Efficacy of Adding Low-Dose Ketamine to Dexmedetomidine Versus Low-Dose Ketamine and Propofol for Conscious Sedation in Patients Undergoing Awake Fiber-optic Intubation.

BACKGROUND AND AIMS: Conscious sedation is the key for successful AFOI. This trial was conducted to compare the effectiveness of dexmedetomidine and low dose of ketamine against propofol and low dose ketamine.
MATERIALS AND METHODS: Sixty patients subjected for general anesthesia were invited to participate in the study and randomly allocated into two equal groups: D-K (n = 30) had been received a bolus dose of both ketamine 0.5mg /kg and dexmedetomidine 1ug/kg over 10 min. Then continuous infusion of ketamine 0.5mg /kg and dexmedetomidine 1ug/kg. The second group (P-K group) (n = 30): had been received a bolus dose of both ketamine 0.5mg/kg and propofol 1mg/kg over 10 min. Then continuous infusion of ketamine 0. 5mg/kg and propofol 1mg/kg.
RESULTS: The intubation time was statistically significant shorter within the D-K group (58.9 ± 6.1) versus P-K group (63.4 ± 5.3) with p-value 0.02. The shorter time needed to achieve the OAA/S score = 2 was in the D-K group (2.25 ± 0.75) versus (2.9 ± 0.79) in P-K group with (P-value 0.004). The intubation scores were insignificant different between both groups except vocal cord opening which was statistical better among D-K group with P-value 0.03. The significant hypotensive recorded data were among P-K group while the decreased heart rate were recorded in D-K group. Eighty percentages of patients had excellent score of satisfaction within the D-K gp against 47% among the patients within P-K gp with P-value 0.01.
CONCLUSION: The concomitant administration of low dose of ketamine with dexmedetomidine had better intubation time and sedation scores with higher patient satisfaction scores than the combination of propofol and low dose of ketamine.

INTRODUCTION

Awake fiber-optic intubation (AFOI) is considered the standard option in dealing with the cases with anticipated difficult airway. Proper conscious sedation is the paramount to increase the tolerability of the intubation and increase its success.[1]

For this purpose, various pharmacological drugs have been tested to provide the proper conscious sedation.[2345] Propofol is the most commonly used intravenous (IV) induction anesthetic agents, but it had been used for AFOI in sparse studies.[678] Propofol is not preferred to be used alone because of increased risk of oversedation and consequently the airway obstruction, but its main benefit is the low incidence of recall. Therefore, it is used in combination with benzodiazepines and/or opioids to minimize the side effects and improve its efficacy.[91011]

Dexmedetomidine has been tested for AFOI in many studies with favorable results.[121314] The comparison between dexmedetomidine and propofol had been done by Tsai et al.[15] They found that both provided satisfactory intubation conditions, but propofol group had more agitation and airway obstruction while dexmedetomidine had a higher recall and grosser limb movement.

Ketamine when used alone causing higher incidence of intense cough. Also, when ketamine added to remifentanil, the incidence of cough had increased from 12% to 44% but without causing desaturation.[16] However Scher et al.[17] had reported the value of adding ketamine to dexmedetomidine by countering the bradycardia effect associated with the dexmedetomidine.

Combination of both dexmedetomidine and propofol has been tested with ketamine and found effective.[1718] However, according to our knowledge, there is no report in English literature compared between dexmedetomidine and propofol with the addition of low dose of ketamine.

We hypothesized that the addition of low dose of ketamine to dexmedetomidine and propofol will counteract the drawbacks of these agents, and both regimens will have at least equal efficacy in intubation conditions without respiratory depression.

PATIENTS AND METHODS

The prospective randomized cohort study had been started after getting the coded number of acceptances from the local Institutional Research Board (coded number is 17.07.32) and the signed written informed consent from the participating patients. The patients who were scheduled for elective surgery under general anesthesia of either sex, aged from 18 to 60 years old, with the physical status I or II according to the American Society of Anesthesiologists (ASA) and the body mass index (BMI) <30 kg/m2, were invited to participate in this study.

Patients’ refusal or uncooperative patients such as those with mental retardation, lack of communication, blindness, and deafness were excluded from the study. Furthermore, patients who had coagulation disorders, respiratory or pulmonary disorders, pregnancy or full stomach, increased intracranial pressure or intraocular pressure, and emergency surgeries or allergy to the drug used in the study or with risk for regurgitation–aspiration were excluded from the study.

Before the operation, every patient was assessed adequately by history, full clinical examination, and routine laboratory investigations. The airway assessment was done by the Simplified Airway Risk Index score.[19] Preanesthetic visit was performed to explain the technique, including steps, benefits, and safety, and to evaluate the patient's best cooperation. The instruction for fasting had been applied as usual. Ranitidine tablet 150 mg and ondansetron tablet 4 mg were given as premedication 2 h before the scheduled surgery.

