RANDOMIZED COMPARISON OF NALBUPHINE AND FENTANYL USED AS PREMEDICATION IN ATTENUATION OF HEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND INTUBATION IN PATIENTS UNDERGOING LAPAROSCOPIC

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RANDOMIZED COMPARISON OF NALBUPHINE AND FENTANYL USED AS PREMEDICATION IN ATTENUATION OF HEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND INTUBATION IN PATIENTS UNDERGOING LAPAROSCOPIC

SURGERIES IN SURGICAL GASTROENTEROLOGY

Dissertation submitted to

THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY, CHENNAI, TAMILNADU

In partial fulfilment for the award of the degree of

DOCTOR OF MEDICINE IN ANAESTHESIOLOGY

BRANCH X

INSTITUTE OF ANAESTHESIOLOGY AND CRITICAL CARE MADRAS MEDICAL COLLEGE CHENNAI - 600 003

APRIL 2020

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CERTIFICATE

This is to certify that the dissertation titled, “ RANDOMIZED COMPARISON OF NALBUPHINE AND FENTANYL USED AS PREMEDICATION IN ATTENUATION OF HEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND INTUBATION IN PATIENTS UNDERGOING LAPAROSCOPIC SURGERIES IN SURGICAL GASTROENTEROLOGY” submitted by DR.VIJAYARUPA.N in partial fulfilment for the award of the degree of DOCTOR OF MEDICINE in ANAESTHESIOLOGY by THE TAMILNADU DR.M.G.R MEDICAL UNIVERSITY, Chennai is a bonafide record of work done by her in the INSTITUTE OF ANAESTHESIOLOGY &

CRITICAL CARE, MADRAS MEDICAL COLLEGE, during the academic year 2017 -2020.

Prof. DR. ANURADHA SWAMINATHAN, MD., DA.,

Professor and Director,

Institute of Anaesthesiology & Critical care, Rajiv Gandhi Govt General Hospital,

Madras Medical College, Chennai – 600003

Prof. DR. R. JAYANTHI, MD, F.R.C.P [Glasg]

The Dean,

Rajiv Gandhi Govt General Hospital, Madras Medical College,

Chennai – 600003.

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CERTIFICATE OF THE GUIDE

This is to certify that the dissertation titled, “ RANDOMIZED COMPARISON OF NALBUPHINE AND FENTANYL USED AS PREMEDICATION IN ATTENUATION OF HEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND INTUBATION IN PATIENTS UNDERGOING LAPAROSCOPIC SURGERIES IN SURGICAL GASTROENTEROLOGY ” is a bonafide research work done by DR. VIJAYARUPA.N in partial fulfilment of the requirement for the degree of DOCTOR OF MEDICINE in Anaesthesiology.

Prof. DR. M. VELLINGIRI MD., DA., Professor of Anaesthesiology,

Institute of Anaesthesiology and Critical Care, Rajiv Gandhi Government General Hospital, Madras Medical College,

Chennai-600 003

Date:

Place: Chennai

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DECLARATION

I hereby declare that the dissertation titled, “RANDOMIZED COMPARISON OF NALBUPHINE AND FENTANYL USED AS PREMEDICATION IN ATTENUATION OF HEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND INTUBATION IN PATIENTS UNDERGOING LAPAROSCOPIC SURGERIES IN SURGICAL GASTROENTEROLOGY” has been prepared by me under the guidance of Prof. DR. M. VELLINGIRI MD., DA., Professor of Anaesthesiology, Institute of Anaesthesiology and Critical Care, Rajiv Gandhi Government General Hospital, Madras Medical College, Chennai, in partial fulfilment of the regulations for the award of the degree of M.D (Anaesthesiology), examination to be held in April 2020.

This study was conducted at Department of Anaesthesiology, INSTITUTE OF ANAESTHESIOLOGY AND CRITICAL CARE, RAJIV GANDHI GOVT GENERAL HOSPITAL, MADRAS MEDICAL COLLEGE, CHENNAI.

I have not submitted this dissertation previously to any journal or any university for the award of any degree or diploma.

DR. VIJAYARUPA.N

Date:

Place: Chennai

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ACKNOWLEDGEMENT

I am extremely thankful to Prof. DR. R. JAYANTHI, MD, F.R.C.P [Glasg], The Dean, Rajiv Gandhi Govt General Hospital, Madras Medical College, Chennai for the permission to carry out this study.

I am immensely grateful to Prof. DR. ANURADHA SWAMINATHAN, MD., DA., Professor and Director, Institute of Anaesthesiology & Critical Care, Rajiv Gandhi Govt General Hospital, Madras Medical College, Chennai, for the concern and support in conducting this study.

I am extremely grateful and indebted to my guide Prof. DR. M.

VELLINGIRI MD., DA., Professor of Anaesthesiology, Institute of Anaesthesiology and Critical Care, Rajiv Gandhi Government General Hospital, Madras Medical College, Chennai for the concern, inspiration, meticulous guidance, expert advice and constant encouragement in doing and preparing this dissertation.

I am extremely thankful to my Assistant Professors DR. RAVI, MD., DR. JAYA, MD., DR. SENTHILKUMAR, MD, DA and

DR. TAJUNISHA, MD., for their constant motivation and valuable suggestions in conducting my study.

I am thankful to PROF DR. O. L.NAGANATH BABU, M.S. M.Ch.,

FRCS, Director and Professor, Department of Surgical Gastroenterology

for permitting me to conduct the study on the patients concerned

.

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I am thankful to the Institutional Ethical Committee for their guidance and approval for this study.

I am thankful to all my colleagues and friends for their help and advice in carrying out this dissertation.

I am grateful to my family for their moral support and encouragement.

Lastly, I am greatly indebted and thankful to all the patients and their

family members for willingly submitting themselves for this study.

