Research and Opinion in Anesthesia & Intensive Care

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 7  |  Issue : 2  |  Page : 182--187

Sedation of mechanically ventilated patients in intensive care units: Dexemedetomidine versus ketofol


Ghada F Amer 
 Department of Anesthesia and Surgical Intensive Care, Mansoura University, Mansoura, Egypt

Correspondence Address:
MD Ghada F Amer
Department of Anesthesia and Surgical Intensive Care, Mansoura Faculty of Medicine, Mansoura University, 3 Elgomhoriya Street, Mansoura City, Dakahlia, 35516
Egypt

Abstract

Background Patients in the ICUs are usually provided with sedation and analgesia to avoid pain and anxiety, facilitate invasive maneuvers, decrease stress and oxygen utilization, and facilitate mechanical ventilation. The Association of Critical Care Medicine recommends the use of nonbenzodiazepine drugs such as propofol and dexmedetomidine in sedating the intensive care patients to improve outcomes. Usual sedation protocols should be changed by incorporating propofol, dexmedetomidine, or drug combinations to reach arousal targets and decreasing benzodiazepine use. Objectives The study was conducted to compare between the sedative effect of dexmedetomidine versus ketamine–propofol combination (ketofol) in ICU patients on mechanical ventilation. Patients and methods A total of 90 patients who needed sedation for postoperative mechanical ventilation and monitoring in ICUs were randomly allocated into two groups: ketofol group, where sedation of the patients was done with ketofol at a loading dose of 500 μg/kg of ketamine and propofol mixture 1 : 1 (ketamine 8 mg/ml and propofol 8 mg/ml), followed by continuous infusion at 8–10 μg/kg/min, and dexmedetomidine group, where patients were sedated with an initial bolus dose of dexmedetomidine of 2 µg/kg intravenous infused over 10 min followed by infusion rate of 0.3–0.5 µg/kg/h. Patients’ hemodynamics, Ramsay sedation scale, and total analgesic requirement were recorded. Results Mean blood pressure and heart rate were statistically significantly lower in dexmedetomidine group than in ketofol group. Ramsay sedation score was clinically efficient in both groups but statistically higher in dexmedetomidine group than ketofol group. Dexmedetomidine group showed faster recovery time and less analgesic requirement than ketofol group. Conclusion Dexmedetomidine is an effective sedative drug for ICU patients, with more hemodynamic stability, less analgesic requirement, and rapid recovery time than ketofol.



How to cite this article:
Amer GF. Sedation of mechanically ventilated patients in intensive care units: Dexemedetomidine versus ketofol.Res Opin Anesth Intensive Care 2020;7:182-187


How to cite this URL:
Amer GF. Sedation of mechanically ventilated patients in intensive care units: Dexemedetomidine versus ketofol. Res Opin Anesth Intensive Care [serial online] 2020 [cited 2020 Oct 24 ];7:182-187
Available from: http://www.roaic.eg.net/text.asp?2020/7/2/182/287985


Full Text

 Introduction



Sedation of mechanically ventilated patients within the ICU is done to ensure comfort of the patient and decrease anxiety. Optimum sedation is recognized as an important tool in improving patient outcomes [1]. Mechanically ventilated patients in the surgical ICU need sedation to stand the endotracheal intubation and the ventilator and to suppress cough and avoid respiratory irritation during intensive care procedures such as bronchial suction, physiotherapy, and catheter placement [2].

The ideal sedative drug should permit rapid change of the level of sedation by changing the dose and should not cause cardiovascular system (CVS) or respiratory depression [3]. It is preferred to be cheap, with short duration, and should have no cumulative effects, permitting for rapid recovery of spontaneous respiration after stoppage of its infusion in patients on mechanical ventilation [4],[5].

Propofol is a hypnotic agent with rapid onset and short duration of action. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that binds to opioid and sigma receptors, leading to dissociative anesthesia, amnesia, and analgesia [6].

Ketofol, a combination of ketamine and propofol in a single syringe, has been shown to be effective in the operating theater and in day case surgeries. It has the advantage of minimizing the respiratory and hemodynamic effects of its constituent drugs [7]. Combined administration of ketamine and propofol was found to decrease the dose of propofol needed for sedation [8]. However, the use of ketofol is a new practice for intensivists, and there are limited data on its use as a sedative in the ICU. It has been recorded that intravenous mixture of ketamine–propofol (ketofol) was used in sedation for 24 h. It was derived from the result that propofol is preferred for the rapid management of anxiety in the ICU patients for less than 24 h, and maintenance dose of ketamine was also used for 24 h, so ketofol was predicted to be administrated safely as a continuous infusion for 24 h, with improvement in their safety and effectiveness and reduction of the adverse effects [7],[9].