In the operative theater, peripheral two IV cannulas of 18 gauges were inserted and 500 ml of saline 0.9% was given. Fifteen minutes before the start of the procedures, 0.5 mg/kg atropine was given intravenously. The standard monitoring devices which include 5-lead electrocardiography, noninvasive blood pressure cuff, and pulse oximetry were connected to the patient, and the data were monitored. Meanwhile, the usage of 5-ml lidocaine 2% had been placed in the cup of nebulizer which connected to oxygen flowmeter for 10 min. Furthermore, the preparation of fiber-optic bronchoscope (Karl Storz, working length: 65 cm, distal tip diameter: 3.7 mm) had been done by checking of light source and refocusing on a gauze piece. Defogging of the bronchoscope had been done by 70% isopropyl alcohol. The light lubrication of the bronchoscope with lidocaine jelly along its entire length facilitates the passage of endotracheal tube (ETT). The bronchoscope was loaded with appropriate size cuffed polyvinyl chloride ETT after proper lubrication.

The eligible patients were randomly classified using computer-generated randomization list into two groups. In the first group, dexmedetomidine and ketamine group (D-K group) (n = 30), patients had received a bolus dose of both ketamine 0.5 mg/kg and dexmedetomidine 1 ug/kg over 10 min, followed by continuous infusion of ketamine at a rate of 0.5 mg/kg and dexmedetomidine at a rate of 1 ug/kg. The drugs were infused using two separate syringe pumps.

In the second group, propofol and ketamine group (P-K group) (n = 30), the patients had received a bolus dose of both ketamine 0.5 mg/kg with propofol 1 mg/kg over 10 min, followed by continuous infusion of ketamine at a rate of 0.5 mg/kg and propofol at a rate of 1 mg/kg. The drugs were infused using two separate syringe pumps.

The sedation level of the patient was assessed using Modified Observer's Assessment of Alertness/Sedation (OAA/S) Scale once per minute after giving the bolus dose where 5 = responds readily to name spoken in normal tone, 4 = lethargic response to name spoken in normal tone, 3 = responds only after name spoken loudly or repeatedly, 2 = responds after mild prodding or shaking, and 1 = does not respond to mild prodding or shaking.[20] When achieved the desired level of sedation score = level 2, topical anesthesia of the oropharynx was applied with 3 buffs of 10% lidocaine spray.

Afterward, the fiberoptic bronchoscope which mounted with ETT was introduced through the mouth and advanced till the posterior aspect of the tongue or visualization of the epiglottis. The tip of fiberoptic bronchoscope was directed downward when the posterior pharyngeal wall was encountered. If the epiglottis obstructed the vision of the vocal cords; redirection or rotation of the bronchoscope was done. After that it was advanced across the vocal cords to reach the trachea. Finally the lubricated ETT was slided over it into the trachea and fixed at 2-3cm above the carina. Before withdrawn the bronchoscope, the inflation of cuff was done. The correct placement of the tracheal tube had been confirmed by the wave form of capnography and chest auscultation. General anesthesia had been administrated and the infusion drugs were discontinued.

The intubation time (from inserting the fiber-optic scope into the mouth till the confirmation of tracheal intubation with capnography) was recorded as the primary outcome. Furthermore, the time taken to achieve sedation ([OAA/S] scale = 2) and intubation scores during the intubation procedure were recorded.

Heart rate (HR), mean arterial pressure (MAP), and peripheral oxygen saturation (SpO2) were recorded before starting bolus dose of sedative drugs (basal), after injection of bolus dose, during bronchoscope introduction, 2 and 5 min after tracheal intubation. Hypotension (reduction of MAP >20% from baseline) was treated with IV fluid and/or phenylephrine 50 mg IV bolus, repeat dose after 5 min. Bradycardia which means reduction of HR <60 beats/min was treated with atropine 0.6 mg IV. Oxygen desaturation (SpO2 <90% for ≥10 s) was treated with oxygen supplementation either through a nasal cannula or oxygen port of bronchoscope. Apnea was defined as the absence of spontaneous respiration for >15 s. If hypoxemia or apnea occurred, spontaneous respiration was encouraged by vocal or tactile stimuli.

The postoperative visit had been done after 24 hours to ask the patients about; the recall (memory of intubation), any adverse events (sore throat, hoarseness of voice) and recording the satisfaction score of the procedure (1 = excellent, 2 = good, 3 = fair and 4 = poor) were recorded. The occurrence of any possible complications such as desaturation (SpO2 less than 90%), vomiting, trauma, or coughing was also recorded.