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ABBREVATIONS

ASA PS American Society of Anaesthesiologist - Physical Status BMI Body mass index

DBP Diastolic blood pressure ECG Electro cardio gram

HR Heart rate

IPF Idiopathic pulmonary fibrosis PAG Periaqueductal grey

IV Intravenous IM Intramuscular

KG Kilogram

LID Levodopa induced dyskinesia MAP Mean arterial pressure

mcg Microgram

mg Milligram

min Minute

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8 ml Millilitre

PNS Peripheral nervous system SBP Systolic blood pressure Ca²⁺ Calcium

CO2 Carbon dioxide

SS Serotonin syndrome

SNRI Serotonin norepinephrine reuptake inhibitors

SSRI’s Selective serotonin reuptake inhibitors

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SL.

NO. TOPIC PAGE

NO.

1 INTRODUCTION

¹⁰

2 AIM AND OBJECTIVES

¹⁴

3 REVIEW OF LITERATURE

¹⁵

4 RESEARCH QUESTION OR HYPOTHESIS

³⁸

5 METHODOLOGY

³⁹

6 OBSERVATIONS AND RESULTS

⁴⁵

7 DISCUSSION

⁷⁶

8 LIMITATION

⁸³

9 RECOMMENDATIONS

⁸⁴

10 SUMMARY

⁸⁵

11 CONCLUSION

⁸⁸

12 BIBLIOGRAPHY

⁸⁹

13 ANNEXURES

A. PROFORMA

⁹⁹

B. INFORMATION TO PARTICIPANTS

¹⁰¹

C. PATIENT CONSENT FORM

¹⁰²

D. INSTITUTIONAL ETHICAL COMMITTEE CLEARANCE

¹⁰⁵

E. MASTER CHART / DATA SHEET

¹⁰⁶

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ABSTRACT

INTRODUCTION

Fentanyl and Nalbuphine are most extensively used in our settings as a premedication Therefore, our aim was to compare the effects of Fentanyl and Nalbuphine on hemodynamic responses to endotracheal intubation to help the choice of a better drug in laparoscopic surgeries.

OBJECTIVE

To compare Nalbuphine and Fentanyl for control of hemodynamic changes during laryngoscopy and endotracheal intubation.

METHODOLOGY

Method adopted is a prospective, randomized control study done on 60 adult patients (30 in each group. GROUP N-Nalbuphine, GROUP F-Fentanyl) between 20- 60years of age of either sex under ASA PS I and II undergoing elective laparoscopic surgery in Institute of Anaesthesiology and Critical Care, Madras Medical College, Chennai-3. After obtaining informed written consent the details regarding socio demographic details and hemodynamic parameters (i.e. heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure) were measured at different interval before, during and after intubation.

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The fluctuations in hemodynamic parameters for both the groups have been analysed.

RESULTS

Both the groups showed increase in the heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) during intubation. However, Nalbuphine group showed higher fluctuations in heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) compared to Fentanyl group.

ASA PS II subjects maintained a slightly high diastolic blood pressure and mean arterial pressure in Fentanyl group.

CONCLUSION

Fentanyl can be used as the better agent compared to Nalbuphine with respect to the hemodynamic stability (i.e. heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure).

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INTRODUCTION

Induction of general anaesthesia is known to induce clinically relevant changes in hemodynamic variables possibly created by direct laryngoscopy and endotracheal intubation. Tracheal intubation causes a reflex upsurge in sympathetic activity that may effect in hypertension, tachycardia, and arrhythmia. (1,2) In 1940, Reid and Brace first defined the hemodynamic response to laryngoscopy and intubation. The increase in pulse rate and blood pressure are frequently transitory, variable and unpredictable. (3)

The hemodynamic response is important especially in patients undergoing laparoscopic surgeries because of the physiological changes caused by pneumoperitoneum created by CO2 insufflation. (3) Various drugs and induction agents have been tried to prevent hemodynamic response of laryngoscopy. These drugs include Thiopentone, Propofol, Esmolol, Lignocaine, Magnesium, Vasodilators and Opioids etc. Each of these mentioned drugs has its own limitations. (4–11)

Fentanyl was synthesised in 1960s and it is more potent than its precursors.

The large safety margin, low side effect profile, relatively short duration of action, and minimal respiratory depression at analgesic doses made it as the first- choice intravenous anaesthetic. It is known for its hemodynamic stability. (12–

14)

Nalbuphine is a semi-synthetic opioid having agonist (

κ

receptor) and antagonist (µ receptor) property. It is chemically related to Naloxone and

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Naltrexone. It is a potent analgesic equivalent to Morphine. Sedation is the most frequently occurring adverse effect. Nalbuphine has few effects on cardiovascular hemodynamic. (15) Unlike, other agonist-antagonist opioids, such as Pentazocine and Butorphanol, will not cause in rise in pulmonary artery blood pressure, heart rate, systemic blood pressure, or atrial filling pressure. (16–

20)

Fentanyl and Nalbuphine are most extensively used in our settings as a premedication. Therefore, our aim was to compare the effects of Fentanyl and Nalbuphine on hemodynamic responses to endotracheal intubation to help the choice of a better drug in laparoscopic surgeries.

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AIM AND OBJECTIVES

AIM

To compare Inj. Nalbuphine and Inj. Fentanyl for control of hemodynamic changes during laryngoscopy and endotracheal intubation.

OBJECTIVES

• Primary Objectives

To study the hemodynamic changes (i.e. heart rate, mean arterial pressure, systolic blood pressure, diastolic blood pressure) during laryngoscopy and intubation during administration of I.V Nalbuphine 0.2mg / kg and I.V Fentanyl 2 mcg / kg as premedication.

• Secondary Objective

To compare side effects and complications of Nalbuphine and Fentanyl

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REVIEW OF LITERATURE

Review of literature of this study is discussed under the following headings:

1) Opioids and Receptors

2) Drugs acting on the Opioid receptors 3) Opioid-sensitive pain modulation system 4) Pharmacology of Fentanyl

5) Pharmacology of Nalbuphine 6) Studies done on the similar topic

a) Global Studies b) Indian Studies

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1. OPIOIDS AND RECEPTORS

1.1 OPIOIDS

Opioids play an important role in the modern perioperative care and pain management. The word opium is derived from the Greek word opion (“poppy juice”); the opium poppy (Papaver somniferum) is the source of 20 distinct alkaloids. Usage of the medicinal poppy juice is being traced from at least 300 BC.

