Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 9  |  Issue : 2  |  Page : 178-185

Dexmedetomidine versus midazolam for sedation of critically ill patients on noninvasive mechanical ventilation


Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, Cairo, Egypt; King Abd el Aziz Specialist Hospital, Taif, Kingdom of Saudi Arabia

Date of Submission23-Apr-2015
Date of Acceptance08-May-2015
Date of Web Publication11-May-2016

Correspondence Address:
Mohamed G.I.M. Allam
King Abd el Aziz Specialist Hospital, Taif 10127, Kingdom of Saudi Arabia

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.179910

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  Abstract 

Introduction
Dexmedetomidine is a highly selective a-2 adrenoceptor agonist and eight times more specific than clonidine. It exerts its major sedative and analgesic effect through stimulation of the a-2 adrenoceptor and the locus coeruleus. Its analgesic effect is also produced by direct stimulation of the a-2 adrenoceptor in the spinal cord. The unique sedative effect of dexmedetomidine that mimics natural sleep makes the postsedative delirium after stopping dexmedetomidine very rare. Moreover, even on the sedative score Richmond Agitation-Sedation Scale (RASS)-1-2, patients can respond easily to verbal command and go back to sleep. The most commonly reported adverse effects are bradycardia and hypotension.
Aim of the work
This was a comparative prospective double-blind study comparing dexmedetomidine versus midazolam as a sedative agent used in noninvasive ventilation (NIV) and short-term intubation and mechanical ventilation (5 days).
Patients and methods
In all, 200 patients admitted to King Abd el Aziz Specialist Hospital, Taif, in the ICU with acute hypoxemia with SpO 2 less than 80% were allocated randomly to two groups. All patients in both groups were subjected to NIV for 3 days and if this failed (persistent hypoxemia, became hemodynamically unstable, or showed marked tracheal secretion), intubation and mechanical ventilation was considered for 5 days. Group A included 100 patients who received midazolam as a sedative agent, whereas group B included 100 patients who received dexmedetomidine as a sedative agent. The number of patients who responded to NIV in both groups was recorded and the number of patients who were extubated and weaned from mechanical ventilation in 5 days in both groups was also recorded together with the complications from sedation.
Results
There was a significant increase in the number of patients who responded to NIV in group B compared with group A. Moreover, there was a significant increase in the number of patients extubated and weaned from mechanical ventilation in the 5-day period in group B compared with group A.
Conclusion
Dexmedetomidine is a safer agent for sedation of critically ill patients with fewer incidences of delirium, and less morbidity and mortality compared with midazolam with the same efficacy.

Keywords: as sedative drugs in acute hypoxemia, dexmedetomidine, midazolam


How to cite this article:
Allam MG. Dexmedetomidine versus midazolam for sedation of critically ill patients on noninvasive mechanical ventilation. Ain-Shams J Anaesthesiol 2016;9:178-85

How to cite this URL:
Allam MG. Dexmedetomidine versus midazolam for sedation of critically ill patients on noninvasive mechanical ventilation. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2020 Jul 15];9:178-85. Available from: http://www.asja.eg.net/text.asp?2016/9/2/178/179910


  Introduction Top


Dexmedetomidine is a potent and highly selective a-2 adrenoceptor agonist and approximately eight times more specific for a-2 adrenoceptors than clonidine [1]. These receptors can be found throughout the body, including the central and peripheral nervous systems, and several organs, such as the liver, pancreas, kidney, and eyes, at the presynaptic and postsynaptic sites [2,3]. Activation of presynaptic a-2 adrenoceptors located in sympathetic nerve endings inhibits the release of norepinephrine. Postsynaptic stimulation of a-2 adrenoceptors inhibits sympathetic activity so that it subsequently causes decreases in blood pressure and heart rate [4]. Dexmedetomidine exerts its major sedative and analgesic effects through stimulation of the a-2 adrenoceptors in the locus coeruleus, which is an important modulator of vigilance and nociceptive neurotransmission [5,6]. The analgesic effects of dexmedetomidine are also produced by directly stimulating a-2 adrenoceptors in the spinal cord. Importantly, dexmedetomidine exerts minimal effects on ventilation [7]. As a result, it may facilitate spontaneous breathing trials and ventilator weaning attempts without discontinuation of the drug infusion before extubation. The most commonly reported adverse events associated with dexmedetomidine are bradycardia and hypotension [8].

The SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) trial [7] showed that in the dexmedetomidine group, there was greater tendency to develop bradycardia compared with the midazolam-treated group (42.2 vs. 18.9%; P < 0.001). However, in the dexmedetomidine-treated group, only 4.9% required interventions for bradycardia, such as stopping the infusion or administration of atropine. With respect to hypotension, there was no significant difference between the dexmedetomidine and the midazolam groups (56.1 vs. 55.7%; P > 0.05).


  Aim of the work Top


The aim of this study was to compare the efficacy and safety of dexmedetomidine versus midazolam (Dormicum) as sedative drugs for patients with acute hypoxemia using noninvasive ventilation (NIV) and for short-term ventilation.


  Patients and methods Top


In all, 200 patients were admitted to King Abd el Aziz Specialist Hospital, Taif, KSA, between May 2011 and December 2013 in the intensive care department with acute hypoxemia (SpO 2 < 80%).

Inclusion criteria

(1) Age older than 18 years.

(2) Signs and symptoms of acute respiratory distress.

(a) Respiratory rate more than 35/min.

(b) SpO 2 less than 80%.

(c) Respiratory acidosis (pH < 7.2).

(d) Hypoxemic (PO 2 < 60 mmHg).

(e) Pulse rate more than 120/min.

Exclusion criteria

(1) Severely altered conscious level (Glasgow Coma Scale < 8/15).

(2) Traumatic causes of hypoxemia (severe head/chest trauma or pneumothorax).

(3) Severe pneumonia diagnosed by chest radiography.

(4) Arrhythmia (required cardio version) or cardiac arrest

(a) The King Abd el Aziz research and ethical committee approved the project.

(b) An informed written consent was obtained from all the patients.

(c) Chest radiography was performed for all patients to exclude pneumonia, pneumothorax, and flail chest and daily to diagnose ventilator-associated pneumonia by new parenchymatous lung infiltrate.

(d) All patients were randomized into two groups: A and B, 100 patients each. Investigators used 'random number tables' to generate the sequences. Random number tables contain a series of numbers that occur equally often and that are arranged in a random (therefore unpredictable) manner. The numbers usually have two or more digits. The use of a random number table forces investigators to decide the correspondence between the numbers and the groups (e.g. odd corresponding to group A and even to group B).

Group A

Group A slowly received a loading dose of 0.05 mg/kg of midazolam (Dormicum) intravenously and a maintenance dose of 0.05-0.1 mg/kg/h through an intravenous infusion adjusted to achieve Richmond Agitation-Sedation Scale (RASS)-2-3.

Group B

Group B slowly received a loading dose of 1 mg/kg of dexmedetomidine intravenously and a maintenance dose of 0.2-0.7 mg/kg/h through an intravenous infusion adjusted to achieve RASS-2-3.

(1) The tolerability and the duration of non invasive ventilation (NIV) were recorded for all patients in both groups.

(2) Any adverse effects or complication during the 3 days of NIV were recorded.

(3) Persistent hypoxemia (SpO 2 < 80%), hemodynamic instability (30% or more decrease in the heart rate or mean blood pressure), and marked tracheal secretion were considered failure of NIV in our study.

(4) The number of cases converted to mechanical ventilation in both groups was recorded.

(5) Patients showing failure of NIV and converted to mechanical ventilation followed for 5 days and the number of patients who could be weaned from mechanical ventilation within this 5-day period were recorded.

(6) Any complications during the 5 days of mechanical ventilation in both groups were recorded.

(7) In group B, any decrease of more than 30% from the baseline in the systolic blood pressure and heart rate was considered hypotension and bradycardia, respectively, and any need for intervention by inotropes was recorded and counted.

(8) For any ventilation needed for more than 5 days, the cause was analyzed and recorded and considered a complication (morbidity) in our study (prolonged ICU stay).

(9) Ventilator-associated pneumonia was recorded in our study by either new parenchymatous lung infiltrate or a positive (+) sputum culture.

(10) Delirium was recorded in our study by the RASS; all the patients in both groups underwent assessments for delirious state after stoppage of sedation. Delirium was considered in our study if the patient had +1 or more in RASS.

(11) The APACHE II score was assessed for all mechanically ventilated patients in both groups once an endotracheal tube applied and patients were connected to the ventilator.

Richmond Agitation-Sedation Scale (RASS)



Statistical analysis

The data were collected and entered into a personal computer. Statistical analysis was carried out using the Statistical Package for Social Sciences (SPSS/version 20) software.

