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Psychosomatic Medicine 67:295-300 (2005)
© 2005 American Psychosomatic Society

ORIGINAL ARTICLES

Relative-Assessed Psychological Factors Predict Sedation Requirement in Critically Ill Patients

Tamar Green, MD, Yori Gidron, PhD, Michael Friger, PhD and Yaniv Almog, MD

From the Medical Intensive Care Unit (T.G., Y.A.) and Department of Epidemiology (M.F.), Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel; and the School of Psychology, University of Southampton, Southhampton, United Kingdom (Y.G.).

Address correspondence and reprint requests to Yaniv Almog, MD, Medical Intensive Care Unit, Soroka University Medical Center, P.O.B. 151, Beer-Sheva 84101, Israel. E-mail: almogya{at}bgumail.bgu.ac.il; dekelgr{at}netvision.net.il


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION AND CONCLUSION
 NOTES
 REFERENCES
 
Objective: Sedation is frequently required in critically ill, mechanically ventilated patients. Sedation and analgesia requirements may vary substantially among patients. This study examined whether psychological factors predict amount of sedation requirements beyond the effects of other biomedical parameters.

Methods: This study used a prospective correlative design in an eight-bed medical intensive care unit at a tertiary university hospital. Fifty-five adult patients requiring mechanical ventilation were included. We evaluated by questionnaires three psychological factors of patients—hostility, anxiety and desire for control (DC)—as completed by patients’ relatives at entry to the intensive care unit. Daily doses of sedatives required were monitored. The primary outcome measurement was midazolam dose expressed in mg/kg/h.

Results: There was a statistically significant correlation between psychological factors and midazolam dose (mg/kg/h): r values = 0.40 for anxiety, 0.43 for hostility, and 0.46 for DC. Age and pulmonary edema were inversely related to midazolam requirements, whereas smoking, chronic obstructive pulmonary disease, fentanyl dose, and therapeutic intervention scoring system were positively correlated with midazolam doses. In a multiple regression, DC accounted for an additional and significant 5.4% of the variance in midazolam after controlling statistically for the effects of the significant background and biomedical predictors. In the final regression equation, DC and fentanyl were the only significant factors associated with higher sedation requirement.

Conclusion: Premorbid psychological profile independently predicts sedation requirement in critically ill, mechanically ventilated patients. Early identification of such a profile may help in sedation management and patient care. The possible mechanisms and clinical implications are discussed.

Key Words: sedation • mechanical ventilation • psychological predictors • ICU

Abbreviations: MV = mechanical ventilation; ICU = intensive care unit; DC = desire for control; APACHE II = Acute Physiology Age Chronic Health Evaluation II; TISS = Therapeutic Intervention Scoring System; COPD = chronic obstructive pulmonary disease.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION AND CONCLUSION
 NOTES
 REFERENCES
 
Sedationis frequently required in critically ill, mechanically ventilated patients in order to alleviate anxiety, relieve pain, and facilitate mechanical ventilation (MV). The goal is to keep the patient sedated at a level that will ensure comfort yet allow easy arousal and partial cooperation. Maintaining patients under such optimal sedation in intensive care units (ICUs) is a common and difficult clinical challenge (1). This goal is difficult to achieve without oversedation on the one hand and agitation on the other. Furthermore, weaning patients or performing extubation after prolonged periods of mechanical ventilation may be very difficult, because withdrawing sedation may lead to extreme agitation, or patients may remain oversedated (1).

Benzodiazepines are the most frequently used sedatives in the ICU because they possess both sedative and hypnotic properties (2–4). Because they lack analgesic properties, opiates (eg, fentanyl) are frequently added to benzodiazepines in order to relieve pain and facilitate sedation (5). Sedation and analgesia requirements may vary substantially from patient to patient. Patient-specific physiologic variables such as age, genomics, renal function, concurrent pathology, previous alcohol abuse, and concurrent drug therapy affect the efficacy and duration of activity of benzodiazepines, mandating the need for individualized titration (1). However, it is unclear whether these factors alone could account for the variability observed in individual sedation needs. One study found prevalent psychological distress in ICU patients after weaning from mechanical ventilation. This distress included reporting nightmares during sedation, fear of dying, and hallucinations (6). However, this was a retrospective study, and it is unclear whether premorbid psychological factors predict patients’ sedation requirements.