Drugs derived from opium are referred as opiates. Morphine is the best opiate that was isolated in 1803, followed by codeine in 1832, and papaverine in 1848. Morphine may be synthesized but it is derived from opium. Opioids are evident in producing analgesia without loss of touch, proprioception or consciousness.

1.2 CLASSIFICATION OF OPIOID

➢ Opioid agonists

➢ Opioid agonist–antagonists

➢ Opioid antagonists

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Table 1: Classification of opioid agonists and antagonists

Agonists Agonists - Antagonists Antagonists

Morphine Pentazocine Naloxone

Morphine-6- glucuronide

Butorphanol Naltrexone

Meperidine Nalbuphine Nalmefene

Sufentanil Buprenorphine

Fentanyl Nalorphine

Alfentanil Bremazocine

Remifentanil Dezocine

Codeine Meptazinol

Hydromorphone Oxymorphone Oxycodone Hydrocodone Propoxyphene Methadone Tramadol Heroin

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1.3 OPIOIDS RECEPTORS

Opioid receptors are classified as

µ,

κ and

δ

receptors. The following receptors of the three subtypes are developed form the ligands which is originally found to bond them in or their tissue of origin (

µ

—morphine, κ -ketocyclazo - cine,

δ

- isolated from vas deferens of mouse).

The above opioid receptors belong to the family of seven transmembrane segment G protein- coupled receptors that includes muscarinic, adrenergic,

γ

aminobutyric acid, and somatostatin receptors. In the brain the opioid receptors are found in periaqueductal grey, locus ceruleus, and rostral ventral medulla.

Opioid receptors are found both on interneurons and primary afferent neurons in the dorsal horn in the spinal cord. Intense analgesia is produced when direct application of opioid agonists to the spinal cord. For supraspinal and spinal analgesia the µ receptors are responsible. Activation of µ1 receptors can produce analgesia but µ2 receptors are responsible for hypoventilation, bradycardia, and physical dependence.

Activation of

κ

receptors influences in inhibition of neurotransmitter release via N-type calcium channels. Respiratory depression characteristic of µ receptor is less prominent with

κ

receptor.

κ

receptor mediated analgesia may be less effective for high intensity painful stimulation than µ receptor mediated.

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Opioid agonist- antagonists act on k receptors.

δ

receptors respond to the endogenous ligands known as enkephalins and these opioid receptors may serve to modulate the activity of the

µ

receptors.

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2. DRUGS ACTING ON THE OPIOID RECEPTORS

Fig 1: µ, κ , σ opioid receptors and the drugs

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3. Opioid-Sensitive Pain Modulation System

Fig 2: Opioid-sensitive pain modulation system (22–25)

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4. PHARMACOLOGY OF FENTANYL

Fentanyl, is a synthetic opioid that are extensively used to supplement general anaesthesia or as primary anaesthetic drugs in very high doses. Fentanyl is a phenylpiperidine-derivative synthetic opioid agonist that is structurally related to Meperidine. Fentanyl is 75 to 125 times more potent analgesic than Morphine. (26–28)

4.1 STRUCTURE OF FENTANYL

Fig 3: Structure of Fentanyl

Fentanyl is

50 to 100 times

more potent than Morphine with reduced vomiting, reduced histamine stimulation, reduced impact on GI motility. (12)

It

has rapid onset of action with shorter duration.

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Preparation

•

It is available as clear, colourless, particle free solution

•

pH of 4.0-7.5

•

Each ml of Fentanyl contains 50 mcg / ml

Mechanism of action

• µ receptor agonist

• The mechanism of action of Fentanyl is as a full µ opioid receptor agonist.

It is used as an anaesthesia adjuvant, an Intravenous anaesthetic.(13,14)

• Acts on G protein coupled receptors and closes the Ca²⁺ channels and thereby decreasing pre and post synaptic responses

▪ Fentanyl causes hyperpolarisation (Post synaptic potassium efflux and presynaptic calcium reduction). Fentanyl has no active metabolites and choice during renal dysfunction.

Routes of administration

•

Premedication – in adults, 50 to 100 mcg I.M

•

Induction dose – 2 to 6 mcg /kg I.V

•

Sympathetic response blunting – 1.5 to 3 mcg /kg I.V

•

Maintenance dose – 0.5 to 5 mcg /kg/ hour I.V.

•

Surgical anaesthesia – 50 to 150 mcg / kg I.V. 5 minutes before the surgical procedure.

•

Spinal – up to 25 mcg can be given

•

Epidural – 50 to 100 mcg

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Pharmacokinetics of fentanyl

•

Described by 3 compartment model.

•

Distribution time is 1.7 minutes.

•

Redistribution of 13 minutes.

•

Terminal elimination half-life - 219 min

•

Volume of distribution – 4L/ kg.

•

Onset of action of Fentanyl after

o

I.V route is immediate

o

I.M route is 7 to 8 min.

•

Duration of action lasts upto 1 to 2 hours after I.M route.

•

Analgesic action lasts up to 30 to 60 minutes after IV route

•

Alteration in pH affects plasma protein binding of the drug

•

Stored in skeletal muscle and fat , released slowly into the blood

•

Metabolized in liver by N - demethylation [ by CYP 450- CYP 3A].

•

Excretion - 75% in urine, 10% unchanged drug, 9% recovered in fecal matter

•

pKa is 8.4

•

Context sensitive half time – 260 min after infusion for 4 hours Pharmacodynamics of Fentanyl

•

It has sedative and analgesic activity

•

Higher doses may produce apnoea

•

Emetic activity of fentanyl is less compared to Morphine / Pethidine

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•

It acts by filling receptors in midbrain, thalamus and spinal cord which may cause minimal cortical depression

•

Depression of respiration may last longer than the analgesic effect

•

Rigidity of chest gets eliminated by Succinylcholine

•

Analgesic and sedative actions are reversed by Naloxone or Nalorphine

•

Cholinergic actions are reversed by Atropine Uses of fentanyl

•

Pre-medication

•

Induction and maintenance of anaesthesia

•

Post-op analgesia

•

Supplementation to general and regional anaesthesia Contraindications

•

Known allergic to Fentanyl Precautions

•

Use of concomitant neuroleptics will cause exaggerated hypotension

•

Muscle rigidity occurs due to faster rate of administration. It is

avoided by giving Fentanyl slowly.

