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Table of Contents
Year : 2012  |  Volume : 15  |  Issue : 3  |  Page : 185-189
ICU sedation with haloperidol-propofol infusion versus midazolam-propofol infusion after coronary artery bypass graft surgery: A prospective, double-blind randomized study

1 Department of Anesthesiology and Critical Care, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Neurosurgery, Tehran University of Medical Sciences, Tehran, Iran

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Date of Submission02-Nov-2011
Date of Acceptance17-Apr-2012
Date of Web Publication4-Jul-2012


Combinations of hypnotics with or without opiates are commonly used in agitated patients. We hypothesized that combination of haloperidol-propofol in comparison with midazolam-propofol would lower consumption of propofol and lead to better hemodynamic and respiratory profile during sedation of agitated patients. Among 108 patients admitted in our ICU, 60 patients were agitated according to Ramsay Sedation Score (RSS) and randomly divided into two groups. Morphine sulfate (0.05 mg/kg) was administered to all patients for relief of postoperative pain. In one group, sedative infusion was started with 1 mg/h of haloperidol plus 25 μg/kg/min of propofol after bolus injection of 2 mg haloperidol. In the other group, midazolam1 mg/h and propofol 25 μg/kg/min were infused after a bolus injection of 2 mg midazolam. Propofol infusion was adjusted to keep bi-spectral index between 61-80 and the RSS between 3-5. Hourly propofol consumption was recorded during 24 h of sedation and compared statistically. We also compared SpO 2 , arterial blood gas variables, hemodynamic parameters and episodes of respiratory depression (SpO 2 ≤85%) requiring respiratory support between the groups. Haloperidol, when added to propofol infusion, decreased its consumption at all the measured times (P = 0.001). There was no significant difference in hemodynamic variables between two groups, but the episodes of respiratory depression was significantly higher in propofol-midazolam group (P = 0.02). We conclude that haloperidol-propofol infusion decreases propofol requirements in the agitated patients. Besides, this combination showed a better profile in terms of occurrence of respiratory depression.

Keywords: Haloperidol, Intensive Care Unit, Midazolam, Post-open heart surgery agitation, Propofol, Sedation

How to cite this article:
Etezadi F, Najafi A, Yarandi KK, Moharari RS, Khajavi MR. ICU sedation with haloperidol-propofol infusion versus midazolam-propofol infusion after coronary artery bypass graft surgery: A prospective, double-blind randomized study. Ann Card Anaesth 2012;15:185-9

How to cite this URL:
Etezadi F, Najafi A, Yarandi KK, Moharari RS, Khajavi MR. ICU sedation with haloperidol-propofol infusion versus midazolam-propofol infusion after coronary artery bypass graft surgery: A prospective, double-blind randomized study. Ann Card Anaesth [serial online] 2012 [cited 2022 Jul 2];15:185-9. Available from:

   Introduction Top

According to recent reports the incidence of psychotic disturbances after cardiac surgery varies from 3 to 72%, (1) depending on cardiac procedure performed and methodological issues of delirium diagnostics.

This disorder prolongs the Intensive Care Unit (ICU) stay and increases the long-term morbidity and mortality. Propofol or midazolam as sedative agents have been extensively used in order to manage this complication. Long term propofol infusion may impose high costs on the patients and health care system and may cause side-effects such as hyperlipidemia, hyperamylasemia and pancreatitis. Higher dose and longer duration of propofol infusion are two risk factors causing these side-effects. [2],[3],[4] However, propofol administration may have some benefits as well. For example, propofol may have a stabilizing effect on the control of breathing. [5] Also, propofol has a potential to reduce oxidative stress. [6],[7] Compared with propofol, midazolam infusions have been associated with a decreased occurrence of hypotension but a more variable time course for recovery of functions after the cessation of its infusion. [8] On the other hand, continuous infusion of haloperidol effectively controls delirium in critically ill patients and is the drug of choice for short-term control of such cases with rare reported side-effects. [9] According to a report, administration of haloperidol may decrease the requirements for bolus injection of sedatives and may also reduce wasting of nursing time and energy in order to manage this problem. [10] Different combinations of drugs are frequently used in clinical anesthesia because of their synergistic effects and reduction of the dose of each individual drug, which in turn may decrease side-effects. Combination of propofol-midazolam have been used for monitored anesthetic care of patients during spinal anesthesia with success in one study. [11] According to another report, it is speculated that the combination of midazolam-propofol may achieve better results when compared with each of the aforementioned drugs alone. [12] With regard to another study, the combination of hypnotic drugs must be individualized based on the conditions of every critically ill patient. [13] Considering the above-mentioned facts and because the combination of haloperidol-propofol has not been studied yet for sedation in the ICU, we conducted a prospective study to assess the combination of propofol and haloperidol infusion versus propofol and midazolam. We hypothesized that the combination of haloperidol-propofol may lead to lower propofol requirement with more stable hemodynamic and better respiratory profile in comparison with midazolam-propofol combination.