Clinical experience with sedated patients in the ICU suggests that highly anxious or aggressive patients may require more sedation and more aid during weaning. In one study with surgical patients, hostility predicted blood pressure during cardiac surgery (7). A related psychological variable, the desire for control (DC), could also affect levels of required sedation particularly if patients are nearly conscious. However, to the best of our knowledge, no research has tested the effects of psychological and personality traits on sedation requirements in ICU. The present investigation was undertaken to examine whether psychological factors pertaining to the patient (and assessed by first-degree relatives) can predict sedation requirements in critically ill patients in the ICU. We hypothesized that anxiety, hostility, and DC will be positively correlated with levels of required sedation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION AND CONCLUSION
 NOTES
 REFERENCES
 
Participants
A total of 324 patients admitted to the medical intensive care unit at Soroka University Medical Center between May 2001 and March 2002 were screened for eligibility. One family declined to participate. Sixty-four patients who met inclusion criteria were recruited, and their relatives were interviewed within 12 hours of admission. Of these patients, nine were excluded, five because they required muscle relaxants, three because they were mechanically ventilated for less than 5 hours, and one because the patient lapsed into a coma after cerebral infarction. Fifty-five patients were included in the study and final analysis who met our inclusion criteria: age older than 18 years, mechanical ventilation for more than 5 hours, and life expectancy greater than 30 days. The exclusion criteria were illicit drug use (eg, cocaine, methamphetamine, lysergic acid diethylamide) or alcohol abuse for the last 5 years, central nervous system pathology that may influence sedation requirements (acute or chronic cerebrovascular disease), known psychiatric disorders, use of paralytic agents for more then 2 hours, chronic ventilator dependency, patients who received propofol continuous infusion for more than 2 hours, and patients who were ventilated elsewhere for more then 24 hours before enrollment. The Ethics Committee of the Soroka University Medical Center approved the study protocol before its initiation. A written informed consent was obtained from an authorized relative of each patient.

Measures
Background and Biomedical Measures
Patients’ medical records were reviewed for primary cause of admission, sociodemographic characteristics (age, marital status, ethnic origin, and years of education), body mass index, comorbidity, drinking, and smoking. During the period of MV, patients’ data were monitored on a daily basis. The level of sedation, assessed by Ramsay scale every 8-hour shift, and medication dose required to achieve that level were assessed on a daily basis (8). All other medications and interventions were also recorded. In addition, hemodynamic, ventilatory, and laboratory data were monitored. Data were retrieved from the patient medical record that was filled by the ICU staff. Acute Physiology Age Chronic Health Evaluation II (APACHE II) was calculated for each patient on admission. APACHE II uses a point score based on initial values of 12 physiologic measurements, age, and previous health status to provide a general measure of severity of illness. The APACHE II is assessed for each patient at the end of the first day of ICU admission, with scores ranging from 0 to 71. Increasing scores correlate with an increasing risk of in-hospital death (9). In addition, the Therapeutic Intervention Scoring System (TISS) is calculated on a daily basis for each patient. The TISS scoring system is focused on nursing activities, but it also reflects the complexity of therapeutic interventions during the ICU stay (10,11). Level of sedation and daily dosage of medications (all expressed as mg/kg/h) required to achieve the target level of sedation were assessed on a daily basis.

The ICU team, also blind to the psychological questionnaire results, filled out the patient’s medical record in relation to required sedation and medications.

Psychological Measures
Psychological assessment of patient variables was performed via questionnaires by interviewing a patient’s relative (eg, spouse, son, daughter) because all patients were intubated and mechanically ventilated. This method was used in previous studies and proved to be more predictive of objective medical outcomes in cardiovascular patients than patients’ self-assessment of the same parameters (eg, hostility) (12). In other patient populations, spouse and patient ratings were found significantly correlated (eg, for quality of life) (13), and agreement on personality measures was found to be particularly strong among spouses (14). Given these previous findings, the obvious restrictions communicating with patients of the current study sample, and our wish to assess patients at entry to the ICU, we considered relative ratings to be a valid method for assessing patients’ psychological traits. To reduce the burden on relatives during such a critical period of their ill family member, we administered only brief psychological measures. Hostility was assessed by the New-Buss questionnaire. This 8-item scale has been found to reflect mainly antagonism and to correlate with other hostility measures in both the United States and Israel. In addition, it is associated with severity of coronary artery disease in young men (15). In the present study, its internal reliability consistency was Cronbach’s {alpha} = 0.85. Anxiety was assessed with the 6-item version of the State-Trait Anxiety Inventory. This abbreviated version of the questionnaire has been previously validated and used (16). Although this brief scale was initially developed for assessing state-anxiety, in the present study we used the term in general to reflect trait-anxiety. In the present study, its internal reliability consistency was Cronbach’s {alpha} = 0.74. DC was assessed by using 6 items from the general subscale of the Berger and Cooper Desire for Control scale (17,18). The DC scale has been found to predict seeking help for depression and suicidal ideation in people who perceive that their current status is out of their control (18). In the present study, its internal reliability consistency was Cronbach’s {alpha} = 0.83. On all questionnaires, every question had a response option with five scores. An average score was calculated based on the response to all questions in each variable (anxiety, hostility, and DC).