Dexmedetomidine was studied as a substitute to usual GABA-based sedation in ICU. It is an alpha-2 agonist, and it acts at locus coeruleus and spinal cord to produce anxiolysis and sedation with no respiratory depression [10]. Furthermore, there are data to recommend that use of dexmedetomidine instead of usual sedating agents (propofol or midazolam) in critical care decreases the delirium [11].

This study was designed to assess the sedative effect of ketofol compared with dexmedetomidine for patients who needed mechanical ventilation in the ICU postoperatively.

 Patients and methods



This randomized double-blind controlled study was conducted in the ICUs, Mansoura University Hospitals, in the period between January 2017 and March 2019 after approval of the institutional research board (IRB) (R.1909614). An informed written consent was obtained from relatives of all patients.

Inclusion criteria

A total of 90 patients, of either sex, with age between 20 and 65 years old were included. These patients were in need for sedation and mechanical ventilation with close monitoring after surgery for needing short-term ventilation for ∼24 h, either because of intraoperative massive bleeding, prolonged surgery more than 6 h in critically cardiac patients, or patients with chronic obstructive pulmonary disease.

Exclusion criteria

Patients with known allergy to propofol, ketamine, or dexmedetomidine; patients with liver dysfunction; patients with renal dysfunction; patients following cardiac arrest; patients with hemodynamic instability at time of randomization with mean arterial blood pressure less than 60 mmHg, and patients who received spinal or epidural anesthesia were excluded.

On arrival to the surgical ICU, the intubated patients were connected to mechanical ventilator [synchronized intermittent mandatory ventilation (SIMV) mode, pressure support 10–15 cmH2O, PEEP 5–8 cmH2O, and FiO2 40%].

Monitoring by 5-lead ECG, capnography, noninvasive arterial blood pressure, and pulse oximetry was done.

Moreover, 12-lead ECG and chest radiograph were done. A blood sample was taken for complete blood count and arterial blood gas analysis.

Patients were randomly allocated using opaque sealed envelope into two equal groups.

Ketofol group (group K): 45 patients were sedated with ketofol, with a loading dose of 500 μg/kg of ketamine+propofol mixture 1 : 1 (ketamine 8 mg/ml+propofol 8 mg/ml) followed by continuous infusion at 8–10 μg/kg/min.

Dexmedetomidine group (group D): 45 patients were sedated with initial bolus dose of dexmedetomidine (2 µg/kg) intravenous infused over 10 min, and then continuous infusion at 0.3–0.5 µg/kg/h. The studied drugs were infused into a peripheral or central vein.

Data were recorded by surgical ICU staff unaware of the study protocol. Vital signs including heart rate, mean blood pressure (MBP), oxygen saturation, were monitored every hour but statistically analyzed every 6 h.

Level of sedation was assessed using Ramsay sedation score (RSS) [12], which consists of the following six grades:Anxious.Cooperative and tranquil.Responding to commands only.Brisk response to light glabellar tap.Sluggish response to light glabellar tap.No response to light glabellar tap.

The degree of sedation was measured immediately on admission to intensive care and then every 3 h and at time of discharge from ICU in both groups; the target was to achieve and maintain RSS more than or equal to 4.

Complication were treated as tachycardia if heart rate above 100 beat/min and bradycardia if heart rate below 60 beat/min. Bradycardia was treated by atropine intravenous 0.5 mg bolus dose. Hypotension was treated if blood pressure was below 90/60 mmHg (systolic/diastolic) and MBP below 70 mmHg. Hypotension could be treated by noradrenaline or dopamine or together. Noradrenaline was used at a dose of 0.1–1 μg/kg/h. Dopamine was used either at dopaminergic dose or beta dose or alpha dose (1–5, 5–10, and more than 10 μg/kg/h, respectively). Doses were titrated according to blood pressure values. Hypertension, if systolic blood pressure was above 170 mmHg, could be treated by nitroglycerine infusion at a dose of 0.5–2 μg/kg/h. Insufficient analgesia was considered if the patient showed tachycardia or hypertension more than 20% of the basal value in spite of adequate sedation level, so fentanyl (20–50 µg intravenous bolus) was administrated and recorded.

Recovery time

Time required for patients to attain the baseline conscious level after stopping infusion of sedation was recorded. The infusion of the sedation was stopped and preparing for extubation was done when there was no evidence of bleeding, cardiovascular stable, normothermic, and with acceptable arterial oxygen gases.