   Materials and Methods Top

After approval of the ethics committee of the Research Deputy of the University, this prospective, double-blind, randomized trial was conducted in the open heart ICU at Tehran Heart Center between March 2009 and August 2010. Informed consent was taken in the preoperative period from all patients who were candidates for open heart surgery. One hundred and eight patients were assessed and 60 cases (56%) were eligible to be enrolled in this study according to our inclusion criteria (Ramsay Sedation Score [RSS] = 1). The exclusion criteria were patients who have already received long-term opioid analgesia for any cause, those with a plan to shortly return to the operating room, those likely to require ongoing endotracheal intubation and mechanical ventilation and patients whose neurologic condition or responses could be difficult to evaluate. Other exclusion criteria included any history of allergy to egg products or propofol itself or history of hyperlipidemia or pancreatitis and history of torsades de pointes or existence of long QT interval in ECG.

All eligible patients (RSS = 1) were randomized into two groups to receive different sedative protocols. Morphine sulphate, 0.05 mg/kg was injected IV to both groups of patients to relieve postoperative surgical pain, and repeated every 6 h up to the end of the study. In the haloperidol group, infusions of 1 mg/h of haloperidol combined with 25 μg/ kg/min of propofol were started after bolus injection of 2 mg of haloperidol. In the midazolam group, bolus injection of 2 mg of midazolam was followed by infusion of 1 mg/h of midazolam and 25 μ/kg/min of propofol. The monitoring protocol in both the groups included electrocardiogram, invasive and noninvasive blood pressure, pulse oxymetry and hourly arterial blood gas measurement. Level of consciousness was measured hourly by the bi-spectral index (BIS® ); the degree of sedation was also calculated hourly using the RSS as the means for adjusting propofol infusion rate. The propofol infusion rate was tightly adjusted every hour in order to keep the BIS average values between 60 and 80 and the RSS from three to five. As much as 5 μg/ kg/min increase or decrease was allowed each time if indicated. Evaluation of the patients and manipulation of propofol infusion rate to meet therapeutic protocols was performed by an intensivist who was blinded to the study. In every patient, the infusion rate of propofol was recorded every hour, and hourly consumption of propofol in milligram was also calculated and then statistically compared between the two groups. SpO 2 , hemodynamic variables and arterial blood gas parameters were recorded every hour during the study. Based on SpO 2 monitoring of all patients, the number of episodes of respiratory depression (SpO 2 < 85%) requiring transient respiratory support in the form of noninvasive Bilevel Positive Airway Pressure/ (BIPAP/CPAP) ventilation were recorded and compared between the groups. After 24 h, the infusion of sedative drugs was tapered gradually during 3 h, and then stopped.

Statistical Analysis

Statistical comparison was done by Microsoft excel software using analysis of covariance between the groups. With regard to "Power = 80%" and "α = 0.05," the required sample size was estimated to be 30 cases in each group. A P-value less than 0.05 was considered statistically significant.

   Results Top

The study progress flow chart is depicted in [Figure 1]. The baseline characteristics and demographics of patients in the two groups were comparable [Table 1]. The mean propofol consumption per hour during the 24 h of study was 60 ± 24 mg/h in the haloperidol group, which was significantly lower than the midazolam group, which was 140 ± 19 mg/h (P = 0.001) [Figure 2]. Compared with baseline measurements, lower mean arterial pressures and heart rates were recorded throughout the study in both groups; there was no significant difference in hemodynamic parameters, SpO 2 and arterial blood gases. The incidence of respiratory depression requiring respiratory support were significantly higher in the midazolam-propofol group (P = 0.02) [Table 2] and [Table 3].
Table 1: Patients' demographic and baseline characteristics

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Table 2: Comparison of hemodynamic parameters

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Table 3: SpO2 and ABG parameters and number of episodes of respiratory depression

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Figure 1: Flow diagram of subject progress through the phases of randomized clinical (RCT)