Procedure
One of the investigators screened consecutive patients admitted to the ICU. The patient’s relative (spouse in most cases) was interviewed within 12 hours of admission using the questionnaires. Patients’ medical records were reviewed for the background and biomedical data described. The investigator conducting the interview was blinded to the amount of sedation administered, and the investigator responsible for sedation titration was blinded to the psychological interview results. It is our unit policy that all patients who require sedation receive both midazolam and fentanyl. However, at times, fentanyl may be omitted because of patient-specific clinical consideration such as hemodynamics, paralytic ileus, and other reasons. Fentanyl at doses administered is not believed to possess sedative effects.

All patients who required fentanyl received it at a fixed dose of 25 µg/h (N = 39) in accordance with our unit sedation protocol. Follow-up was terminated on performing extubation or tracheotomy; discharge from the ICU; 14 days of follow-up; or patient’s death. The outcome measurement was midazolam dose calculated as mg/kg/d in order to adjust the comparison for patients’ weight variability.

Statistical Analysis
The relations between the continuous demographic and clinical characteristics with midazolam were tested with Spearman correlations. For dichotomous predictors (eg, gender) we used t-tests, and for categorical predictors with more than two categories, we used analyses of variance. Concerning the psychological predictors, we first tested the associations among all psychological variable themselves. Because these predictors emerged highly intercorrelated (see Results), and in order to prevent singularity and multicolinearity, we first entered all three psychological factors into a simultaneous multiple regression alone, with midazolam as the dependent variable. The best significant psychological predictor was selected for further analysis. We then conducted a hierarchical multiple regression with midazolam regressed first on the significant background and biomedical predictors, and then on the most important psychological predictor. We examined the percent of increment in explained variance in midazolam accounted for by the best psychological predictor, after controlling for significant background and biomedical predictors.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION AND CONCLUSION
 NOTES
 REFERENCES
 
The demographic and clinical characteristics of the study population are presented in Table 1. Our data collection included daily doses of midazolam that were used for sedation (N = 55). Patients’ mean age was 66 ± 13 years, 71% were married, half were women, and in nearly 90% of patients, the main reason for admission into the ICU was related to lung functioning. Of the entire sample, 19 spouses and 36 first-degree relatives completed the questionnaires for patients. No differences were found in rating anxiety, hostility, or DC between patients who were rated by their spouse and those rated by other relatives.


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  		TABLE 1. Summary of Demographic and Clinical Characteristics

 

Univariate Analyses
No statistically significant correlation was found between sex, weight, ethnic origin, marital status, and education with midazolam doses (data not shown). Table 2 depicts the relations between continuous predictors and midazolam dosages. Age was significantly and inversely related to midazolam dosages, and TISS was significantly positively correlated with midazolam dosages. Midazolam requirements were significantly higher in patients who smoked (mean = 0.15 ± 0.18 mg/kg/h) than in nonsmokers (mean = 0.05 ± 0.06 mg/kg/h; p = .036). Table 3 presents mean midazolam dosages according to patients’ comorbidity and main reason for admission into the ICU. As shown in Table 3, patients with pulmonary edema required less midazolam than those without such a condition, whereas those with chronic obstructive pulmonary disease (COPD) required more midazolam than those without COPD. In addition, patients who were administered fentanyl required significantly more midazolam (mean = 0.087 ± 0.07 mg/kg/h) than those not prescribed fentanyl (mean = 0.009 ± 0.02 mg/kg/h; t[52] = 6.19; p < .001). Because prescribing this drug correlated with midazolam doses, and because it constituted part of the treatment regime, we then examined the relation between prescribing fentanyl and the three psychological predictors. Patients received fentanyl were rated by their relative as higher on DC (mean = 3.07 ± 0.85), higher on hostility (mean = 2.39 ± 0.88), and lower on anxiety (mean = 2.59 ± 0.64) than those not prescribed fentanyl (mean = 2.35 ± 0.95, 1.77 ± 0.72, 3.08 ± 0.5, respectively; all p-values <.05).