•

Non epileptic myoclonic movements may be seen. It is managed by assisted or controlled ventilation.

•

Drug dependence / drug abuse patients may require higher than normal

doses to produce therapeutic effects of Fentanyl.

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•

Bradycardia caused by Fentanyl is treated with Atropine injection

•

Respiratory problems – caution to be taken in patients with poor respiratory efforts. Opioids may cause further decrease in respiratory drive or increases airway resistance.

•

Impaired kidney and liver functions – due to excretion and metabolism.

Serotonin syndrome [SS]

•

It occurs due to concomitant use of selective serotonin reuptake inhibitors [ SSRI’s ] , serotonin norepinephrine reuptake inhibitors [ SNRI’s]

•

Manifestations of SS – Altered mental status, Rigidity, Tachycardia, coma

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Fig 4. Action of Fentanyl

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NALBUPHINE

Nalbuphine is as a Competitive Opioid Antagonist and Partial Opioid Agonist.

The chemical composition is 17 – cyclobutyl methyl 4,5 alpha epoxymorphinian 3,6 alpha 14 triol hydrochloride. Its molecular weight is 393.91 and hydrophilic in nature. The pKa is 8.71and 9.96.

Routes of administration

•

Subcutaneously

•

Intra muscularly

•

Intravenously Mechanism of action

• Nalbuphine has double mechanism of action. First, it acts as an antagonist (blocker) to the µ opioid receptor and second as an agonist (activator) to the κ receptor opioid receptor.

•

Limited analgesia is caused by activation of supraspinal and spinal κ receptor.

Pharmacological actions

•

The analgesic activity of Nalbuphine is similar to Morphine.

•

Metabolization takes place in liver.

•

Excretion is via kidneys

•

Onset of the action initiates within 2 to 3 minutes after I.V

injection of Nalbuphine.

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•

Duration of action is about 3-6 hours

•

The elimination half-life is about 5 hours

•

Once the dose reaches 30 mg it produces ceiling effect. That is, it does not produce respiratory depression after dose accumulates 30 mg.

Preparation

•

It is available in 1 ml ampoule. Each ml contains 10 mg

Clinical uses

▪ Nalbuphine extended release formulations are used for the treatment of chronic pruritus, chronic cough in patients with idiopathic pulmonary fibrosis (IPF) and Levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease.

▪

To supplement balanced anaesthesia

▪

Obstetric analgesia, morphine induced pruritis.

▪

0.05 to 0.1 mg/kg/min for analgesia and sedation in myocardial revascularization procedures.

▪

Preoperative and post-operative analgesia

▪

4 mg IV Nalbuphine used to prevent intrathecal Morphine

induced vomiting.

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Contraindication

•

Allergy to Nalbuphine Precautions

Nalbuphine should be used with caution in following situations:

•

Myocardial infarction

•

Impaired hepatic and renal functions.

•

Impaired respirations

•

Higher incidence of bradycardia

•

All intubation sets should be available while injecting Nalbuphine

•

Biliary tract surgery – it will cause sphincter of oddi spasm Side effects of Nalbuphine

•

Sedation

•

Nausea and vomiting

•

Headache

•

Dizziness

•

Bradycardia

•

Dry mouth

•

Allergic reactions

Naloxone is used to reverse the effects of Nalbuphine

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Molecular Formula of Nalbuphine - C21H27NO4

Fig 5: Structure of Nalbuphine

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Nalbuphine is a safe and efficient semi-synthetic narcotic. The metabolites of Nalbuphine are NAL coupled with its two hydroxylated (3′- hydroxyNalbuphine and 4′-hydroxyNalbuphine) and two conjugated metabolites (Nalbuphine-3-β-d-glucuronide and Nalbuphine-6-β-d-glucuronide). (32,33) This is represented in the image below:

Fig 6: Metabolites of Nalbuphine

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The following image represents the action of Nalbuphine in various parts of the body,(34)

Fig 7: Action of Nalbuphine

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The recommended dose of Nalbuphine is 10mg/70kg given every 3 to 6 hours as needed. The formulations include subcutaneous, intramuscular and intravenous routes. The maximum suggested single dose is 20mg, while the maximum suggested daily dose is 160mg. (35) William K.Schmidt et al, in their review concluded that Nalbuphine is a safe and highly efficacious analgesic. It possesses a remarkably less narcotic abuse danger in humans. Unlike nalorphine or pentazocine, Nalbuphine have very few behavioural or autonomic side effects of opioids. (17,36–38)

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STUDIES DONE ON THE SIMILAR TOPIC

GLOBAL STUDIES

1) B. LefÃ¨vre et al, compared Nalbuphine hydrochloride and Fentanyl as intravenous analgesics. This study was among 24 medically compromised patients undergoing oral surgery in France. Analgesia and sedation seemed satisfactory. The results were similar according to the surgeon, anaesthesiologists, and patients in the two groups, and there were no significant hemodynamic differences in blood pressure or heart rate. Nalbuphine produced less respiratory depression. (39)

2) Rawal N and Wennhager M, compared Nalbuphine hydrochloride and Fentanyl 60 women undergoing gynaecological surgery under IV anaesthesia in Sweden. They concluded that Fentanyl was more effective in suppressing the cardiovascular responses compared with Nalbuphine group showing mild to moderate surges in pulse rate during the intubation phase and in blood Pressure.

