COMPARATIVE STUDY BETWEEN KETAMINE AND PROPOFOL COMBINATION VERSUS PROPOFOL ALONE FOR SEDATION OF PATIENTS UNDERGOING UPPER GASTROINTESTINAL TRACT ENDOSCOPY

COMPARATIVE STUDY BETWEEN KETAMINE AND PROPOFOL COMBINATION VERSUS PROPOFOL ALONE FOR SEDATION OF PATIENTS UNDERGOING UPPER GASTROINTESTINAL TRACT ENDOSCOPY

By

El-Sayed Ahmed El-Feqy, Ahmed Mahmoud Mohamed El-Garhey and Abd El-Azeim Maamon Dawoud*

Department of Anesthesiology and Intensive Care, Faculty of Medicine, Al-Azhar University

*Corresponding author: Abd El-Azeim Maamon Dawoud,

E-mail: abdomaamon90@gmail.com

ABSTRACT

Background: Upper gastrointestinal (GI) endoscopy can cause pain and anxiety to the patients which in turn lead to hemodynamic instability and impairment in the patient tolerance. Consequently, adequate sedation and analgesia are required in such procedure to maintain the optimal conditions for patient's relief and recovery.

Objective: This work aimed to determine whether the use of ketofol instead of propofol resulted in fewer adverse respiratory events requiring physician intervention when used for procedural sedation and analgesia.

Patients and Methods:  After approval of the Medical Ethical Committee at Al-Azhar University Hospitals, and after patient written consents, 60 patients of American Society of Anesthesiologists (ASA) physical status I or II, scheduled for elective upper GI endoscopy under sedation  were enrolled in this randomized, controlled, prospective, double-blind, clinical trial study.  Patients were randomly assigned into two equal groups:

Group (I)  received 0.5 mg /kg propofol i.v.  Within a period of 30-40 seconds.

Group (II)  received 50mg ketamine plus 0.5 mg/kg propofol in 10 ml normal saline within a period of 30-40 seconds.

Results: The dose of propofol was equal in both groups. Hypoventilation was significantly lower in the group (ІІ), compared to the group (І).

     No significant difference was reported between both groups regarding hypoxia, heart rate, adverse effects, and systolic blood pressure, recorded after the procedure and 25-minute after the onset of procedure. Systolic blood pressure was significantly higher in the group (ІІ), compared to the group (І), throughout the 20 minutes following propofol induction.

Conclusion: Combination of propofol and ketamine used for procedural sedation and analgesia in upper GI endoscopy had higher safety than the propofol alone. Respiratory and hemodynamic stability were more noted in the ketofol group than the propofol-only group.

Key words: Ketamine, Propofol, Deep sedation, upper GI endoscopy.

INTRODUCTION

     Propofol is a commonly used anasthetic agent characterized by sedative, amnesic and anxiolytic effects, but no analgesic effect. It has an early-onset action with a single dose and a short half-life. So, it is characterized by rapid recovery (Shah et al., 2011).

     Ketamine is a non-barbiturate anasthetic agent that binds to N-methyl D-Aspartate (NMDA) receptors, causing dissociative anesthesia. It has acceptable analgesic and sedative effects, with minimal cardiovascular risk (Ozgul et al., 2013).

     This study was designed to determine whether the use of Ketofol, compared to propofol results in fewer adverse respiratory and hemodynamic events when used for procedural sedation and analgesia in upper GI endoscopy.

PATIENTS AND METHODS

     After approval of the Medical Ethical Committee at Al-Azhar University Hospitals, and after patient written consents, 60 patients of American Society of Anesthesiologists (ASA) physical status I or II, scheduled for elective upper GI endoscopy under sedation  were enrolled in this randomized, controlled, prospective, double-blind, clinical trial study from April 2019 to September 2019 after .

Preoperative preparation: Routine preoperative assessment was done for all patients on the day before operation including history, clinical examination    and laboratory investigations.