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  		TABLE 2. Spearman Correlations Between the Continuous Predictors and Midazolam in ICU Patients

 

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  		TABLE 3. Association Between Primary Cause of Admission and Chronic Diseases to Midazolam Dose (mg/kg/h)

 

In contrast, no association was found between the APACHE II score, daily doses of PaCO2, PaO2/FiO2, and urea levels with midazolam doses. Maximal daily temperature, maximal and minimal systolic blood pressure, maximal and minimal mean arterial pressure, and maximal and minimal pulse rate had no association with midazolam doses. Nor did administration of steroids and vasopressor therapy predict midazolam dose. Finally, we did not find significant differences in midazolam dose between patients who died during the study and those who survived.

Association Between Psychological Predictors and Midazolam
We first examined the relations among the psychological predictors themselves. Hostility was positively strongly correlated with anxiety (r = 0.67; p < .001) and with DC (r = 0.70; p < .001). Finally, anxiety was moderately and positively correlated with DC (r = 0.49; p < .001). These correlations support the construct validity of the psychological measures. In addition, as show in Table 2, all three psychological variables were significantly positively correlated with midazolam dosages. The high intercorrelations among the psychological predictors themselves suggested a great deal of overlap among them, risking the possibility of singularity and multicolinearity in the final multivariate regression equation. To avoid this consequence, to increase our statistical power, and to yield a more parsimonious model, we entered these three variables simultaneously into a multiple regression with midazolam as the dependent variable. In this regression, only DC was a significant independent predictor of midazolam. This predictor was entered in the subsequent analysis.

Multivariate Analysis
Table 4 depicts the results of a hierarchical multiple regression in which midazolam dosages were regressed first on the significant biomedical predictors, and then on DC in the second stage. In this analysis, age, TISS, pulmonary edema, COPD, fentanyl dose, and smoking explained 43.2% of the variance in midazolam requirement. After controlling for these background and biomedical predictors, DC accounted for an additional and significant 5.4% of the variance in midazolam (F-change [1,46] = 4.82; p < .05). In the final regression equation, DC and fentanyl were the only significant factors associated with higher sedation requirement.


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  		TABLE 4. Hierarchical Multiple Regression of Statistically Significant Univariate Predictors and Midazolam Dose

 


   DISCUSSION AND CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION AND CONCLUSION
NOTES
 REFERENCES
 
As hypothesized, we found that anxiety, hostility, and DC were strong predictors of sedation requirement. Given the relatively large overlap between these variables, we then let them compete for predicting sedation requirements, and DC emerged as the best predictor. In a multiple regression, DC added a significant contribution to predicting sedation requirements after we controlled statistically for age, TISS, pulmonary edema, COPD, fentanyl use, and smoking. Furthermore, in this multivariate analysis, DC and fentanyl were the only significant factors associated with higher sedation requirement. Our results add to a growing body of evidence suggesting an association between psychological factors and objective measurable physiologic variables (19–22) and extend them to the domain of ICU, where patient awareness is mainly removed.

An unexpected observation in our study was that fentanyl use was associated with higher midazolam requirement. We suggest that fentanyl use is a marker of higher sedation need rather than its cause. Furthermore, patients who received fentanyl scored higher on their hostility and DC questions. These data suggest that fentanyl may indeed be a marker of higher sedation requirements. Additional studies designed to evaluate this question specifically are required in order to clarify this issue.

Our results suggest that even under unconscious conditions, the body’s coping with a life-threatening crisis, pain, and inconvenience of the therapeutic modalities in the ICU is influenced by personality traits. Because the ICU experience is clearly associated with complete loss of control over every aspect of personal autonomy, it stands to reason that individuals who regard control as an important aspect would require higher doses of sedation under these circumstances. Other biological mechanisms may also explain the DC-sedation relation: DC during uncontrollable stress has been shown to result with greater immune suppression (23). By analogy, we further speculate that DC could also affect other physiologic variables such as sedation requirement. Our observations suggest that a better understanding of all patients’ biomedical and psychosocial related variables might help in their management, specifically in relation to the amount of sedation they require.

