Background Continuous infusions of sedative drugs in the intensivecare unit may prolong the duration of mechanical ventilation,prolong the length of stay in the intensive care unit and thehospital, impede efforts to perform daily neurologic examinations,and increase the need for tests to assess alterations in mentalstatus. Whether regular interruption of such infusions mightaccelerate recovery is not known.
Methods We conducted a randomized, controlled trial involving128 adult patients who were receiving mechanical ventilationand continuous infusions of sedative drugs in a medical intensivecare unit. In the intervention group, the sedative infusionswere interrupted until the patients were awake, on a daily basis;in the control group, the infusions were interrupted only atthe discretion of the clinicians in the intensive care unit.
Results The median duration of mechanical ventilation was 4.9days in the intervention group, as compared with 7.3 days inthe control group (P=0.004), and the median length of stay inthe intensive care unit was 6.4 days as compared with 9.9 days,respectively (P=0.02). Six of the patients in the interventiongroup (9 percent) underwent diagnostic testing to assess changesin mental status, as compared with 16 of the patients in thecontrol group (27 percent, P=0.02). Complications (e.g., removalof the endotracheal tube by the patient) occurred in three ofthe patients in the intervention group (4 percent) and fourof the patients in the control group (7 percent, P=0.88).
Conclusions In patients who are receiving mechanical ventilation,daily interruption of sedative-drug infusions decreases theduration of mechanical ventilation and the length of stay inthe intensive care unit.
Critically ill patients who require mechanical ventilation areoften given continuous intravenous infusions of sedative drugsto treat anxiety and agitation and to facilitate their care.Benzodiazepines are the agents most commonly given,1,2 but somepatients are given other nonanalgesic sedatives, such as propofol3,4or haloperidol.5 Opiates are often given as well, since nonopiatesedatives have no analgesic properties. New approaches to mechanicalventilation, often involving the use of permissive hypercapnia(i.e., allowing the partial pressure of arterial carbon dioxideto reach 50 mm Hg or higher), can cause patients substantialdiscomfort, necessitating high levels of sedation.6,7
In many intensive care units, sedatives are infused continuously.1,2As compared with intermittent bolus infusion, this approachprovides a more constant level of sedation and may increasepatients' comfort.8,9 However, administration of sedatives bycontinuous infusion has been identified as an independent predictorof a longer duration of mechanical ventilation as well as alonger stay in the intensive care unit and in the hospital.10
Continuous infusion of sedatives has other disadvantages. Extendedsedation may limit clinicians' ability to interpret physicalexaminations. It may be difficult to distinguish changes inmental status that are due to the action of a sedative fromthose that are due to neurologic injury. Therefore, cliniciansmay be compelled to order diagnostic studies to rule out newneurologic injury when patients do not awaken rapidly afterthe sedative infusion is discontinued.
The benefit of administering sedatives by continuous infusionmust be balanced against these disadvantages. Daily interruptionof sedative infusions to allow patients to "wake up" may improvethe situation by allowing clinicians to streamline the administrationof sedatives while ensuring optimal comfort for patients. Weundertook this study to determine whether daily interruptionof sedative infusions in critically ill patients receiving mechanicalventilation would decrease the duration of mechanical ventilationand the length of stay in the intensive care unit and in thehospital.
Methods
Patients
We studied patients in the medical intensive care unit who wereintubated and receiving mechanical ventilation and who weredeemed by the intensive care unit team to require sedation bycontinuous intravenous infusion. Included among these patientswere all those who showed agitation or discomfort after recoveringfrom the effects of the drugs used to facilitate endotrachealintubation (e.g., thiopental or etomidate). The exclusion criteriawere pregnancy, transfer from an outside institution where sedativeshad already been administered, and admission after resuscitationfrom cardiac arrest. The patients were randomly assigned toone of two strategies: daily interruption of the infusion ofsedatives beginning 48 hours after enrollment (the interventiongroup) or continuous infusion of sedatives with interruptiononly at the discretion of the intensive care unit team (thecontrol group). Within each group, the patients were then randomlyassigned to receive either midazolam or propofol. The randomassignments were generated by computer and then concealed insealed envelopes. Patients' assignment to the intervention groupor the control group was known only to the study investigators,but the sedatives were given on an open-label basis.