Statistical analysis

On the basis of a pilot study and using a priori G program, the sample size was 25 patients in each group with 30% difference in intubation time. The power of the study was 0.9 and a Type 1 error was 0.05. The consideration of nearly 20 % of cases can be drop out, therefore 30 patients were invited in each group.

The statistical evaluation was done using IBM® SPSS statistics (Statistical Package for the Social Sciences) for windows (version 24) United States. Mann–Whitney U-test was used for nonparametric data and Fisher's exact test was used for categorical data. The normality of the data was checked using the Shapiro–Wilk test. The expression of continuous variables was expressed as mean (standard deviation), but the categorical variables were expressed as proportion (%). The data were considered statistically significant if P ≤ 0.05.

RESULTS

During the period of the study which had been started from August 2017 till August 2018, sixty patients were enrolled and analyzed their data as shown in Figure 1. The included patients were 31 males and 29 females. Both groups were comparable as regard sex, age, body mass index and ASA physical status as shown in Table 1.

Figure 1

Study flow diagram

Table 1

Patient characteristics of the two studied groups

	D-K group (n=30)	P-K group (n=30)	P
Age (years)	43.6±11.6	40.80±13.5	0.6
Sex
Male	56% (17)	46% (14)	0.7
Female	40% (13)	60% (16)
BMI	27.9±2.5	29.2±1.6	0.4
ASA-PS (I/II)	18/12	17/13	0.7

BMI=Body mass index, ASA-PS=American Society of Anesthesiologists’ physical status. Values are in mean±SD, number and %.

The intubation time was statistically significant shorter within the D-K group (58.9 ± 6.1) versus P-K group (63.4 ± 5.3) with P-value 0.02. Also, the time needed for the OAA/S score to achieve = 2 was statistically shorter in D-K group (2.25 ± 0.75) versus (2.9 ± 0.79) in P-K group with (P-value 0.004) as presented in Table 2.

Table 2

Intubation time and the time taken to achieve Observer’s Assessment of Alertness/Sedation=2 within the studied groups

	D-K group (n=30)	P-K group (n=30)	P
Intubation time (s)	58.9±6.1	63.4±5.3*	0.002
The time taken to achieve OAA/S=2 (min)	2.25±0.75	2.9±0.79*	0.004

OAA/S=Observer Assessment of Alertness/Sedation. Values are in mean±SD. *: Statistically significant P ≤ 0.05, when compared with the other group

In spite of that, all patients had a successful AFOI, but there was a statistical significant better vocal cord opening among the D-K group than P-K group with (P = 0.03). The other items of intubation scores which include cough and limb movement did not have a statistical significant difference among both groups, as plotted in Table 3.

Table 3

Intubation scores in the two studied groups

	Grade	D-K group (n=30)	P-K group (n=30)	P
Vocal cord movement	Open	80% (24)*	47% (14)	0.03
	Moving	20% (6) *	50% (15)
	Closing	-	3% (1)
	Closed	-	-
Coughing	None	83% (25)	77% (23)	0.27
	Slight	17% (5)	20% (6)
	Moderate	-	3% (1)
	Severe	-	-
Limb movement	None	47% (14)	47% (14)	0.66
	Slight	47% (14)	50% (15)
	Moderate	6% (2)	3% (1)
	Severe	-	-

Values are in number and %. *: Statistically significant P ≤ 0.05, when compared with the other group

There was a statistically significant reduction in HR among the D-K group in comparison with P-K group during the introduction of bronchoscope, 2 min, and 5 min after tracheal intubation with P = 0.017, 0.07, and 0.039, respectively, as shown in Figure 2a. In contrast, the MAP showed a statistically significant reduction in P-K group versus D-K group during the same readings with P = 0.001 as shown in Figure 2b. While there was no significant difference between the studied groups as regard peripheral oxygen saturation (SpO2) as presented in Figure 2c.

Figure 2

(a) The recorded changes in the heart rate in both the studied groups. (b) The recorded changes in the mean blood pressure in both the studied groups. (c) The recorded changes of the peripheral oxygen saturation in both the studied groups

The satisfaction score was statistically significantly higher among the patients within the D-K group with 80% of patients who had an excellent score against 47% among the patients within P-K group with P = 0.01, as shown in Table 4.

Table 4

Satisfaction score, patients’ recall of the event, and adverse effects in the two studied groups

	Grade	D-K group (n=30)	P-K group (n=30)	P
Satisfaction score (1-4)	Excellent	73% (22)	66% (20)*	0.01
	Good	25% (7)	30% (9)
	Fair	2% (1)	4%(2)
	Poor	-	-
Patients’ recall		7% (2)	-	0.15
Adverse events	Sore throat	33% (10)	47% (14)	0.3
	Hoarseness of voice	16% (5)	30% (9)
	Hypoxic episodes	-	10% (3)

Values are in number and %. *: Statistically significant P ≤ 0.05, when compared with the other group

There was no statistically significant differences displayed among both groups as regards Patients’ recall (memory of intubation) and adverse effects whether sore throat or hoarseness of voice in Table 4.