The statistical test calculated the following: number, percent, arithmetic mean, and SD. For categorized parameters, the c2 -test was used, whereas for the two groups, a t-test was used for parametric data. The level of significance was 0.05.

Sample size

Sample size was calculated on the basis of a previous study on 'Comparison between dexmedetomidine and midazolam as sedative agents in intensive care' using the Med Calc statistical software.

Assuming the area under receiver operating characteristic to be 0.80, an a of 0.05, and a power of the study of 90.0%, a minimum sample size required to compare between dexmedetomidine and midazolam as sedative agents in intensive care was 100 patients in each group for this study.


  Results Top


In group A, at the end of the third day of NIV, 49 out of 100 patients were intubated and mechanically ventilated and followed for 5 days [Table 1] [Table 2] [Table 3].
Table 1 Age and sex demographics in our study

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Table 2 Medical causes of acute hypoxemia of the patients in our study

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Table 3 Hours of noninvasive ventilation in groups A and B

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In group B, at the end of the third day of NIV, 27 out of 100 patients were intubated and mechanically ventilated and also followed for 5 days.

Twenty-six patients out of 49 in group A could not be weaned during our study (5 days) and developed ventilator-associated pneumonia. Eighteen of these patients died from severe sepsis and septic shock with multiorgan failure and the remaining eight were weaned within 2 weeks.

However, eight patients out of 27 in group B could not be weaned within the 5-day period also because of ventilator-associated pneumonia. Two patients died from severe sepsis, septic shock, and multiorgan failure and the remaining six were weaned within 2 weeks [Figure 1] [Figure 2] [Figure 3] and [Table 4] [Table 5] [Table 6].
Figure 1: Hours of noninvasive ventilation in group A and gr oup B

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Figure 2: Causes of failure of noninvasive ventilation in both groups

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Figure 3: Diagnosis of the patients who underwent endotracheal intubation and mechanical ventilation in both groups

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Table 4 Causes of failure of noninvasive ventilation in both groups

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Table 5 Demographic data of mechanically ventilated patients in both groups (49 patients in group A and 27 patients in group B)

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Table 6 Diagnosis of the cases intubated and mechanically ventilated in both groups

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Group A (100 patients)

(1) Fifty-one patients responded to NIV.

(2) Twenty-three patients were intubated and mechanically ventilated and could be weaned within 5 days (duration of our study).

(3) Eighteen patients died from ventilator-associated pneumonia, septic shock, and multiorgan failure (considered mortality).

(4) Eight patients were intubated and mechanically ventilated and could be weaned within 2 weeks (considered morbidity).

Group B (100 patients)

(1) Seventy-three patients responded to NIV.

(2) Nineteen patients were intubated and mechanically ventilated and could be weaned within 5 days (duration of our study).

(3) Two patients died from ventilator-associated pneumonia, septic shock, and multiorgan failure (considered mortality).

(4) Six patients were intubated and mechanically ventilated and could be weaned within 2 weeks (considered morbidity) [Table 7].
Table 7 Hypoxic index (PO2/FiO2) of groups A and B during the 5 days of endotracheal intubation and mechanical ventilation

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In group A, at the end of 5 days from intubation and mechanical ventilation, only 23 of 47 patients could be weaned.

In group B, at the end of the 5 days from intubation and mechanical ventilation, only 19 of 27 patients could be weaned [Table 8] and [Table 9] and [Figure 4] and [Figure 5].
Figure 4: Hypoxic index recorded in both groups

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Figure 5: Data of patients in both groups during the 5 days of endotracheal intubation and mechanical ventilation

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Table 8 APACHE II score for groups A and B during the 5 days of endotracheal intubation and mechanical ventilation

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Table 9 Complications reported in both groups

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  Discussion Top


The expected sedation scores on the RASS-2-3 were achieved in all patients in both groups after the loading dose and within 1 h from starting the maintenance dose.

The cardiorespiratory symptoms and signs (SpO 2 , respiratory rate, and work of breathing) improved in all patients in both groups within 1 h from starting sedation.

(1) During the 3 days of NIV:

(a) Tolerability to NIV was better in group B compared with group A as nine patients on the first day, three patients on the second day, and two patients on the third day could tolerate NIV for more than 12 h, whereas only one patient in group A could tolerate NIV more than 12 h and this was only on the first day. This can be attributed to the analgesic effect of dexmedetomidine, which relieves the pain of tight application of the noninvasive mask for a long period compared with midazolam, which exerts no analgesic effect.