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Figure 2: Comparison of midazolam-propofol versus haloperidol-propofol infusion rates in the first 24 h of intensive care following cardiac surgery

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   Discussion Top

Large-sized surgical incision, old age, medical comorbidities and inflammatory reactions due to cardiopulmonary bypass pump attachment are some of the main causes responsible for the high incidence of agitation and transient cerebral complications after open heart surgery. [14] To reduce the risk of self-induced injury and prevention of oxygen overconsumption due to agitation and hyperactivity administration of sedatives is recommended. Numerous drugs including midazolam, haloperidol, propofol and dexmedetomidine have been used to induce sedation in different groups of patients admitted in the ICU. [15],[16],[17],[18] Each drug has its own benefits and side-effects. As a general principle, it is accepted that when higher dosage of a drugs is administrated, it is more likely to be associated with side-effects. Thus, a combination of medications with synergistic effects is used. Midazolam is an agent with low risk of respiratory and hemodynamic complications and acceptable risk of amnesia; however, its infusion can cause prolonged drowsiness, especially in the elderly. On the other hand, when used in combination with propofol it has a synergistic effect, which increases the risk of respiratory depression. In addition, midazolam administration can exacerbate agitation and even delirium. [19]

Propofol is a good choice for infusion due to its short half-life; however, its respiratory complications are more likely following high-dose infusion in comparison with midazolam. Additionally, there are concerns about its cost and complications attributed to its long-term administration, including hyperlipidemia, pancreatitis and propofol syndrome. Similar to midazolam, propofol can also exacerbate delirium, [19] which is the main cited mechanism of agitation in post open heart surgery ICU patients. Haloperidol is the drug of choice when aggressive behavior is the dominant feature; and it can be considered a useful choice for these cases as compared to propofol and midazolam. However, these patients generally suffer from multiple underlying cardiovascular problems, which limit its use as a single drug. Therefore, it is often preferred to use haloperidol in conjunction with another hypnotic drug such as propofol. No significant difference were found regarding cardiovascular complications between the groups of our study, but the respiratory complications were significantly less in the haloperidol-propofol group.

Two potential mechanisms may contribute to this beneficial effect:

  1. The synergistic effect of haloperidol with propofol leads to satisfactory behavior control with lower doses of propofol, which would have reduced its respiratory complications.
  2. Some studies have shown that haloperidol may enhance hypoxia induced increases in ventilation in animals and humans because of its antidopaminergic effects at the carotid body. [20-24] This can further justify the significant difference found in respiratory complications between the groups in our study.

We can thus conclude that the combination of haloperidol and propofol may reduce the likelihood of respiratory side-effects attributed to propofol, and provide adequate sedation for the agitated / delirious patients admitted in the post open heart ICU. No additional cardiovascular complications were found in the cases treated with haloperidol-propofol combination in comparison with the midazolam-propofol group.

The major limitation is that only the post open heart surgical agitated patients were enrolled in this study; therefore, the results are only applicable to these patients. The other limitation is that the patients were not checked regarding the incidence of hyperlipidemia and hyperamylasemia. However, the duration and dose of propofol infusion of the cases included in this study is not expected to cause these complications. Also, the admission duration of the patients in the ICU was not recorded in our study, which can be considered as another potential drawback of this research.

   Conclusion Top

Sedating the agitated patients with the haloperidol-propofol combination allow use of lower doses of propofol in comparison with midazolam-propofol combination, and can be suggested as a suitable strategy for sedation in the agitated patients admitted in the post open heart surgery ICU. The combination of haloperidol-propofol reduces the rate of respiratory complications attributed to the previous sedative hypnotic combinations.

   Acknowledgement Top

Authors would like to thank research deputy of Tehran University of Medical Sciences for their full support.

