TITLE: 
Effect of nalbuphine and pentazocine on attenuation of hemodynamic changes during laryngoscopy and endotracheal intubation: A clinical study



ABSTRACT.BACKGROUND:
Narcotic drugs have been used to attenuate laryngoscopy and intubation induced circulatory responses, but are not always available due to tough narcotics laws. Nalbuphine a synthetic opioid, free from restrictions has been in use for post-operative pain relief. Hence, we decided to compare nalbuphine and pentazocine for attenuation of hemodynamic effects during larygoscopy and endotracheal intubation in a randomized, double-blind clinical study.

ABSTRACT.MATERIALS AND METHODS:
A total of 60 patients (ASA I and II) of either sex, between 18 years and 50 years were given either nalbuphine 0.2 mg/kg (group N, n = 30) or pentazocine 0.5 mg/kg (group P, n = 30) 5 min before induction of general anesthesia. After, induction with thiopentone and endotracheal intubation with succinylcholine balanced anesthesia was maintained with O2:N2O, 0.2% halothane and non-depolarizing relaxants for surgical duration. Changes in heart rate (HR), systolic blood pressure (SBP), diastolic pressure, mean arterial pressure, and rate pressure product calculated by HR × SBP were recorded at various time intervals.

ABSTRACT.RESULTS:
A non-significant fall (P > 0.05) up to 3 min and thereafter a significant rise (P < 0.05) in all the parameters were observed throughout the remaining study period with nalbuphine, whereas a continuous and significant (P < 0.05) rise in these parameters were observed with pentazocine. Maximum rise in both the group was observed immediately after larygoscopy and intubation and these started to return toward the basal values at the end of the study period, but remained above the initial values. (pentazocine > nalbuphine P = <0.01).

ABSTRACT.CONCLUSION:
Nalbuphine effectively reduces the tachycardia, hypertension, and cardiac workload associated with laryngoscopy and endotracheal intubation.

BODY.INTRODUCTION:
Hemodynamic changes due to stress responses caused by laryngoscopy and intubation are variable, transient and well-tolerated in American Society of Anesthesiologist I and II patients, but are of great concern for anesthesiologist especially in patients with pre-existing hypertension, myocardial ischemia, and cerebral pathologies with raised intracranial pressure as sudden rise in the heart rate (HR) and the blood pressure (BP) may cause high incidence of arrhythmias, myocardial ischemia, and cerebral hemorrhage.[12]
Numerous drugs including topical and/or intravenous lignocaine,[34] short acting beta blockers,[5] Ca++ channel blockers,[6] vasodilators,[78] magnesium sulphate,[9] α2-agonists,[1011] and opiates drugs[121314] have been used to attenuate these responses. Opiate like fentanyl not only produces intense analgesia, but effectively attenuates these cardiovascular responses to stress, but associated problems such as post-operative nausea and vomiting, respiratory depression and unavailability owing to tough narcotic laws make its use difficult in routine. Pentazocine, a synthetically prepared prototypical mixed agonist-antagonist narcotic (opioid analgesic) drug of the benzomorphan class of opioids is widely used in perioperative period as this is free from narcotic laws, but hypertension and tachycardia limits it use during anesthesia, especially in hypertensive and cardiac patients.
Recently, nalbuphine a synthetic opioid agonist-antagonist analgesic of the phenanthrene series free from tough narcotics laws is being marketed in India as peri-operative analgesic. This drug causes a reduction in HR and BP, but is sparingly evaluated for attenuation of stress responses during intubation. This has made us to evaluate and compare the effects of nalbuphine and pentazocine, on hemodynamic parameters during laryngoscopy and endotracheal intubation in a randomized double-blind clinical study.

BODY.MATERIALS AND METHODS:
After obtaining approval from Institutional Ethical Committee, and well-informed written consent, 60 patients (ASA grade I and II) of either sex and between the ages of 18 years and 50 years posted for various surgical procedures under general anesthesia were divided into two groups of small, fixed and equal size (n = 30 each group) by simple random sampling or unrestricted sampling (lottery method) according to drugs used as below:

Any patient with extreme of ages, major organ dysfunction, hypertension, myocardial ischemia, arrhythmias, cerebral pathology, and on medication such as Ca++ channel blocker, hypnotic or narcotic analgesic were not included in this study.
All patients received an uniform premedication with Inj. glycopyrrolate 0.2 mg I.M., 30 min before the start of anesthesia. Upon arrival in operative room, baseline HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MAP) were recorded by non invasive blood pressure automatic apparatus (model infinity vista by Drager) thrice at an interval of 1 min and mean of these three values were recorded as basal value. Other monitoring including Electrocardiogram and SpO2 were also recorded to observe any complications. After securing an intravenous line the study drug was injected slowly over a period of 2 min by a resident doctor who was not involved in the study and did not know the contents of the syringe. After 3 min of pre-oxygenation, the general anesthesia was induced with thiopentone sodium 5 mg/kg followed by succinylcholine 1.5 mg/kg. Endotracheal intubation with appropriate size tube was done and lungs were ventilated with O2:N2O (33%:66%) and 0.2% halothane using Bain's circuit with a fresh gas flow of 110 ml/kg. Muscle relaxation was provided by Inj. vecuronium 0.08 mg/kg (loading dose) and 0.02 mg/kg (incremental doses). All the patients were reversed with Inj. glycopyrrolate 0.4 mg and Inj. Neostigmine 2.5 mg at the end of the procedure.
HR, SBP, DBP, and MAP were recorded at 0 min (basal value), 1, 3, 5 min after the study drug, immediately after intubation and again at 1, 3, 5 min after the intubation. Rate pressure product (RPP) was calculated by formula: HR × SBP. Our study was terminated at 5 min after intubation, but all vitals were monitored throughout the anesthesia period as compulsory monitoring schedule. The observations recorded in both groups were tabulated and statistical analysis carried out by using appropriate statistical software (Epi Calc 2000 v1.02 version). Student t test was used for intra and inter group comparison. P > 0.05 was taken to be statistically insignificant, P < 0.05 taken statistically significant and P < 0.01 taken to be statistically highly significant.

