Objectives: Patients who undergo cardiac surgery have an increased risk of delirium. Currently, there are few choices of treatment for postoperative hyperactive delirium in cardiac surgical patients. The aim of this study was to assess the effect of morphine compared with a haloperidol-based regimen in hyperactive-type delirium in patients after cardiac surgery.
Design: A prospective, randomized clinical study. Setting: A single community hospital.
Participants: Fifty-three consecutive, adult, delirious patients.
Interventions: Patients were randomized into 2 groups; in group 1, patients received 5 mg of haloperidol intra-muscularly and in group 2, patients received 5 mg of morphine sulfate intramuscularly to control delirium symptoms.
Measurements and Main Results: During the second and third hour of the morphine treatment, statistically low
Richmond Agitation and Sedation Scale scores were found and the target Richmond Agitation and Sedation Scale scores percentages were statistically higher than those of the haloperidol group (p ¼ 0.042 and p ¼ 0.028, respec-tively). The number of patients requiring additive sedatives was significantly more in the haloperidol group when compared with the morphine group (p ¼ 0.011).
Conclusion: During the treatment of patients, it was determined that the patients who were receiving morphine treatment responded more quickly compared with the patients receiving haloperidol treatment. Morphine was found to be a reasonable alternative to haloperidol in the treatment of postoperative hyperactive delirious patients after cardiac surgery.
KEY WORDS: delirium, treatment, haloperidol, morphine, cardiac surgery, intensive care unit (ICU)
POSTOPERATIVE DELIRIUM is a common complication after cardiac surgery. It is defined clinically as an acute confusion state characterized by disorientation, a disturbed sleep-wake cycle, memory impairment, perceptual distur-bances, and altered psychomotor activity. In the literature, the incidence of delirium varied between 13.5% and 21% after cardiac surgery.1-3 Risk factors for postoperative delirium include older age, cognitive dysfunction, functional impair-ment, multiple comorbidities, and malnutrition. Delirium is associated with worse outcomes including prolonged hospital stay, increased incidence of discharge to other institutional facilities, and higher mortality.
Traditionally, haloperidol has been prescribed as the pri-mary agent of choice for the treatment of delirium symptoms for patients in critical condition.5,6 Clinicians have been challenged to consider alternative agents because of adverse effects such as extrapyramidal symptoms with haloperidol use. Especially in agitated delirious patients after cardiac surgery, haloperidol sometimes is ineffective and, often, it requires additional sedatives. New atypical antipsychotics have been developed that are attractive alternatives to haloperidol because of the improved safety profiles but are flawed by limited data to support efficacy and dosing in patients.
In this study, the authors hypothesized that morphine might be superior to haloperidol in the initial management of hyperactive delirium following cardiac surgery because of its analgesic, anxiolytic, and sedative properties. The mean objective was to evaluate the effect of morphine on post-operative hyperactive-type delirious patients and compare morphine and haloperidol in the treatment regimen.
METHODS
In this study, 787 consecutive patients who had cardiac surgery with or without cardiopulmonary bypass were enrolled prospectively after obtaining the hospital’s Ethical Committee approval. During a period between January 2010 and July 2012, patients who had a history of dementia and/or abnormal level of consciousness, Parkinson’s disease, and recent seizures prior to surgery were excluded.
Postoperatively, all the patients were analyzed daily by using the confusion assessment method for the intensive care unit (CAM-ICU).7,8 Abnormal or delirious behavior was recorded by the bedside nurse and reviewed by the research team. Delirium is defined according to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders IV criteria.9 On the basis of a structured interview, the CAM-ICU algorithm consisted of 4 clinical criteria: acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness. For delirium to be diagnosed, both the first and second criteria have to be present, with either criterion 3 or 4.