(b) Efficacy of NIV: 73 patients responded to NIV in group B compared with 51 patients in group A. Failed cases were nine patients daily in the consecutive 3 days with total 27 patients in group B compared to 19, 17 and 13 patients failed in the consecutive 3 days of NIV in group A with of 49 patients. This can be attributed to better tolerability to NIV and the ability of the medical team and respiratory therapists to communicate with patients even during sedation and provide them instructions and reassurance.

(c) Complications: postsedation delirium was markedly decreased in group B: only eight patients compared with 21 patients in group A at the end of the 3 days of NIV. Bradycardia reported in group B was higher (20 patients in total; 10 of these patients required a small dose of inotropes - dopamine 5 mg/kg/min - for a short time) compared with only nine patients in group A; six of these patients required a small dose of inotropes for a short time. Hypotension that required a small dose of vasoconstrictor (noradrenaline 0.02 mg/kg/min) was recorded in two patients in each group. Ten patients in group B and none in group A showed hypotension that did not need any intervention. This was considered a minor complication and could be understood from the previously described mechanism of action of dexmedetomidine.

(2) During the 5 days of mechanical ventilation:

(a) Efficacy: 19 out of 27 patients responded to mechanical ventilation in group B compared with only 23 out of 49 patients in group A. This can be attributed to the ability of the medical team and respiratory therapists to communicate with patients and reassure them even under sedation.

Complications

Postsedation delirium was markedly decreased in group B: only 13 patients compared with 41 patients in group A at the end of the 5 days of mechanical ventilation. This proves the unique advantage of dexmedetomidine in preventing delirium after short-term and long-term use as a sedative drug. While bradycardia reported in group B was higher 31 patients total; five of these patients required a small dose of inotropes (dopamine 5 mg/kg/min) for a short time compared with only 11 patients in group A. Seven of these patients required a small dose of inotropes for a short time. Hypotension that required a small dose of vasoconstrictor (noradrenaline 0.02 mg/kg/min) was recorded in 13 patients in group A and 16 patients in B.

Twenty-three patients in group B and only three patients in group A showed hypotension that did not need any intervention. This is still considered a minor complication.

There was no significant difference between the two groups in the development of bradycardia that required an intervention after 5 days of mechanical ventilation and in the development of hypotension that required an intervention during the 3 days of NIV.

On reviewing morbidity in our study, we found a significant decrease in prolonged ventilation (2 weeks) and the number of patients who had ventilator-associated pneumonia in group B (eight patients only) compared with group A (26 patients).

The same results were found in mortality (death because of ventilator-associated pneumonia complicated by septic shock and multiorgan failure). Eighteen patients in group A died, whereas only two died in group B. This can be attributed to the ability to maintain contact with the patients even during sedation and encourage them to cough (while under NIV) and respond to instructions of chest physiotherapist and psychologically support them and thus weaned from ventilation earlier and prevented all the complications of prolonged ventilation.

Pandharipande et al. (2007) [10] compared dexmedetomidine with lorazepam in two groups both in medical and in surgical ICU and arrived at the same conclusion as our study and found dexmedetomidine to be a reliable, safe, and short-acting sedative agent with very minimal postsedation delirium compared with lorazepam.

Ruokonen et al. (2009) [11], in their pilot study carried out in both medical and surgical ICU comparing dexmedetomidine with propofol and midazolam in three groups, found a marked statistical reduction in postsedation delirium in the group in which dexmedetomidine was used compared with the midazolam and propofol groups and less hemodynamic instability on comparing the dexmedetomidine group with the propofol group.

Reade et al. (2009) [12], in their pilot study comparing the use of haloperidol versus dexmedetomidine in both medical and surgical ICU to control hyperactivity after prolonged ICU stay, found no statistical difference between the two drugs.

Yapici et al. (2011) [13] used dexmedetomidine and midazolam in postcardiac surgery and found no statistical difference between the two drugs in the hemodynamics and a marked reduction in delirium postsedation in the group in which dexmedetomidine was used.

Shehabi et al. (2009) [14] compared two groups: in one group, morphine 10-70 mg/kg/h was used as an intravenous infusion and in the other group, dexmedetomidine 0.1-0.7 mg/kg/h was used in open heart surgery; no statistical difference was found in the analgesic effect, with a marked reduction in postsedation delirium in the group in which dexmedetomidine was used.