BODY.RESULTS:
Both groups were comparable for their demographic data [Table 1] and baseline variables [Table 2].
Table 1Demographic data
Table 2Statistical analysis of various hemodynamic parameters
BODY.HR:
In group N, after an initial decrease in mean HR, clinically significant increase (+19.56%) was observed immediately after endotracheal intubation (IAETI). Thereafter, HR again started to decrease, but remained above the mean basal values. In contrast, a continuous increase in mean HR was observed maximum being at IAETI (+24.11%) in group P, which started to decrease thereafter but it, remained well above the mean basal values [Table 2].
On intergroup comparison these changes were statistically insignificant (P > 0.05) until IAETI, but became statistically highly significant (P < 0.01) towards the end of the study period [Table 3].
Table 3Inter-group comparison of various hemodynamic parameters

BODY.BP:
All the three parameters of BP namely SBP, DBP and MAP showed a similar pattern.
In group N, mean values of BP after an initial decrease until 5 min after the study drug showed a clinically significant rise at IAETI (maximum) and until 3 min thereafter, but fell below the mean basal values at the end of the study period. In group P, a continuous increase from mean basal values of BP were recorded throughout the study period maximum being at IAETI and remained well above the mean basal values at the end of the study period [Table 2].
On intergroup comparison, these changes were statistically insignificant (P > 0.05) until 5 min after study drugs, but became highly statistically significant a (P < 0.01) at IAETI and statistically significant (P < 0.05) toward the end of the study period [Table 3].

BODY.RPP:
In group N, after an initial fall in mean RPP a clinically significant rise (+28.42%) was observed at IAETI which decreased to + 2.72% at the end of the study period. In group P, a continuous increase in the mean RPP above the basal value was observed throughout the study period maximum being at IAETI (+42.0%). Although mean RPP decreased thereafter, but remained well above the basal value (17.7%) [Table 2].
On intergroup comparison, except for the initial 1 min after the study drugs all the changes were statistically highly significant (P < 0.01) [Table 3].


BODY.DISCUSSION:
In this comparative study, we evaluated the changes in hemodynamic parameter after the injection of the study drugs, and laryngoscopy and endotracheal intubation.
A non-significant fall (P > 0.05) in HR and all the three parameters of BP (SBP, DBP, MAP) till 3 min was observed with nalbuphine, which could be attributed to strong and predominant k agonistic action.[15] Further a non-significant (P > 0.05) rise in HR and fall in BP at 5 min of injection could be attributed to effect of thiopentone sodium used as an induction agent for general anesthesia, a drug very well known for producing hypotension and associated reflex induced tachycardia.[1617]
Both the drugs could not abolish the tachycardia associated with laryngocopy and intubation. A clinically significant rise in HR was observed with pentazocine (+24.11%) as compared to nalbuphine (+19.56%), although these values were statistically insignificant on intergroup comparison (P > 0.05). A statistically highly significant rise (P < 0.01) from basal mean values in all the three parameters of BP was observed immediately after intubation in both groups, but clinically this rise was more apparent with pentazocine. Ahsan-ul-Haq et al.[18] reported an increase in HR (+15.5%) and MAP (+10.5%) with nalbuphine immediately after intubation. Adachi et al.[13] reported that pentazocine 0.5 mg/kg failed to diminish the circulatory response to intubation.
RPP is a very sensitive index for myocardial work load and increased myocardial oxygen consumption.[19] In our study it is evident that nalbuphine is able to produce significant decrease in RPP as compared to pentazocine immediately after intubation (−28.42% and −42.0% respectively). Toward the end of the study period RPP returned very near to basal values in group N as against to group P (+2.12% and +17.7% respectively).
Both the drugs used in our study are mixed opioid agonist antagonist. Nalbuphine binds to μ, κ, and δ opioid receptors, and is primarily κ agonist and μ antagonist.[15] In group N, the initial fall in all the hemodynamic parameters is because of its strong and predominant κ agonistic action. Rise in hemodynamic parameters after intubation are due to sympathoadrenal stimulation.[20]
Pentazocine is a partial κ agonist and μ antagonist[21] and is known to cause an increase in arterial BP, HR, systemic vascular resistance and blood catecholamine levels while depressing the myocardial contractility and increasing the cardiac workload, which may be the cause of the steady rise in all the hemodynamic parameters in group P.

BODY.CONCLUSION:
We conclude that nalbuphine effectively reduces the tachycardia, hypertension, and cardiac workload associated with laryngoscopy and endotracheal intubation.

Question: Compared to pentazocine 0.5 mg/kg what was the result of nalbuphine 0.2 mg/kg on Rate pressure product (RPP)?
Evidence: .
On intergroup comparison, these changes were statistically insignificant (P > 0.05) until 5 min after study drugs, but became highly statistically significant a (P < 0.01) at IAETI and statistically significant (P < 0.05) toward the end of the study period [Table 3
Answer: significantly decreased