Even though Fentanyl was associated with respiratory depression in a notable number of patients, the quality and duration of postoperative analgesia were comparable. (40)

3) Farahat I Ahmed studied the effect of intrathecal Fentanyl and Nalbuphine hydrochloride used as an adjuvant to Bupivacaine. The comparison is as spinal anaesthetic in elective caesarean surgeries. This study is a randomized, double-blind study which was done among 80 full-term in Zagazig,

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Egypt. They concluded that Fentanyl was superior in onset of sensory and motor block. Nalbuphine is superior in high duration of postoperative comprehensive and effective analgesia and in declining occurrences of side effects like pruritus and shivering.(41)

4) B. KAY et al, compared the Fentanyl and Nalbuphine in 30 patients from Manchester who received thiopentone 4 mg/kg. After 90 seconds, Fentanyl 5μg/kg or Nalbuphine 0.3 mg/kg, either saline, Succinylcholine 1.5 mg/kg, was administered. The stress response during the endotracheal intubation was prominent after saline was decreased after Nalbuphine indicating value of p <

0.05. However, increase in heart rate still persisted. Further, neither rise in BP nor HR increased in those patients who received Fentanyl. (42)

Indian Studies

5) Kumkum Gupta et al, compared Nalbuphine hydrochloride and Fentanyl as an adjuvant to 0.5% hyperbaric Bupivacaine. This study participants belong to orthopaedic surgery of lower limbs under subarachnoid block. The study participants were sixty-eight adult patients in two groups of 34 each from Meerut, Uttar Pradesh. Both the Nalbuphine hydrochloride and Fentanyl groups are comparable in onset and cephalic extension of block. They concluded that intrathecal Nalbuphine is clinically more efficient than Fentanyl for augmenting the postoperative analgesia.(43)

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6) Umesh N Prabhakaraiah et al, compared Fentanyl and Nalbuphine hydrochloride as an adjuvant to Bupivacaine for lower abdominal surgeries under spinal anaesthesia through a randomized, double-blind study. This study was done among the 60 patients in patients from Mandya Institute of Medical Sciences, Mandya, Karnataka. Intraoperative hemodynamic were comparable between both the Nalbuphine hydrochloride and Fentanyl groups. They concluded that during administration of the Fentanyl as an adjuvant to Bupivacaine, it was noticed that the same was more efficient than Nalbuphine in early postoperative analgesia. (44)

7) Tripat Kaur Bindra et al, compared the intrathecal Nalbuphine and intrathecal Fentanyl in caesarean section surgeries. This study was a double- blind randomized comparative study. This study was done among the 150 parturient from Patiala, Punjab. Both the intrathecal Nalbuphine and intrathecal Fentanyl were equally effective and increased duration of block and minimal side effects. intrathecal Nalbuphine becomes the choice by having the added advantage of prolonging postoperative analgesia. (45)

8) Neha Sharma and Hetal Parikh compared the hemodynamic responses to Nalbuphine and Fentanyl during intubation. They did this study among 60 patients in Vadodara, Gujarat. Both the drugs (Nalbuphine and Fentanyl) show almost equal rise in heart rate at intubation. However, increase in blood pressure was significantly more in Nalbuphine as compared to Fentanyl. (46)

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RESEARCH QUESTION OR HYPOTHESIS

RESEARCH QUESTION

What is the difference in hemodynamic response between Nalbuphine and Fentanyl used as the premedication during laryngoscopy and endotracheal intubation in patients undergoing laparoscopic surgeries?

Null Hypothesis

There is no difference in hemodynamic response between Nalbuphine and Fentanyl used as the premedication during laryngoscopy and endotracheal intubation in patients undergoing laparoscopic surgeries.

Alternate Hypothesis

There is a difference in hemodynamic response between Nalbuphine and Fentanyl used as the premedication during laryngoscopy and endotracheal intubation in patients undergoing laparoscopic surgeries.

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METHODOLOGY

STUDY SUBJECTS

60 adult patients between 20 - 60years of age of either sex under ASA PS I

& II undergoing elective laparoscopic surgery divided into two groups:

• Group N-Nalbuphine

• Group F-Fentanyl

STUDY DESIGN

Prospective, Randomized control study STUDY SETTING

Institute of Anaesthesiology and Critical Care, Rajiv Gandhi Government General Hospital Madras Medical College, Chennai-3

STUDY PERIOD

One year - FEB 2018 to FEB 2019 INCLUSION CRITERIA

• Age 20-60 years of either sex

• ASA PS I & II

• Elective surgery

• Informed patient consent

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40 EXCLUSION CRITERIA

• Patient’s refusal

• Known allergy to trial drugs

• ASA PS III or more

• Emergency surgeries

• Patients with difficult intubation

SAMPLE SIZE

Total of 60 Patients were considered for the study. Amongst the above sample, 30 patients for GROUP N - Nalbuphine and 30 patients for GROUP F- Fentanyl were administered.

ETHICAL CONSIDERATION:

Institutional Ethical Committee approval was obtained before the start of the study. Informed written consent was obtained from each participant.

• Source of Funding: NIL

• Conflict of Interest: NIL

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41 STUDY PROCEDURE

Post approval from the ethical committee for conducting the study on 60 patients being posted for laparoscopic surgery under general anesthesia and requiring endotracheal intubation. For one year of study period the data points were collected, monitored and the same analyzed statistically.

These patients were randomly divided into two groups.

• Group N: Inj. Nalbuphine dose 0.2mg/kg IV

• Group F: Inj. Fentanyl dose 2μg/kg IV

After obtaining the medical history the detailed pre-anaesthetic evaluation of each case was conducted. Also, systemic examination was performed to detect the presence of any systemic disorder. Routine investigations were carried out accordingly. Prior to surgery all patients were kept nil orally for 6-8 hrs. Baseline heart rate, blood pressure, SPO2, ECG were recorded.

10 minutes before giving study drug all patients were premedicated with Inj.

Ondansetron 4mg I.V, Inj. Midazolam 1mg I.V, Inj. Glycopyrrolate 0.2 mg I.V, Inj. Ranitidine 50mg I.V.

• Group F received Inj Fentanyl 2 μg/kg I.V

• Group N received Inj Nalbuphine 0.2mg/kg I.V

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42

Both the drugs were diluted in 10 ml of distilled water and administered slow I.V over 1 minute. Induction was done with Thiopentone sodium 2.5% I.V till the loss of eyelid reflexes and Inj Suxamethonium 2mg/kg I.V after 3 min of pre- oxygenation and administration of the study drugs.