Anesthetic technique: All patients were secured by peripheral intravenous line. They received 4 ml/ kg/h Ringer Lactate solution, 2 liters of nasal O2 during the procedure, and 0.03 mg/kg midazolam IV as a premedication.

Group (I) received 0.5 mg/kg propofol i.v.  In a period of 30-45 second. If patients did not achieve adequate sedation (Ramsey 4 on Ramsey sedation scale) after 2 min, another dose of 0.5 mg/kg propofol was applied every 2 min. The maximum dose of propofol was 2 mg/kg.

Group (II) received 50 mg ketamine plus 0.5 mg/kg propofol i.v. in 10 ml normal saline combination in a period of 30-45 second. If patients did not achieve adequate sedation (Ramsey 4 on Ramsey sedation scale) after 2 min., the same dose of this combination every 2 min. was given Pre defined maximum dose for ketamine-propofol was 2 mg/kg.

     The Ramsay sedation scale was widely used for assessment of the depth of anathesia. The depth of sedation was maintained at the level 6 of Ramsay sedation scale throughout the procedure (Dawson et al., 2010).

     Recovery from sedation was evaluated every 5 minutes, following end of the procedure, using the Modified Aldrete Score (MAS). The MAS was the standard post-anathetic recovery scoring system. MAS ≥9 was required before discharge from the recovery unit (Valasareddy et al., 2018).

     Peripheral O2 saturation, respiratory rate (RR), blood pressure, heart rate (HR), ECG, and capnography were detected preoperatively and every five minutes during the procedure.

     Sample size was calculated using STATA version 11 programs, setting the type -1 error (α) at 0.05 and the power (1-β) at 0.8. According to Tutal et al. (2016), the percentage of respiratory distress among the propofol group was 19.1% compared to none among the ketofol group. Accordingly, 30 cases were required in each group.

     Our primary outcome was the occurrence of respiratory events, such as hypoxia, (defined as SPO2 < 93%), and hypoventilation (defined as RR < 8 breath/min). The secondary outcomes included HR, BP, nausea, vomiting, aspiration, emergence delirium, and laryngospasm.

Statistical analysis:

     Data were analyzed based on the t-test and the P-value, using the statistical software package SPSS for Window Version 20.0. Quantitative data were expressed as medians (ranges), means ± standard deviation (SD), whilst qualitative data were expressed as frequency and percentage. The Chi-square (X2) test was used to compare the incidence of two qualitative parameters. All data were statistically compared at the two-sided 5% level of significance. P-value <0.05 was considered significant.

RESULTS

Sixty patients were eligible for our procedure. They were randomized into either the ketofol group or the propofol-only group, 30 patients for each. No statistically significant difference was found between the the two groups, regarding the patients demographic characteristics (Table 1).

Table (1) : Demographic characteristics of the study groups

     Hypoxia and hypoventilation were demonstrated and compared between both groups. Patients group I showed higher frequency of hypoxia, compared to the group II , 5 cases (16.7%) , 1 case (3.3%) respectively (P >0.05). Three cases (10.0%) in group II, and 13 cases (43.3%) in group I had hypoventilation, which was statistically significant (Table 2).

Table (2): Comparison between groups regarding side effects and respiratory events

     Regarding oxygen saturation, our results showed a highly statistically significant difference between groups at 5, 10 and 20 minutes following induction. At 25 min, group ІІ was not significantly different from  group І (Table 3).

Table (3): Comparison between groups according to SPO2

     Our results showed that group ІІ had higher cardiovascular stability than group І. Regarding the systolic blood pressure (SBP), there was a statistically significant difference between both groups at 5, 10, 15, and 20 minutes following induction. At 25 min, the ІІ group was not significantly different from the  group І  (Table 4).

Table (4): Comparison between groups according to SBP

     As regared heart rate, there was no statistically significant difference between groups (Table 5).

Table (5): Comparison between groups according to heart rate

     Regarding the side effects, group II showed no statistically significant difference, compared to group I in terms of nausea, vomiting, aspiration, emergence delirium and laryngeal spasm  (Table 6).