Statistical analysis

Sample size calculation

G power analysis program (Universitat Dusseldorf, Germany) was used to estimate the sedation score in both ketofol and dexmedetomidine groups, with an effective size of 0.8 and power of 80% and alpha error of 0.05. It produced a sample size of 90 patients (45 patients in each group).

Statistical methods

Data were analyzed with SPSS for Windows (Statistical Package for Social Scientists), version 21 (IBM Corporation, New York, New York, USA). The normality of continuous data was first analyzed with Kolmogorov–Smirnov test. Qualitative data were described using number and percent. Association between these variables was tested using c2 or Fisher exact test. Continuous variables were presented as mean±SD, and categorical data were presented as median (minimum–maximum). The two groups were compared with unpaired Student t test (parametric) and Mann–Whitney test (nonparametric). For intragroup comparisons, paired Student t test was used to compare the first result (basal) in each group with the other results, pairwise. Statistical differences showing P value less than 0.05 were considered significant.

 Results



Patients’ demographic data regarding age, sex, weight, and American Society of Anesthesiologist physical status showed no significant difference between both groups ([Table 1]).{Table 1}

There was a significant decrease in heart rate in dexmedetomidine group compared with ketofol group at 1, 6, 12, 18, and 24 h, with P value less than 0.001. Comparing heart rate to the basal value taken at the time of admission to ICU, there was a significant decrease in heart rate in both groups compared with the basal value at all time intervals ([Table 2]).{Table 2}

MBP values showed significant decrease in both groups compared with the basal value taken at the time of admission to ICU in the same group at all time intervals. There was a significant decrease in MBP in dexmedetomidine group compared with ketofol group at 6, 12, 18, and 24 h, with P value less than 0.001 ([Table 3]).{Table 3}

Oxygen saturation of the studied group showed no significant difference between both groups at all time intervals ([Table 4]).{Table 4}

RSS showed statistical difference between both ketofol and dexmedetomidine groups, but clinically no significant difference, as both RSS 4 and 5 represented effective sedation for the patients. However, compared with basal values, there was a significant increase in sedation level in both groups at all recorded time intervals, except at the time of discharge from ICU, where there was no difference ([Table 5]).{Table 5}

[Table 6] shows rapid recovery time with less total fentanyl requirement in dexmedetomidine group compared with ketofol group ([Figure 1]).{Table 6}{Figure 1}

 Discussion



In this prospective randomized study, ICU patients who needed postoperative mechanical ventilation were sedated efficiently with both dexmedetomidine and ketofol with shorter recovery time and less analgesic requirement in dexmedetomidine group than ketofol group.

Limited data in the research were available about ketofol as a sedative of the patients in ICUs, but numerous trials studied ketofol as a sedative in minor procedures [9]. Previous studies reported that dexmedetomidine causes sedation and analgesia with no considerable depression of respiration [1],[5]. In this study, although RSS was not similar in the two groups at different time intervals, this difference was not clinically significant as both RSS 4 and 5 indicated efficient sedation for the patients, which was in parallel to Jakob et al. [13], who reported that in ICU patients on long-term mechanical ventilation, dexmedetomidine was equivalent to midazolam and propofol in sedation. On the contrary to the results of this study, Corbett et al. [14] obtained lower sedation score (∼2–3) with dexmedetomidine than that with propofol (∼4–5).

Contrary to the results of this study, Shah et al. [15] studied 30 patients who needed postoperative sedation and mechanical ventilation: 15 patients were sedated with dexmedetomidine and 15 patients were sedated with propofol. They reported that the heart rate and MBP between the groups were not significantly different, whereas the mean RSS was between 2 and 4 and between 2 and 3 for dexmedetomidine and propofol groups, respectively.

In the current study, sedation with dexmedetomidine showed decrease in heart rate and mean arterial blood pressure than ketofol; this is in parallel to the results of Elmoutaz and Rashwan [16] who compared between ketofol and dexmedetomidine for sedation of postoperative mechanically ventilated patients with obstructive sleep apnea and found that mean arterial blood pressure was lower in dexmedetomidine group than ketofol group.

Paliwal et al. [17] showed a significant lower heart rate in dexmedetomidine group, which is in agreement with the present study, although the MBP showed more decrease in propofol group, which in contrast to this study; this may be owing to the difference in the studied drugs, as ketamine–propofol combination was used instead of propofol alone in our study.Oxygen saturation was comparable in the two groups of the study. This is in agreement with Venn and Grounds [18] who did not find a considerable difference in oxygen saturation between patients sedated with dexmedetomidine and propofol.