After 90 seconds of administration of Succinylcholine, laryngoscopy and intubation was performed. All the patients were intubated using Macintosh curve blade laryngoscope with appropriate size of endotracheal tubes.

Surgery were allowed to start after 15 min of intubation when patients were not stimulated during the observation period. Heart rate, blood pressure was monitored continuously and recorded at pre induction, intubation and at 01 min, 03 min, 05 min, 10 min and 15-min post-intubation. The patients were monitored for arrythmias and ST-T changes.

Patients were observed intraoperatively and postoperatively for any complication like nausea, vomiting, respiratory depression, sedation, arrythmias, bradycardia, muscular rigidity and pruritus.

Results were considered significant for P values < 0.05.

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43

Fig 8: Materials and Methods

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44 STATISTICAL METHODS

• Numerical variables like age, heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure are represented in mean, median, mode and standard deviation. They are visualised using histograms.

• Categorical variables like gender, groups are represented in frequencies and percentages. They are visualised using pie charts and bar diagrams are used as appropriate.

• Data was entered in MS excel sheet and analysed using SPSS software version 16.

• Baseline, pre-induction, intubation, 01 min, 03 min, 05 min, 10 min and 15-minute values of heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure are represented with their means plotted in line diagrams.

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45

OBSERVATIONS AND RESULTS

Observations and Results of the study is discussed under the following headings:

1) Groups of the study population

2) Age distribution among the two groups of the study population 3) Gender distribution among the two groups of the study population

4) Body mass index distribution among the two groups of the study population 5) ASA PS score among the two groups of the study population

6) Heart rate at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the two groups of the study population

7) Systolic blood pressure at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the two groups of the study population 8) Diastolic blood pressure at baseline, pre-induction, intubation,

9) 1 min, 3 min, 5 min, 10 min and 15 min among the two groups of the study population

10) Mean arterial pressure at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the two groups of the study population 11) Heart rate at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10

min and 15 min among the ASA PS I & II categories of the study population 12) Systolic blood pressure at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the ASA PS I & II categories of the study population

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46

a) Diastolic blood pressure at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the ASA PS I & II categories of the study population

b) Mean arterial pressure at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the ASA PS I & II categories of the study population

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47 Groups of the study population

In the study population of 60, 30 each were present in the groups of Fentanyl and Nalbuphine. This is represented in the following table and pie chart.

Table 2: Groups of the study population

Groups Frequency Percent

Fentanyl 30 50

Nalbuphine 30 50

Graph 1: Groups of the study population

30, 50%

Groups

Fentanyl Nalbuphine

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48

Age distribution among the two groups of the study population:

The mean age of the Fentanyl group is 42 and that of Nalbuphine group is 41 with standard deviation of 8 and 7 respectively. The Median age in Fentanyl group is 41 and of Nalbuphine group is 40.5. The mean, median, mode, standard deviation, minimum and maximum values of the Fentanyl and Nalbuphine groups are represented in the following table.

Table 3: Age distribution among the two groups of the study population

Measures Fentanyl Nalbuphine

Mean 42.0333 40.9000

Median 41.0000 40.5000

Mode 37.00^a 32.00^a

Standard Deviation 8.09207 7.06790

Minimum 29.00 29.00

Maximum 59.00 54.00

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49

Graph 2:

Age distribution among Fentanyl group

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50

Graph 3: Age distribution among Nalbuphine group:

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51

In both the groups, majority of the study population were belonging to 31-40 age category. This is represented in the following bar diagram.

Graph 4: Age distribution between the two groups

1

13

11

5

1

14

11

4

0 2 4 6 8 10 12 14 16

<30 30-40 41-50 51-60

Age

Fentanyl Nalbuphine

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52 Gender distribution among the two groups

In the Fentanyl group, 16 were males and 14 were females. In the Nalbuphine group there are equal number of males and females (15 each). This is represented in the following table and bar diagram.

Table 4: Gender distribution between the two groups

Fentanyl Nalbuphine

Gender Frequency Percent Frequency Percent

Female 14 46.7 15 50.0

Male 16 53.3 15 50.0

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53

Graph 5: Gender distribution between the two groups

14

15 16

15

0 2 4 6 8 10 12 14 16 18

Fentanyl Nalbuphine

Gender

Female Male

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54

Body Mass Index distribution among the two groups

In the study population majority were with normal BMI, followed by overweight represented by approximately around 50% in both the groups and 33.3% in overweight category. This is represented in the following table and bar chart.

Table 5: Body mass index distribution between the two groups

BMI Category Frequency Percent Frequency Percent

Undernourished

0 0 2 6.7

Normal

17 56.7 14 46.7

Overweight

10 33.3 10 33.3

Obese

3 10.0 4 13.3

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55

Graph 6: Body Mass Index distribution between the two groups

0

17

10

3 2

14

10

4

0 2 4 6 8 10 12 14 16 18

Undernourished Normal Overweight Obese

Body Mass Index distribution

Fentanyl Nalbuphine

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56

ASA PS category I & II among the two groups

In the Fentanyl group, 16 were having ASA PS score I and 14 were having ASA PS score II. In the Nalbuphine group, 14 were having ASA PS status I and 16 were having ASA PS status II. This is represented in the following table and bar diagram.

Table 6: ASA PS category I & II among the two groups

ASA PS Score Frequency Percent Frequency Percent

I 16 46.7 14 50.0

II 14 53.3 16 50.0

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57

Graph 7: ASA PS I & II category distribution between the two groups

16

14 14

16

0 2 4 6 8 10 12 14 16 18

Fentanyl Nalbuphine

ASA PS I & II category

I II

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58

HEART RATE AMONG THE TWO GROUPS

In the hemodynamic stability, heart rate was assessed at baseline, pre- induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min between the two groups of the study population. There is a peak observed in both the groups during the intubation, followed by slow decline and reaching the baseline from the fifth minute onwards. The rise during intubation was more in the Nalbuphine group.