Table (6): Comparison between groups according to side effects.

DISCUSSION

     This study highlighted the safety of adding ketamine to propofol for procedural sedation and analgesia in upper GI endoscopy. Ketamine is N-methyl-D-aspartate receptor antagonist, which is primarily used as a hypnotic with analgesic effects. Indeed, it has minimal respiratory side effects, compared to other hypnotics like propofol. Importantly, it preserves the heart rate and the blood pressure, which is attributable to its protective sympathomimetic activity (Peltoniemi et al., 2016). Nevertheless, high doses might cause hallucination, visual problems, nausea, vomiting and laryngospasm (Tutal et al., 2016).  Propofol is a commonly used sedative agent because of its short half-life, amnestic, anxiolytic, and antiemetic properties. Nevertheless, serious side effects may limit its spread such as respiratory depression, and hypotension. Hypotension is attributed to decreased cardiac output, and peripheral vascular resistance (Tutal et al., 2016). Indeed, propofol is combined to ketamine, in an attempt to reduce these side effects. The combination of propofol and ketamine  has  been  efficiently  used, either separate or in the same syringe, in variety of settings, including  coronary  artery  surgery  in  adults,  interventional radiology,  sedation  for  spinal  anesthesia, gynecological  and ophthalmological procedures (Aydogan et al., 2013).

     Hypoventilation was significantly more frequent in the propofol-only group, compared to the ketofol group (43.3% vs 10.0% respectively). Our results agreed with Tandon et al. (2014) who compared ketofol to propofol in upper GIT endoscopy and showed that airway assistance  was  used in  15%  in the  propofol group  compared  to 3%  in  the ketofol  group. Nevertheless, the study done by Ferguson et al. (2016), comparing the two drugs showed close results between the two groups. Hypoventilation was noted in 9% with  ketofol  and  4%  with  propofol,  and  respiratory interventions  in  14%  with  ketofol  and  16%  with  propofol. This discrepancy may be attributable to the different applied procedures and the confounding effect of opioids.

     According to hypoxia, no statistically significant difference was found between both groups. This result agreed with Ferguson et al. (2016) with occurence of hypoxia in 8% of patients with propofol, and 6% of patients with ketofol. Aspiration did not occur is any patient with both groups.

     Our  study  showed  that  using  propofol  alone  led  to significant  decrease  in  blood  pressure  as  hypotension occurred  in  30%  of  the  patients,  but  the  addition  of ketamine  to  propofol  has  aborted  the  hemodynamic instability  that  occurred  with  propofol alone  as  hypotension  occurred  in  6.7%  of  the  patients  with ketofol. Propofol decreases systemic vascular resistance, cardiac contractility, and the preload, which all cause a decrease in arterial blood pressure. Propofol also inhibits arterial baroreflex and hypotension induced tachycardia (Stayer et al., 2010). There are some previous studies  that  reported  propofol-ketamine  combination  is  safe in  means  of  hemodynamic  stability  in  groups  of  pediatrics, emergency  room,  and  regional  analgesia  patients (Tutal et al., 2016).

     Smischney et al. (2012)  compared  ketamine-propofol and  propofol  in  general  anesthesia  induction  and  reported lower  myocardial  depression  and  vasodilation  in  the ketamine-propofol group.

     Providers  have  typically  been  reluctant  to  use ketamine  in  adults  because  of  concern  about  emergence phenomena,  with  rates  of  10% to 20% being quoted in the literature (Ferguson et al., 2016). The rates of unpleasant emergence delirium in our study were lower suggesting that in this regimen,  one  of  the  adverse  events  most  likely  to  deter providers  from  the  use  of  ketamine  is  less  likely  to  occur with ketofol than when ketamine is used as a single agent. A previous randomized controlled trial by  Perumal et al. (2015) who used ketamine with and  without  midazolam  for  emergency department sedation in adults showed a similar reduction in emergence phenomena when midazolam was combined with ketamine  in  adults. 

