. Fluid input and output will be closely monitored. Blood loss will benoted and blood replacement therapy will be given as required.

The vital signs includingmean arterial blood pressure (MAP) & heart rate (HR) will be continuallymonitored and recorded at different intraoperative time (points, includingbaseline, induction, 1, 2, and 3 hours after administration of lignocaine,skull ï¬xation, skin incision, dura opening, tumor resection, dura suturing,skin suturing, end of surgery, spontaneous breathing recovery, and extubation.

All patients will receiveinj. 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 postoperativeanesthesia care unit (PACU).

**InPACU:**

MAP and HR will be recordedat 15minute intervals in the PACU. Patients will be assessed for acutepostoperative pain in the PACU at 15-minute intervals using the numeric ratingscale (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 willbe noted as follows: intraoperative consumption of propofol and fentanyl, firstrequirement of rescue postoperative analgesic (paracetamol, tramadol),complications including hypertension (systolic blood pressure >20% of baselinevalue), tachycardia (HR >100 beats/min) and PONV.

Safety reporting Safety monitoring will be performed continuouslythroughout the study.

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

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

 Commonside 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.

Unlikelybut serious side effects of lignocaine include:

- drowsiness,

- mental/mood changes,

- [ringing in the ears](https://www.rxlist.com/script/main/art.asp?articlekey=20474),

- dizziness,

- vision changes,

- tremors,

- numbness,

- headache, or

- backache.

Commonside effects of dexmeditomidine include:

- low or [high blood pressure](https://www.rxlist.com/high_blood_pressure_hypertension_medications/drugs-condition.htm) ([hypotension](https://www.rxlist.com/script/main/art.asp?articlekey=3864) or [hypertension](https://www.rxlist.com/script/main/art.asp?articlekey=3846)),

- slow heart rate ([bradycardia](https://www.rxlist.com/script/main/art.asp?articlekey=2515)),

- nausea,

- [dry mouth](https://www.rxlist.com/script/main/art.asp?articlekey=24997),

- irregular heartbeat,

- fever,

- vomiting,

- low blood plasma,

- fluid buildup between [lungs](https://www.rxlist.com/script/main/art.asp?articlekey=4209) and chest,

- agitation,

- [anemia](https://www.rxlist.com/script/main/art.asp?articlekey=15491),

- fast heart rate,

- chills,

- [high blood sugar](https://www.rxlist.com/script/main/art.asp?articlekey=32860) ([hyperglycemia](https://www.rxlist.com/script/main/art.asp?articlekey=3836)),

- low blood oxygen,

- extremely elevated body temperature ([hyperthermia](https://www.rxlist.com/script/main/art.asp?articlekey=3848)),

- complete or partial collapse of a lung,

- post-procedure bleeding,

- low blood calcium,

- decreased urination,

- [wheezing](https://www.rxlist.com/script/main/art.asp?articlekey=9401),

- 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 tostudy 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 tobe 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 ofthe subjects concerned in consultation with the Ethics Committee and thehospital authorities.

Withdrawal criteriaUnder the following circumstances subjects will bewithdrawn from study

·        Voluntary withdrawal ofinformed consent

·        In the event of an AE/SAEwhich prevents further participation in the study, as per the discretion of theinvestigator

·        In the event of protocolviolation----

o   Patientsenrolled into study in spite of having exclusion criteria or other protocolviolations

o   Useof non-permitted concomitant medications

·        Unplanned postoperativemechanical ventilation

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

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

Statistical analysis  The demographic, diseaserelated variables will be presented with standard frequency for categorical andwith mean (Standard Deviation)/ Median (interquartile range) for numericalvariables. Standard statistical test for significance will be used to assessthe difference between/ among groups. The data will be analyzed using student ttest for continuous parametric variables, Mann-Whitney U test for continuousnonparametric 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 patientcare           = Yes

2 .Attainment of moreknowledge        = Yes

3 .Bridging the lacunae inthe knowledge = Yes

References1.    MagniG, La Rosa I, Gimignani S, et al. Early post-operative complications afterintracranial surgery. J NeurosurgAnesthesiol. 2007;19:229–234.

2.    BreivikH. Postoperative pain management: why is it difficult to show that it improvesoutcome? Eur J Anaesthesiol. 1998;15:748–751.

3.    BreivikH, Stubhaug A. Management of acute postoperative pain: still a long way to go!.Pain. 2008;137:233–234.

4.    CarrD, Goudas L. Acute pain. Lancet. 1999;353:2051–2058.

5.    N.Quiney, R. Cooper, M. Stoneham & F. Walters (1996) Pain after craniotomy. Atime for reappraisal?, British Journal of Neurosurgery, 10:3, 295-300, DOI:10.1080/02688699650040179

6.    JolyV, Richebe P, Guignard B, et al. Remifentanil-induced postoperativehyperalgesia and its prevention with small dose ketamine.