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59

The statistical means of the heart rate plotted in the line diagram below.

Graph 8: Heart rate variation between the two groups

The mean heart rate between two groups at different times were not significant with p-values more than 0.05. Only the heart rate during intubation is close to 0.05. (0.09). This is represented in the following table.

86.2

84.5667

95.3

92.2667

87.8333

85.1667

83.4333

82.3667 89.7

86.6333

101.57

96.1

92.3

88.3

83.8333

82.7667

80 85 90 95 100 105

Baseline Preoperative Intubation One min Three min Five min ten min Fifteen min

Heart Rate

Fentanyl Nalbuphrine

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60

Table 7: Heart rate between the two groups

Observations Group Mean Std. Deviation p-Value

Heart rate Baseline

Fentanyl 86.2000 16.47234

0.342(>0.05-Not Significant) Nalbuphine 89.7000 11.35068

Heart rate Pre-induction

Fentanyl 84.5667 16.31095

Heart rate Intubation

Fentanyl 95.3000 16.28443

Heart rate 01 min

Fentanyl 92.2667 16.25854

Heart rate 03 min

Fentanyl 87.8333 15.77664

Heart rate 05 min

Fentanyl 85.1667 15.56540

Heart rate 10 min

Fentanyl 83.4333 15.37056

0.905(>0.05-Not Significant)

Nalbuphine 83.8333 9.89630

Heart rate 15 min

Fentanyl 82.3667 15.24622

0.904 (>0.05-Not Significant)

Nalbuphine 82.7667 9.89839

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61

SYSTOLIC BLOOD PRESSURE AMONG THE TWO GROUPS

Systolic blood pressure was assessed at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the two groups of the study population. There is a peak observed in both the groups during the intubation, followed by slow decline and reaching the baseline from the fifteenth minute onwards. However, the rise during intubation was more in the Nalbuphine group and at the end of the fifteenth minute, the mean systolic blood pressure was higher than the baseline.

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62

The statistical means of the systolic blood pressure plotted in the line diagram below.

Graph 9: Systolic Blood Pressure between the two groups

The mean systolic blood pressure between two groups at baseline and Premedication were not significant with p-values more than 0.05. After that all the six points showed a significantly higher systolic blood pressure among the Nalbuphine group with p-values less than 0.05. This is represented in the following table.

121.7666667

115.3333333

127.8

125.6

121.6

119.3

118.2

114.5666667 120.6

116.8333333

136.9666667

133.3666667

131.3

129.2

125.3

122.3333333

BASELINE PREOPERATIVEINTUBATION ONE MIN THREE MIN FIVE MIN TEN MIN FIFTEEN MIN

Systolic Blood Pressure

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63

Table 8: Systolic Blood Pressure between the two groups

Observations Group Mean Standard

Deviation p-Value

Systolic BP Baseline

Fentanyl 121.7667 10.57219

0.676 (> 0.05- Not Significant) Nalbuphine 120.6000 10.96578

Systolic BP Pre-induction

Fentanyl 115.3333 10.05273

0.579 (>0.05- Not Significant) Nalbuphine 116.8333 10.74174

Systolic BP Intubation

Fentanyl 127.8000 10.43998 0.001 (<0.05 - Significant) Nalbuphine 136.9667 10.75265

Systolic BP 01 min

Fentanyl 125.6000 10.20683

0.006 (<0.05 - Significant) Nalbuphine 133.3667 10.66248

Fentanyl 121.6000 10.00207

Fentanyl 119.3000 9.87211

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64

DIASTOLIC BLOOD PRESSURE AMONG THE TWO GROUPS

Diastolic blood pressure was assessed at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the two groups of the study population. There is a peak observed in both the groups during the intubation, followed by slow decline and reaching the baseline from the tenth minute onwards. The rise during intubation was more in the Nalbuphine group and at the end of the fifteenth minute, the mean diastolic blood pressure was higher than the baseline. The statistical means of the diastolic blood pressure plotted in the line diagram below.

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65

Graph 10: Diastolic Blood Pressure between the two groups

The mean diastolic blood pressure between two groups at baseline and Premedication were not significant with p-values more than 0.05. At the intubation time there is a significantly higher diastolic blood pressure among the Nalbuphine group with p-values less than 0.05. After that at all the points, the mean diastolic blood pressure between two groups were not significant with p- values more than 0.05. But the p-values were just high than 0.05. This is represented in the following table.

79.1333

77.1333

82.2333

81.6

79.5667

78.3333

75.6

74.5333 77.6667

77.2333

86.7333

85.3333

83.2667

82.1667

79.1

77.7667

68 70 72 74 76 78 80 82 84 86 88

Diastolic Blood Pressure

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66

Table 9: Diastolic Blood Pressure between the two groups

Observations Group Mean Standard

Deviation p-Value Diastolic BP

Baseline

Fentanyl 79.1333 8.44346 0.496(>0.05-Not Significant) Nalbuphine 77.6667 8.13394

Diastolic BP Pre-induction

Fentanyl 77.1333 8.40662 0.963(>0.05-Not Significant) Nalbuphine 77.2333 8.08866

Diastolic BP Intubation

Fentanyl 82.2333 8.28660 0.038(<0.05 - Significant) Nalbuphine 86.7333 8.12800

Diastolic BP 01 min

Fentanyl 81.6000 8.18577 0.085(>0.05-Not Significant) Nalbuphine 85.3333 8.29347

Diastolic BP 03 min

Fentanyl 79.5667 8.10144 0.083(>0.05-Not Significant) Nalbuphine 83.2667 8.15764

Diastolic BP 05 min

Fentanyl 78.3333 7.94087 0.070(>0.05-Not Significant) Nalbuphine 82.1667 8.15405

Diastolic BP 10 min

Fentanyl 75.6000 7.77086

0.085(>0.05-Not Significant) Nalbuphine 79.1000 7.68945

Diastolic BP 15 min

Fentanyl 74.5333 7.59189

0.106(>0.05-Not

Significant)

Nalbuphine 77.7667 7.68197

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67

MEAN ARTERIAL PRESSURE AMONG THE TWO GROUPS

Mean arterial pressure was assessed at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min between the two groups of the study population. There is a peak observed in both the groups during the intubation, followed by slow decline and reaching the baseline from the fifteenth minute onwards. The rise during intubation was more in the Nalbuphine group and at the end of the fifteenth minute, the mean arterial pressure was higher than the baseline.