Patients who were diagnosed with delirium were evaluated further by the Richmond Agitation and Sedation Scale (RASS).10,11 Based on this scale, patients who had a RASS score of o0 were diagnosed with hypoactive delirium and who had a RASS score of 4þ2 were diagnosed with hyperactive delirium. Hypoactive delirium patients were treated with peroral, low-dose haloperidol under the control of a psychiatrist. Hypoactive-type delirium patients were excluded from the study; whereas hyperactive delirium patients were randomized into 2 groups. The clinical evaluation was made by the intensivist, together with the consultant psychiatrist, who was blinded to the study groups to avoid bias. In group 1 (n = 26), the patients received 5 mg of haloperidol intramuscularly and in group 2 (n = 27), the patients received 5 mg of morphine sulfate intramuscularly. This process was repeated every hour until the adequate sedation and target RASS scores (between 1 and þ1) were achieved. In patients who were still agitated despite the administration of 20 mg/d of morphine or 20 mg/d of haloperidol, 2.5 mg of lorazepam perorally, twice a day was added to the treatment regimen. All delirious patients were re-evaluated every 12 hours by CAM-ICU and RASS until discharged from the hospital or for a maximum of 10 days following surgery. Patients were considered delirium free when they were free of symptoms for more than 24 hours.
Outcomes of the study included duration time of delirious behavior, daily total medication doses, need for additional sedative drug, RASS scores, the percentage of patients who maintained a RASS score within the target scores, reintubation, redo-surgery, length of ICU and hospital stay, readmission to the ICU, and hospital mortality rate.
A standardized anesthetic technique was utilized, which consisted of administration of 15 to 25 mg/kg of fentanyl given intravenously combined with administration of 0.1 to 0.15 mg/kg of midazolam. Neuromuscular blockade was achieved by infusion of 0.1 mg/kg/h of vecuronium bromide, and the lungs were ventilated to normocapnia with a mixture of 50% oxygen and 50% nitrous oxide. To maintain anesthesia, infusion of 2 to 5 mg/kg/h of fentanyl, infusion of 50 to 80 mg/kg/h of midazolam, and isoflurane were used. All surgeries were performed with systemic moderate hypothermia (321C).
Surgical techniques were standardized and were not modified during the entire study. Surgery was performed under mild hypothermia by using antegrade and retrograde blood cardioplegia. Nonpulsatile extracorporeal circulation and a membrane oxygenator were used. During CPB, flow rates were kept between 2 and 2.6 L/min/m2 and mean arterial pressure was maintained between 70 and 80 mmHg. Adequacy of tissue perfusion was monitored with arterial blood gas analysis, pH, lactate level, base deficit, and urine output. Blood products, including packed red blood cells, were given to maintain a hemoglobin level of at least 8 g/dL. After achieving adequate intravas-cular volume, norepinephrine was used to maintain a mean arterial blood pressure of at least 70 mmHg and dopamine to maintain a cardiac index of at least 2.5 L/min/m2. The intra-aortic balloon counterpulsa-tion was initiated when mean blood pressure was less than 70 mmHg and mixed venous oxygen saturation was below 65% despite adequate inotropic support. Glyceryl trinitrate infusion was used for blood pressure control. During admission to the ICU, every patient was ventilated in assist-control mode to maintain pH between 7.35 and 7.45, PaCO2 between 35 and 45 mmHg, and PaO2 4 95%. Ventilation was weaned as per ICU protocol.
Postoperative analgesia was achieved by providing 1 g of para-cetamol intravenously every 8 hours and 50 mg of dexketoprofen intravenously twice a day. Postoperative pain was recorded once a day using the verbal version of the visual analog scale, in which a rating of 0 corresponds to no pain, ratings of 1 to 4 indicate moderate pain, and ratings of 5 to 10 correspond to severe pain. Patients were asked to rate their pain level at rest, after extubation (postoperative day 0), post-operative day 1 (approximately 24 hours after surgery), and post-operative day 2 (approximately 48 hours after surgery).
Patients who were compliant, extubated with stable hemodynamic parameters, and without bleeding were discharged from the ICU to private rooms where they stayed with family members.