7.    WangX, Liu N, Chen J, Xu Z, Wang F, Ding C. Effect of intravenous dexmedetomidineduring general anesthesia on acute postoperative pain in adults : a systematicreview and meta-analysis of randomized controlled trials.

8.    Meta-analysisNA, Liu Y, Liang F, Liu X, Shao X, Jiang N. Dexmedetomidine ReducesPerioperative Opioid Consumption and Postoperative Pain Intensity in.2017;00(00):1–10.

9.    GrewalA. Dexmedetomidine: new avenues. J AnaesthesiolClinPharmacol.2011;27(3):297–302.

10. SadjakA, Wintersteiger R, Zakel D, et al. [Peripheral analgesic effect ofintra-articularly applied clonidine]. Schmerz. 2006;20(4):293–294, 296–299.

11. Khasar  SG, Green  PG,  Chou B,  Levine  JD. Peripheral  nociceptive  effects of alpha 2-adrenergic receptoragonists in the rat. Neuroscience.1995;66(2):427–432.

12.  Liang F,  Liu  M, Fu  X,  Zhou X,  Chen  P, Han  F.  Dexmedetomidine  attenuates neuropathic  pain  in chronic  constriction  injury by  suppressing  NR2B, NF-kB,  and  iNOS activation.  Saudi  Pharm J 2017;25(4):649–654.

13. GroudineSB, Fisher HA, Kaufman RP Jr et al. Intravenous lidocaine speeds the return ofbowel function, decreases postoperative pain, and shortens hospital stay inpatients undergoing radical retropubic prostatectomy. AnesthAnalg 1998; 86:235–9

14. KoppertW, Weigand M, Neumann F et al. Perioperative intravenous lidocaine haspreventive effects on postoperative pain and morphine consumption after majorabdominal surgery. AnesthAnalg 2004; 98: 1050–5

15. KabaA, Laurent SR, Detroz BJ et al. Intravenous lidocaine infusion facilitatesacute rehabilitation after laparoscopic colectomy. Anesthesiology 2007; 106:11–8

16. KuoCP, Jao SW, Chen KM et al. Comparison of the effects of thoracic epiduralanalgesia and i.v. infusion with lidocaine on cytokine response, postoperativepain and bowel function in patients undergoing colonic surgery. Br J Anaesth2006; 97: 640–6

17. PengY, Zhang W, Kass IS. Lidocaine Reduces Acute Postoperative Pain AfterSupratentorial Tumor Surgery in the PACU : A Secondary. 2015;00(00):1–7.

18. XuSQ, Li YH, Wang SB, Hu SH. Effects of intravenous lidocaine, dexmedetomidineand their combination on postoperative pain and bowel function recovery afterabdominal hysterectomy. 2017;83(7):685–94, Doi: 10.23736/s0375-9393.16.11472-5

Detailed Description

Not available

Study Timeline

• Study Start: 2018-10-09
• Study Completion: 2018-12-19
• Last Update Posted: 2020-02-08

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

1.ASA-I and II scheduled for elective craniotomy 2.Either sex 3.Age group 18 to 70 years 4.Preop GCS 15/15 5.No neuropsychiatric illness, alcohol or drug abuse 6.Co-operative and able to give informed consent in person.

Exclusion Criteria

• 1.ASA III and above 2.Age less than 18 years and more than 70 years 3.Preoperative GCS <15 4.Allergy to study drug 5.Severe respiratory, renal or hepatic disease 6.
• Psychiatric medical history 7.Severe hypotension (mean arterial pressure [MAP] <60 mmHg) or bradycardia (heart rate<40 bpm), arrhythmia, or urticaria due to lignocaine or dexmedetomidine infusion during the surgery 8.Patient requiring post-op mechanical ventilation (planned/unplanned).

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
acute postoperative pain in the PACU using the numeric rating scale (NRS)	postoperative

Secondary Outcome Measures

Name	Time	Method
intraoperative consumption of propofol and fentanyl,	inraoperative
first requirement of postoperative analgesic (paracetamol, tramadol)	postoperative
complications including hypertension (systolic blood pressure more than 20% of baseline value), tachycardia (HR more than 100 beats/min) and PONV.	postoperative

Trial Locations

Locations (1)

Neurosurgery operation theatre, Institute of Neurosciences, Kolkata; 🇮🇳 Kolkata, WEST BENGAL, India

Neurosurgery operation theatre, Institute of Neurosciences, Kolkata

🇮🇳Kolkata, WEST BENGAL, India

Dr Ardija Singh

Principal investigator

9167955606

doc.ardija@gmail.com