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68

The statistical means of the mean arterial pressure plotted in the line diagram below.

Graph 11: Mean Arterial Pressure between the two groups

The mean arterial blood pressure between two groups at baseline and premedication were not significant with p-values more than 0.05. At the intubation time there is significantly higher mean arterial blood pressure among the nalbuphine group with p-values less than 0.05. After that at all the points, the mean arterial blood pressure between two groups were significant with p-values less than 0.05. This is represented in the following table

93.1

89.5

97.0333

96

93.1667

91.6667

89.4333

87.5 91.5333

90

103.1667

100.9667

98.8667

96.8333

94.6667

92.4

80 85 90 95 100 105

MEAN ARTERIAL PRESSURE

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69

Table 10: Mean Arterial Pressure between the two groups

Observations Group Mean Standard

Deviation p-Value Mean Arterial

Pressure

Baseline

Fentanyl 93.1000 8.84873 0.482 (>0.05-Not Significant) Nalbuphine 91.5333 8.29929

Mean Arterial Pressure

Pre-induction

Fentanyl 89.5000 8.45984

0.820 (>0.05-Not Significant) Nalbuphine 90.0000 8.52178

Mean Arterial Pressure

Intubation

Mean Arterial Pressure

01 min

Fentanyl 96.0000 8.36248 0.024 (<0.05- Significant) Nalbuphine 100.9667 8.27328

Mean Arterial Pressure

03 min

Mean Arterial Pressure

05 min

Fentanyl 91.6667 8.02725

0.014 (<0.05- Significant) Nalbuphine 96.8333 7.72851

Mean Arterial Pressure

10 min

Mean Arterial Pressure

15 min

Fentanyl 87.5000 7.79810

0.017 (<0.05- Significant) Nalbuphine 92.4000 7.66362

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70

HEART RATE AMONG THE ASA PS I & II CATEGORIES

Heart rate at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min assessed among the ASA PS I & II categories of the study population.

ASA PS II was maintaining a minimal low heart rate in Fentanyl group and slightly high heart rate among Nalbuphine group. The statistical means of the Heart rate plotted in the line diagram below.

Graph 12: Heart Rate Variation between ASA PS I & II statuses

87.06

85.31

95.75

92.75

88.1

85.3

83.6

82.5 85.21

83.71

94.79

91.71

87.42

85

83.3

82.2 90.42

87.10 101.50

95.40

91.60

87.60

83.60

82.70 89.06

86.2

101.6

96.8

92.9

88.9

84

82.8

80 85 90 95 100 105

Heart Rate

Fentanyl ASA I Fentanyl ASA II NALBUPHINE ASA I NALBUPHINE ASA II

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71

SYSTOLIC BLOOD PRESSURE AMONG THE ASA PS I & II CATEGORIES

Systolic blood pressure at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the ASA PS I & II categories of the study population carried out.

ASA PS II was maintaining a minimal low systolic blood pressure in Fentanyl group and slightly high systolic blood pressure among Nalbuphine group. The means of the systolic blood pressure plotted in the line diagram below.

Graph 13: Systolic Blood Pressure between ASA PS I & II category

123

117.0625

128.9375

126.625

122.625

120.375

119.1875

115.75 120.3571

113.3571

126.5

124.4286

120.4286

118.0714

117.0714

113.2143 118.0714

114.2857

134.7143

130.9286

128.9286

126.7857 123

120 122.8125

119.0625

138.9375

135.5

133.375

131.3125

127.3125

124.375

105 110 115 120 125 130 135 140 145

Systolic Blood Pressure

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72

DIASTOLIC BLOOD PRESSURE AMONG THE ASA PS I & II CATEGORIES

Diastolic blood pressure at Baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the ASA PS I & II categories of the study population carried out.

ASA PS II was maintaining a slightly high diastolic blood pressure in fentanyl group and notably high diastolic blood pressure among Nalbuphine group. the means of the diastolic blood pressure plotted in the line diagram below.

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73

Graph 14: Diastolic Blood Pressure between ASA PSI & II category

79.125

77.1875

82.1875

81.625

79.4375

78.125

75.4375

74.5625 79.1429

77.0714 82.2857

81.5714

79.7143

78.5714

75.7857

74.5 77.2857

76.5714

85.2857

83.8571

81.7143

80.6429

77.9286

76.2857

78 77.8125

88

86.625

84.625

83.5

80.125

79.0625

74 76 78 80 82 84 86 88 90

Diastolic Blood Pressure

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74

MEAN ARTERIAL PRESSURE AMONG THE ASA PS CATEGORIES Mean arterial pressure at baseline, pre-induction, intubation, 1 min, 3 min, 5 min, 10 min and 15 min among the ASA PS I & II categories of the study population carried out.

ASA PS II was maintaining a minimal low mean arterial pressure in fentanyl group and slightly high mean arterial pressure among Nalbuphine group. The statistical means of the mean arterial pressure plotted in the line diagram below.

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75

Graph 15: Mean Arterial Pressure between ASA PS I & II category

93.5

90.0625

97.3125

96.3125

93.4375

91.875

89.625

87.875 92.6429

88.8571

96.7143

95.6429

92.8571

91.4286

89.2143

87.0714 90.3571

88.7143

101.36

99.0714

97

94.2857

93.5714

90.5714 92.5625

91.125

104.75

102.63

100.50

99.0625

95.625

94

BASELINE PREOPERATIVE INTUBATION ONE MIN THREE MIN FIVE MIN TEN MIN FIFTEEN MIN

RANDOMIZED COMPARISON OF NALBUPHINE AND FENTANYL USED AS PREMEDICATION IN ATTENUATION OF HEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND INTUBATION IN PATIENTS UNDERGOING LAPAROSCOPIC