Statistical analysis was performed by SPSS for Windows 16.0 version (Chicago, IL). Continuous data were given as mean standard deviation, categoric data were expressed in percent (%). For compar-ison of the continuous variables, the Student t-test and the Mann-Whitney U test were used. The chi-square (w2) test was used to analyze relationships between categoric data. Statistical significance level was defined as p o 0.05.
RESULTS
In the study, there were 53 hyperactive-type delirium patients. Preoperative characteristics for haloperidol and mor-phine treatment groups are summarized in Table 1, operative and postoperative characteristics of both groups are summar-ized in Table 2. Demographic and medical data were similar between the groups. The mean age of group morphine patients was 66.00 8.39 years (range, 40-82 years) and group haloperidol patients was 65.74 9.67 years (range, 49-82 years) (p ¼ 0.917). The most common surgical procedures were coronary artery bypass graft (n ¼ 44, 83.0%), aortic surgery (n ¼ 4, 7.5%), combined valve/coronary artery bypass graft surgery (n ¼ 4, 7.5%), and valvular surgery (n ¼ 1, 1.8%). To assess the postoperative pain, the authors used the visual analog scale score in the patients. The authors found that in both groups moderate pain levels were recorded. There were no statistically significant differences between the 2 groups (p ¼ 0.846, p ¼ 0.696, and p ¼ 0.673).
Most patients who developed delirium (n ¼ 33, 62.2%) were diagnosed within 24 hours postoperatively (1.25 0.9 days, range 1-6 days). The mean duration of delirium was 36.0 16.1 hours (range 12-90 hours) for all delirium patients. The duration of delirium was not significant in the morphine group compared with the haloperidol group (31.56 v 33.9 hours, p ¼ 0.607). However, patients who were treated with morphine required significantly less additive sedative drug (8 patients v 1 patient, p ¼ 0.011).
RASS scores of the morphine and haloperidol groups are presented in Figure 1 and daily total doses of morphine and haloperidol are presented in Figure 2. When compared with haloperidol-treated patients, RASS scores were significantly lower in the morphine group at the second and third hour after drug administration. The percentage of patients who main-tained a RASS score within the target range is presented in Figure 3. During the second hour of the treatment, the number of patients within target RASS scores was significantly higher in the morphine group compared with the haloperidol group (63.0% v 30.8%, p ¼ 0.028). The severity of delirium was reduced in both groups in conjunction with decreased RASS scores and drug dose.
The duration of ICU stay (3.3 days v 2.8 days, p ¼ 0.402) and hospital stay (8.5 days v 8.9 days, p ¼ 0.607) were not significant in patients in group haloperidol compared with those in group morphine. There was no statistically significant difference in hospital mortality (p ¼ 0.610) and no serious adverse effects were observed in either the morphine or haloperidol groups.
DISCUSSION
Postoperative delirium is one of the devastating complica-tions after cardiac surgery. It correlates with increased hospital stay and increased mortality and morbidity.1-4 It usually presents around the first 24 hours postoperatively and resolves in most patients within 48 hours.12 Almost 61% of the delirious patients in this study were identified within the 24 hours after surgery and resolved, on average, in 32 hours.
The classification of postoperative delirium is based upon psychomotor symptoms.13,14 Hyperactive delirium is character-ized by agitation, restlessness, attempting to remove catheters, and emotional lability. Hypoactive delirium is characterized by pure lethargy, withdrawal, flat affect, apathy, and decreased responsiveness. Mixed form is characterized by fluctuation between lethargy and agitation. In this study, postoperative delirium was seen in 9.5% of the patients and 70.7% of those cases were classified as hyperactive-type delirium.
The pathophysiology of delirium is multifactorial. Although there are many hypothesized pathophysiologic mechanisms involved in the development of delirium, most are thought to be related to imbalances in neurotransmitters that modulate cognition, behavior, and mood. The stress responses to surgery and anesthesia, inadequate perfusion of the brain cells during the surgery, hypoxia, hypoglycemia, electrolyte imbalances, volume depletion, infection, drug interactions, and neurotrans-mitters have been implicated as possible mechanisms for postoperative delirium.15,16
The most critical steps in delirium management are preven-tion and early recognition. Both prevention and treatment should focus on the minimization and/or elimination of predisposing and precipitating factors. Protocols and evidence-based strategies for prevention and treatment of delirium will no doubt emerge as more evidence becomes available from ongoing randomized clinical trials of both nonpharmacologic and pharmacologic strategies.