We routinely attempt to evaluate patients’ responses to treatment and their prognosis by interviewing them and their relatives. Clinicians often rely on clinical impressions of psychological facets as a source of information to guide sedation therapy. However, our results suggest that by using brief standardized psychometric methods for evaluating patients’ personality, clinicians can easily achieve a more comprehensive biopsychosocial evaluation that has predictive validity.

Our findings support a few previous ones demonstrating that psychological factors such as hostility predict hemodynamic responses during surgery (7) and expand these findings to additional variables (anxiety, DC) and to the context of the ICU. It is unclear to us why DC was the most important psychological predictor. DC may reflect a more intrinsic/basic personality variable that is manifested during conscious and unconscious situations. Future studies may wish to examine whether patients high on DC manifest greater motoric and hemodynamic responses in the ICU, which could explain our results.

It has been previously shown that oversedation correlates with increased length of stay and decrease in ventilator-free days (24). It follows that optimizing sedation could affect such important measures of utilization. It would be important to explore how clinicians may manage patients high on DC during their stay in the ICU. Future intervention trials may examine the effects of pharmacological or behavioral interventions on such patients. Pharmacological interventions can be developed only after understanding the mechanisms by which DC may affect sedation requirements. Behavioral interventions may include the use of implicit messages provided to patients during their stay in the ICU. Research has shown that patients learn and manifest implicit memory of information received while unconscious, particularly information related to threatening content (25).

We also studied a wide range of physiological variables. In a univariate analysis, only a few were found to have a positive predictive value. Age was inversely related to midazolam dose. Hammerlein et al. (26) showed that elderly patients exhibit slower clearance of benzodiazepines or of their active metabolites, contributing to a marked prolongation of their effects. This mechanism can explain the age-dependent differences observed in our study. Severity of illness, as reflected by APACHE II scores, did not predict sedation requirements. We excluded patients with central nervous system pathology; therefore, scoring for Glasgow coma score (the most heavily weighted component of the score) was minimal. This could have restricted the range of scores on this measure, potentially reducing its correlation with sedation requirements. Furthermore, APACHE II is assessed only on admission, whereas TISS, which did predict sedation requirements, is assessed on a daily basis. Therefore, TISS appears to be a better predictor of sedation requirements while receiving mechanical ventilation.

Although our hypotheses were confirmed, our study has few limitations. The limited sample size resulted in a less than optimal number of observations per predictor in the regression model (fewer than 10 patients per predictor). Furthermore, the ethnic diversity of the sample is limited, which hampers the generalizability of the results. Nevertheless, the fact that the psychological factors significantly predicted sedation requirements in a relatively small sample suggests that their effect on this outcome may be of clinical significance. This is also supported by the fact that in the multivariate analysis, DC significantly predicted sedation requirement, independent of biomedical factors. In our study, patients received both short-term and long-term sedation, and therefore, sedation needs were expressed in mg/kg/h in order to address these differences. However, it is well known that long-term midazolam administration results in the accumulation of active metabolites. The dose of patients who received long-term sedation could have been affected by such accumulation. In addition, the brief psychological measures used, and the reliance only on spousal/relative reports may have reduced our ability to detect additional relationships. Even though we did not validate the questionnaires selected for this study on a separate sample of relatives, we used only valid measures. Additional prospective studies are needed to replicate our findings and address these limitations.

In summary, we found three psychological predictors for sedation needs during MV, one of which emerged as an independent predictor: DC. Early identification of such a psychological profile may suggest the need for higher doses of sedation. Applying this knowledge could improve sedation quality and patient care. Future intervention studies may examine the effects of treating patients high on DC on their sedation requirements and long-term clinical outcomes.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION AND CONCLUSION
 NOTES
REFERENCES
 
This work was performed as Tamar Green’s MD thesis.

Received for publication March 26, 2004; revision received October 3, 2004.

DOI:10.1097/01.psy.0000156928.12980.99


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION AND CONCLUSION
 NOTES
 REFERENCES
 

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