In the present study, recovery time was 35.33±3.67 min for the patients sedated by ketofol and 22.33±4.14 min for the patients sedated by dexmedetomidine. However, Hamimy et al. [7] found that median recovery time for ketofol group was 30 min, and Andolfatto and Willman [9] recorded the average recovery time of 14 min; this difference in recovery time may be explained by the different number of patients.

In dexmedetomidine group, there was marked decrease in analgesic requirement than ketofol group. This is in agreement with Srivastava et al. [19], who studied dexmedetomidine, propofol, and midazolam for postoperative sedation in neurosurgical patients and reported that mechanically ventilated neurosurgical patients sedated with dexmedetomidine needed less analgesia than those sedated with propofol.

Limitations of the study

Further studies with longer duration of mechanical ventilation are recommended.

 Conclusion



The study concluded that dexmedetomidine induced effective sedation of patients who needed postoperative mechanical ventilation, with better hemodynamic stability, faster recovery of the patients, and less analgesic requirement than ketofol.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Tonner PH, Weiler N. Sedation and analgesia in the intensive care unit. Curr Opin Anaesthesiol 2003; 16:113–121.
2Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas C. Clinical practice guidelines for the management of pain,agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263–306.
3Zhang Z, Chen K, Ni H, Zhang X, Fan H. Sedation of mechanically ventilated adults in intensive care unit: a network meta-analysis. Sci Rep 2017; 7:449–479.
4Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 291:1753–1762.
5Shehabi Y, Bellomo R, Mehta S, Riker R, Takala J. Intensive care sedation: the past, present and the future. Crit Care 2013; 17:322.
6Mughal A, Urooj S, Akhtar J, Javaid H, Sheikh B, Zafar S. Comparison of propofol-ketamine (ketofol) and propofol-fentanyl (fenofol) for sedation, recovery and hemodynamics in pediatric patients undergoing burns dressing change. Indo Am J Pharma Res 2019; 9:1967–1974.
7Hamimy IW, Zaghloul A, Mahmoud AAA. The application of a new regimen for short term sedation in the ICU (ketofol) − case series. Egypt J Anaesth 2012; 28:179–182.
8Willman EV, Andolfatto G. A prospective evaluation of ‘ketofol’ ketamine/propofol combination for procedural sedation and analgesia in the emergency department. Ann Emerg Med 2007; 49:23–30.
9Andolfatto G, Willman EV. A prospective case series of single syringe ketamine-propofol (ketofol) for emergency department procedural sedation and analgesia in adults. Acad Emerg Med 2011; 3:237–245.
10Devabhakthuni S, Pajoumand M, Williams C, Kufera JA, Watson K, Stein DM. Evaluation of dexmedetomedine :safety and clinical outcomes in clinical outcomes in critically ill trauma patients. J Trauma 2011; 71:1164–1171.
11Bekker A, Sturaitis MK. Dexmedetomidine for neurological surgery. Neurosurgery 2005; 57:1–10.
12Ramsay MAE. Intensive care: problems of over and under sedation. Baillier’s Clin Anaesthesiol 2000; 14:419–432.
13Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012; 307:1151–1160.
14Corbett SM, Rebuck JA, Greene CM, Callas PW, Neale BW et al. Dexmedetomidine does not improve patient satisfaction when compared to propofol during mechanical ventilation. Crit Care Med 2005; 33:940–945.
15Shah PN, Dongre V, Patil V, Pandya S, Mungantiwar A, Choulwar A.Comparison of post-operative ICU sedation between dexmedetomidine and propofol in Indian population. Indian J Crit Care Med 2014; 18:291–296.
16Elmoutaz HM, Rashwan DO. Efficacy of dexmedetomidine versus ketofol for sedation of postoperative mechanically ventilated patients with obstructive sleep apnea. Crit Care Res Pract 2018; 2018:1–8.
17Paliwal B, Rai P, Kamal M, Singariya G, Singhal M, Gupta P et al. Comparison between dexmedetomidine and propofol with validation of bispectral index for sedation in mechanically ventilated intensive care patients. J Clin Diagn Res 2015; 9:1–5.
18Venn RM, Grounds RM. Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions. Br J Anaesth 2001; 87:684–690.
19Srivastava VK, Agrawal S, Kumar S, Mishra A, Sharma S, Kumar R. Comparison of dexmedetomidine, propofol and midazolam for short-term sedation in postoperatively mechanically ventilated neurosurgical patients. J Clin Diagn Res 2014; 8:GC04–GC07.