Jakob et al. (2012) [15] carried out two studies: The MIDEX trial involved 500 patients and compared dexmedetomidine with midazolam and the PRODEX trial involved 498 patients and compared dexmedetomidine with propofol. The two studies focused on four points: time at target sedation level without the use of rescue therapy, tolerability to the duration of mechanical ventilation, hemodynamic stability, and postsedation delirium.

The authors found

(1) In both trials no significant differences in time at target sedation between all sedatives (dexmedetomidine-midazolam and dexmedetomidine-propofol).

(2) In the MIDEX trial, dexmedetomidine significantly decreased the median duration of mechanical ventilation compared with midazolam (123 vs. 164 h, respectively), but not compared with propofol (97 vs. 118 h, respectively) in the PRODEX trial.

(3) Hypotension and bradycardia were more common with dexmedetomidine in the MIDEX, whereas the incidences of hypotension and bradycardia were similar in the PRODEX trial.

(4) After a 48-h follow-up period, dexmedetomidine led to significantly lower incidences of postsedation delirium compared with both midazolam and propofol groups in both trials.

These results are very similar to ours and they prove the superiority of dexmedetomidine in decreasing postsedation delirium and decreasing the duration of mechanical ventilation.


  Conclusion Top


Dexmedetomidine is a safer agent for sedation of critically ill patients with fewer incidences of delirium, and lower morbidity and mortality compared with midazolam with the same efficacy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bhaba N, Goa K, McClellan K. Dexmedetomidine. Drugs 2000; 59: 263-268.  Back to cited text no. 1
    
2.
Gertler R, Brown H, Mitchell D, et al. Dexmedetomidine: a novel sedative-analgesic agent. BUMC Proc 2001; 14:13-21.  Back to cited text no. 2
    
3.
Venn R, Bradshaw C, Spencer R, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia 1999; 54:1136-1142.  Back to cited text no. 3
    
4.
Arnold H, Hollands J, Skrupky L, et al. Optimizing sustained use of sedation in mechanically ventilated: focus on safety. Curr Drug Saf 2010; 5:6-12.  Back to cited text no. 4
    
5.
Bekker A, Sturaitis M. Dexmedetomidine for neurological surgery. Neurosurgery 2005; 57:1-10.  Back to cited text no. 5
    
6.
Szumita P, Baroletti S, Anger K, et al. Sedation and analgesia in the intensive care unit: evaluation of the role of dexmedetomidine. Am J Health Syst Pharm 2002; 64:37-44.  Back to cited text no. 6
    
7.
Riker R, Shehabi Y, Bokesch P, et al. Dexmedetomidine vs. midazolam for sedation of critically ill: a randomized trial. JAMA 2009; 301:489-499.  Back to cited text no. 7
    
8.
Maldonado J, Wysong A, van der Starre P, et al. Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics 2009; 50:206-217.  Back to cited text no. 8
    
9.
Sessler CN, Gosnell M, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care. Am J Respir Crit Care Med 2002; 166:1338-1344.  Back to cited text no. 9
    
10.
Pandharipande P, Pun B, Herr D, et al. Effect of sedation with dexmedetomidine vs. lorazepam on acute brain dysfunction in mechanically ventilated: the MENDS randomized controlled trial. JAMA 2007; 298:2644-2653.  Back to cited text no. 10
    
11.
Ruokonen E, Parviainen I, Jakob SM, et al. Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation. Intensive Care Med 2009; 35:282-290.  Back to cited text no. 11
[PUBMED]    
12.
Reade M, O'Sullivan K, Bates S, et al. Dexmedetomidine vs. haloperidol in delirious, agitated, intubated: a randomized open-label trial. Crit Care 2009; 13:R75.  Back to cited text no. 12
    
13.
Yapici N, Coruh T, Kehlibar T, et al. Dexmedetomidine in cardiac surgery who fail extubation and present with a delirium state. Heart Surg Forum 2011; 14:E93-E98.  Back to cited text no. 13
    
14.
Shehabi Y, Grant P, Wolfenden H, et al. Prevalence of delirium with dexmedetomidine compared with morphine-based therapy after cardiac surgery. Anesthesiology 2009; 111:1075-1084.  Back to cited text no. 14
    
15.
Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs. midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012; 307: 1151-1159.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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