Nonpharmacologic strategies included repeated reorienta-tion of patients, repetitive provision of cognitively stimulating activities for the patients multiple times a day, early mobiliza-tion activities, nonpharmacologic sleep protocol, maintenance of a day-night sleep, range of motion exercises, timely removal of catheters, and physical restraints. Furthermore, use of eye glasses and magnifying lenses, hearing aids and earwax disimpaction, early correction of dehydration, use of a sched-uled pain management protocol, placing familiar objects, clocks, and calendars in the room, and minimization of unnecessary noise or stimuli also are considered as nonphar-macologic strategies.15,17
Pharmacologic strategies include optimizing the quantity and type of sedative and analgesic medications delivered to patients or instituting currently recommended medications such as antipsychotics. Identification of safe and efficient agents to reduce the incidence, duration, and severity of delirium is one of the hot topics in critical care.
There are currently no medications approved by the Food and Drug Administration for both the prevention and the treatment of delirium. Haloperidol is known to be the first-line agent in postoperative delirium patients. Also, it is recommended as the drug of choice for the treatment of delirium by American Psychiatric Association and Society of Critical Care Medicine guidelines as it does not cause any hemodynamic and respiratory depression.1,5,6 Haloperidol is a dopamine-receptor antagonist that works by inhibiting dopamine neurotransmission, with resulting improvements in the positive symptomatology of hallucinations, agitation, and combative behavior, and often results in a sedative effect.1 Common doses for delirium patients range from 4 to 20 mg/d, but higher doses are used frequently for the treatment of acute agitation. Also, it is useful in patients who are ventilated but are in a position to be weaned off the treatment.18
Opioids are the main agents used for analgesia in the ICU.19-21 Morphine sulfate is the preferred opioid analgesic in patients with stable hemodynamics. Analgesia greatly affects the need for sedation and other therapies. One of the major factors contributing to the postoperative delirium is rest pain.22-24 Morrison et al found that avoidance of opioids or limited use of opioids increased the risk of delirium, presumably because of inadequate control of pain in hip fracture patients.25 Unrelieved pain induces a powerful stress response characterized by tachycardia, increased myocardial oxygen consumption, hyper-coagulability, immunosuppression, and persistent catabolism. At low doses, opioids provide analgesia and in high doses they provide anxiolysis and sedation.26
Ensuring adequate pain control is essential; the use of opioids may be necessary. The average dose used in delirium patients in this study was higher than that required for the usual analgesic effect of morphine. The anxiolytic effect of morphine might be the underlying mechanism. Other studies also have demonstrated that morphine does have an anxio-lytic effect.27 This is the first study comparing haloperidol with morphine in hyperactive delirium patients and the findings suggest that morphine treatment responded more quickly as compared with the agitated patients under halo-peridol treatment. Statistically low RASS scores were observed, especially during the second and third hour of the morphine treatment. In addition, the number of patients within the target RASS score percentages was statistically higher in the morphine group as compared with the haloperidol group. The number of patients requiring additive sedatives was significantly more in the haloperidol group when compared with the morphine group. It should be noted that one major limitation of the study was that it was conducted in a relatively small group of patients who had hypoactive delirium after cardiac surgery.
In conclusion, the results demonstrated that morphine was a good alternative to haloperidol for the management of hyper-active delirium symptoms after cardiac surgery because of its rapid action and absence of side effects. Moreover, the morphine group revealed several advantages over the haloper-idol group. Morphine has the advantage of keeping the respiratory and hemodynamic stability besides its rapid and effective action on agitated delirium patients after cardiac surgery. Well-designed, randomized, placebo-controlled trials are needed to inform critical care clinicians regarding the efficacy and safety of both drugs in the prevention and treatment of hyperactive-type delirium.