DISCUSSION

AFOI is a recommended method for securing airway in the predicted difficult airway scenarios. It offered many troubles for the patients as well as the anesthetist. Hence, the goals are to maintain the comfort level of the patient and ease for the anesthetist. These goals could be achieved by a sedative drug when administrated resulted in better cooperation of the patient, hemodynamic stability, and maintained patent airway with spontaneous ventilation.

The concomitant administration of low dose of ketamine with dexmedetomidine had better intubation time and sedation scores with higher patient satisfaction scores than the combination of propofol and low dose of ketamine.

The intubation time was significantly shorter in the dexmedetomidine and ketamine group than the other group. This could be explained by the more favorable vocal cord opening which recorded significantly among this group. This is in accordance with Tsai et al.[15]

The satisfaction score was statistical significant better within dexmedetomidine group and ketamine. This is because of the difference between dexmedetomidine and propofol in sedation profile. The sedative effects of both had been studied in intensive care.[2122] The sedative effect of dexmedetomidine was characterized by easily arousal to cooperate and obey the orders without expressing irritability. This is very helpful during AFOI when the patient instructed to take deep breath or clear secretion.

Dexmedetomidine was advocated for AFOI on the basis of its ability to produce sedation with easily arousability, analgesia with amnesia, and anxiolysis. Its antisialagogue and respiratory-sparing effect make it a unique drug for AFOI. Dexmedetomidine activates the postsynaptic α-2-adrenal receptors in the locus coeruleus and induces sedation by activation of the endogenous sleep-promoting pathway without the risk of airway obstruction and respiratory depression.[23] However, when used with large and rapid initial loading doses (1–2 ug/kg over 2 min), it caused respiratory complications such as irregular ventilation which may extend to episodes of apnea and a peak dose of hypertension which may exacerbate a bradycardia-related fall in cardiac output.[312] To avoid these untoward complications with high doses of dexmedetomidine, we used it with low dose of ketamine.

Hemodynamic stability was achieved in both groups but with more bradycardic effect within D-K group and hypertensive effect in P-K group. The bradycardic effect could be explained mainly by the reduction in norepinephrine release due to activation of presynaptic alpha 2 receptors in the peripheral nervous system. The sympatholytic effect of dexmedetomidine which presented by hypotension and bradycardia was counteracted by the cardiostimulatory effects of ketamine. This is in agreement with Sinha et al.[24] who had compared between D-K in the first group and dexmedetomidine alone in the second group. The hemodynamic stability was more evident within the first group due to the addition of ketamine.

This finding was in agreement with Chalam[25] who compared two IV regimens dexmedetomidine against propofol for AFOI in patients with cervical discectomy. There was a statistical significant fall in HR after 5 min of bolus infusion within the dexmedetomidine group (68.60 ± 7.28) against the propofol group (77.72 ± 8.69). However, Salem et al.[26] concluded no statistical significance variation in HR within dexmedetomidine and propofol. The contrast with our results owing to the difference in doses, difference in procedure and the usage of fentanyl.

While the hypotensive effect recorded within the group of propofol and ketamine could be attributed due to the peripheral vasodilation caused by the inhibitory effect on the sympathetic outflow and depression of myocardial contractility.[27] The result of this study passes in accordance with Techanivate et al.[28] who compared which of dexmedetomidine or propofol had more hypotensive effect during colonoscopy. They concluded that the incidence of hypotension in propofol group was significantly greater than dexmedetomidine (50% vs. 20% with P = 0.015).

The administration of combination of P-K had been suggested theoretically because the pitfalls of both drugs are dose dependent. Therefore, the combination will reduce the dosage of each drug. Moreover, both drugs had an opposing cardiovascular effect. This combination had been tested by Erdogan Kayhan et al.[18] in patients who had received electroconvulsive therapy and they found more stability in respiratory and hemodynamic effects.

Limitation

The main limitation of our study was the comparison of fixed doses of dexmedetomidine and propofol. Therefore, we recommended further studies comparing different doses of dexmedetomidine or propofol in combination with ketamine.

CONCLUSION

The present study demonstrated that dexmedetomidine is better than propofol when used for conscious sedation during AFOI in patients with anticipated difficult airway as dexmedetomidine appeared to offer better patient tolerance, better preservation of a patent airway, spontaneous ventilation, better analgesia, and less effect on hemodynamic variables, in comparison to propofol. These properties make it a useful drug for providing conscious sedation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.