   References Top

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2.Devlin JW, Lau AK, Tanios MA. Propofol-associated hypertriglyceridemia and pancreatitis in the intensive care unit: an analysis of frequency and risk factors. Pharmacotherapy 2005; 25:1348-52.  Back to cited text no. 2
3.Mateu J, Barrachina F. Hypertriglyceridaemia associated with propofol sedation in critically ill patients. Intensive Care Med 1996; 22: 834-5.  Back to cited text no. 3
4.Eddleston JM, Shelly MP. The effect on serum lipid concentrations of a prolonged infusion of propofol-hypertriglyceridaemia associated with propofol administration. Intensive Care Med 1991; 17: 424-6.  Back to cited text no. 4
5.Klimathianaki M, Kondili E, Alexopoulou C, Prinianakis G, Georgopoulos D. Effect of propofol on breathing stability in adult ICU patients with brain damage. Respir Physiol Neurobiol 2010;171: 232-8.  Back to cited text no. 5
6.Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H. The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neurosci Ther 2008;14: 95-106.  Back to cited text no. 6
7.Menon DK, Young Y, Tew DN, Bacon PJ. New horizons in ICU sedation: exploring non-sedative effects of ICU sedation. Clin Intensive Care 1994; 5(5 Suppl):22-6.  Back to cited text no. 7
8.Shafer A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit Care Med 1998; 26: 947-56.  Back to cited text no. 8
9.Riker RR, Fraser GL, Richen P. Movement disorders associated with withdrawal from high-dose intravenous haloperidol therapy in delirious ICU patients. Chest 1997; 111:1778-81.  Back to cited text no. 9
10.Riker RR, Fraser GL, Cox PM. Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med 1994; 22: 433-40.  Back to cited text no. 10
11.Young C, Knudsen N, Hilton A, Reves JG. Sedation in the intensive care unit. Crit Care Med 2000; 28: 854-66.  Back to cited text no. 11
12.Hsiao PC, Tang YY, Liaw WJ, Yue-Cune Chang YH, Chen FC, Wang KY. Postoperative sedation after major surgery with midazolam or propofol in the ICU: Effects on amnesia and anxiety. Acta Anaesthesiol Taiwan 2006; 44: 93-9.  Back to cited text no. 12
13.Rhee KY, Yun MJ, Kim DK, Seol TK, Kim KO. Sedation with midazolam-propofol combination versus propofol alone during spinal anesthesia: Prospective Randomized Study. Korean J Anesthesiol 2005;49: s10-3.  Back to cited text no. 13
14.Rasmussen L, Stygall J, Newman SP. Cognitive dysfunction and other long-term complications of surgery and anesthesia. In: Miller RD, editor. Miller's Anesthesia. 7 th ed. Philadelphia: Elsevier Churchill Livingstone; 2010. p. 2805-20.  Back to cited text no. 14
15.Esmaoglu A, Ulgey A, Akin A, Boyaci A. Comparison between dexmedetomidine and midazolam for sedation of eclampsiapatients in the intensive care unit. J Crit Care 2009; 24: 551-5.  Back to cited text no. 15
16.Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301: 489-99.  Back to cited text no. 16
17.Herr DL, Sum-Ping ST, England M. ICU sedation after coronary artery bypass graft surgery: Dexmedetomidine-based versus propofol-based sedation regimens. J Cardiothorac Vasc Anesth 2003; 17: 576-84.  Back to cited text no. 17
18.Corbett SM, Rebuck JA, Greene CM, Callas PW, Neale BW, Healey MA, et al. Dexmedetomidine does not improve patient satisfaction when compared with propofol during mechanical ventilation. Crit Care Med 2005; 33: 940-5.  Back to cited text no. 18
19.Riker RR, Fraser GL. Altering intensive care sedation paradigms to improve patient outcomes. Crit Care Clin 2009; 25: 527-38, viii-ix. Review.  Back to cited text no. 19
20.Fukuda K. Opioids In: Miller RD, editor. Miller's Anesthesia. 7th ed. Philadelphia: Elsevier Churchill Livingstone; 2010. p. 824-769.  Back to cited text no. 20
21.Osanai S, Akiba Y, Matsumoto H, Nakano H, Kikuchi K. Effect of dopamine receptor on hypoxic ventilatory response. Nihon Kyobu Shikkan Gakkai Zasshi 1997; 35: 1318-23.  Back to cited text no. 21
22.Tatsumi K, Pickett CK, Weil JV. Decreased carotid body hypoxic sensitivity in chronic hypoxia: role of dopamine. Respir Physiol 1995;101: 47-57.  Back to cited text no. 22
23.Pedersen ME, Dorrington KL, Robbins PA. Effects of haloperidol on ventilation during isocapnic hypoxia in humans. J Appl Physiol 1997; 83:1110-5.  Back to cited text no. 23
24.Smatresk NJ, Pokorski M, Lahiri S. Opposing effects of dopamine receptor blockade on ventilation and carotid chemoreceptor activity. J Appl Physiol 1983;54:1567-73.  Back to cited text no. 24

Correspondence Address:
Mohammad Reza Khajavi
Hassan Abad Sq., Sina Hospital, Tehran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0971-9784.97974

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