CONCLUSION

     Ketofol was a good choice for safe and effective sedation and analgesia in patients undergoing upper GI endoscopy. It resulted in less adverse respiratory events and a better hemodynamic stability. The frequency of postoperative nausea, vomiting and delirium were comparable in both groups.

CONFLICTS OF INTEREST

     There were no conflicts of interest regarding the present study.

REFERENCES

1. Aydogan, H., Aydogan, T., Uyanikoglu, A., Kucuk, A., Yuce, H., Karahan, A. and Yalcin, S. (2013): Propofol-ketamine combination has shorter recovery times with similar hemodynamics compared to propofol alone in upper gastrointestinal endo-scopy in adults. A randomized trial. Acta Medica, 29: 77-82
2. Dawson, R., von Fintel, N. and Nairn, S. (2010): Sedation assessment using the Ramsay scale. Emergency Nurse, 18(3): 18-20.
3. Ferguson, I., Bell, A., Treston, G., New, L., Ding, M. and Holdgate, A. (2016): Propofol or ketofol for procedural sedation and analgesia in emergency medicine the POKER studies: a randomized double-blind clinical trial. Annals of Emergency Medicine, 68(5): 574-582.‏
4. Ozgul, U., Begec, Z., Karahan, K., Erdogan, M. A., Aydogan, M. S., Colak, C. and Ersoy, M. O. (2013): Comparison of propofol and ketamine-propofol mixture (Ketofol) on laryngeal tube-suction II conditions and hemodynamics: a randomized, prospective, double-blind trial. Current Therapeutic Research, 75: 39-43.
5. Peltoniemi, M. A., Hagelberg, N. M., Olkkola, K. T. and Saari, T. I. (2016): Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clinical Pharmacokinetics, 55(9): 1059-1077.
6. Perumal, D., Adhimoolam, M., Selvaraj, N., Lazarus, S. and Mohammed, M. (2015): Midazolam premedication for ketamine-induced emergence phenomenon: a prospective observational study." Journal of Research in Pharmacy Practice, 4(2 ):89-93.
7. Shah, A., Mosdossy, G., McLeod, S., Lehnhardt, K., Peddle, M. and Rieder, M. (2011): A blinded, randomized controlled trial to evaluate ketamine/propofol versus ketamine alone for procedural sedation in children. Annals of Emergency Medicine, 57(5): 425-433.
8. Smischney, N., Beach, M. L., Loftus, R. W., Dodds, T. M. and Koff, M. D. (2012): Ketamine/propofol admixture (ketofol) is associated with improved hemodynamics as an induction agent: a randomized, controlled trial. Journal of Trauma and Acute Care Surgery, 73(1): 94-101.
9. Stayer, Stephen A. and Yang Liu. (2010):  Pulmonary hypertension of the newborn.  Best practice and research Clinical anaesthesiology, 24 (3): 375-386.‏
10. Tandon M, Pandey VK, Dubey GK, Pandey, C. and Wadhwa, N. (2014): Addition of sub anaesthetic dose of ketamine reduces gag reflex during propofol based sedation for upper gastrointestinal endoscopy: a prospective randomised double-blind study. J Anaesth. , 58(4):436-441.
11. Tutal, Z. B., Gulec, H., Derelı, N., Babayıgıt, M., Kurtay, A., Inceoz, H. and Horasanlı, E. (2016): Propofol-ketamine combination: a choice with less complications and better hemodynamic stability compared to propofol? On a prospective study in a group of colonoscopy patients. Irish Journal of Medical Science , 185(3) : 699-704.‏
12. Valasareddy, K., Titu, G., Anil, R., Segaran, K., George, K. and Ranjan, R. (2018): Recovery Profile Using Modified Aldrete Score in Post Anaesthesia Care Unit After Sevoflurane or Desflurane Anaesthesia: A Prospective Randomised Study. Journal of Clinical and Diagnostic Research, 12(9) : 1-4.