All four subgroups simultaneously received an infusion of morphinefor analgesia. The infusion of the combination of a nonanalgesicsedative drug (propofol or midazolam) and morphine will henceforthbe referred to as the infusion of sedative drugs. The protocolsfor the infusion of sedatives are shown in Table 1. Nurses adjustedthe dosage and rate of infusion according to standard proceduresat our institution (to achieve a score of 3 or 4 on the Ramsaysedation scale, which measures sedation on a scale of 1 [agitatedor restless] to 6 [asleep and unresponsive to stimuli]11).
Table 1. Protocols for the Infusion of Sedative Drugs in the Study Patients.
Base-line demographic data, Acute Physiology and Chronic HealthEvaluation (APACHE II) scores,12 and the reason for admissionto the intensive care unit were recorded for all patients. Thenumber of patients with pulmonary edema, acute respiratory distresssyndrome, or status asthmaticus who underwent ventilation withthe use of permissive hypercapnia (intentional hypoventilationto allow an arterial carbon dioxide tension of 50 mm Hg) wasalso recorded. The paralytic drug cisatracurium was given topatients with the acute respiratory distress syndrome or statusasthmaticus whose ventilation was deemed ineffective while theywere receiving the sedative infusions.
The study was approved by the institutional review board atthe University of Chicago. The requirement for consent frompatients was waived because the intervention, though not routinelyapplied, was within the established standard of care at ourinstitution.
Study Protocol
In the intervention group, an investigator not directly involvedin the patients' care interrupted the infusion of midazolamor propofol and the infusion of morphine simultaneously on adaily basis until the patients were awake and could follow instructionsor until they became uncomfortable or agitated and were deemedto require the resumption of sedation. If a patient was receivinga paralytic drug, the sedative infusion was not interrupted.A research nurse who was not directly involved in the patients'care evaluated the patients each day throughout the period wheninfusions were stopped until the patients were either awakeor uncomfortable and in need of resumed sedation. This nurseimmediately contacted a study physician when a patient awakened,at which time the study physician examined the patient and decidedwhether to resume the infusions. For the patients in the interventiongroup who were receiving paralytic drugs, the sedative infusionswere stopped daily (after administration of the paralytic drughad been stopped) in a manner identical to that for the patientsin the intervention group who were not receiving paralytic drugs.The sedative infusions were started again after the patientwas awake or, if agitation prevented successful waking, at halfthe previous rates and were adjusted according to the need forsedation.
The patients in the control group were monitored each day byresearch staff, and the total daily doses of sedative drugsinfused were recorded. The adjustment of the dosage of sedativedrugs in the control group was left to the discretion of theintensive care unit team. Apart from daily interruption andresumption of sedative-drug infusions in the intervention group,all other decisions regarding patient care were made by theintensive care unit team.
Each day, we assessed each patient's mental status with respectto wakefulness. A patient was considered "awake" if he or shewas able to perform at least three of the following four actions,which could be assessed objectively: open the eyes in responseto a voice, use the eyes to follow the investigator on request,squeeze a hand on request, and stick out the tongue on request.13The percentage of days on which the patient was classified asawake (the number of days awake divided by the total numberof days during which sedative-drug infusions were given) wasrecorded. Patients were considered to have been awake on anygiven day if they had been awake at any time during that day.
End Points
The primary end points of the study were the duration of mechanicalventilation, the length of stay in the intensive care unit,and the length of stay in the hospital. The total doses of eithermidazolam or propofol and of morphine administered were recorded,as were the average rates of infusion (calculated as total milligramsof drug per kilogram of body weight, divided by the total numberof hours from the start of the infusion to its termination).
The use of neurologic tests (e.g., computed tomography [CT]of the brain, magnetic resonance imaging [MRI] of the brain,and lumbar puncture) was recorded, as were the numbers of patientsrequiring paralytic drugs, reintubation, noninvasive ventilation,or tracheostomy. Adverse events (e.g., removal of the endotrachealtube by the patient), transfer to a facility equipped to providelong-term ventilation, withdrawal of care (a change in carefrom curative measures to measures aimed at comfort), and deathin the hospital were also recorded. The specific end pointsto be studied were not disclosed to any of the caregivers.
Statistical Analysis
Data were analyzed on an intention-to-treat basis. Patientswho died during the first or second day in the intensive careunit and those from whom the endotracheal tube was successfullyremoved during the first or second day, before the sedativeinfusion could be interrupted, were not included in the analysis.All patients were followed until discharge from the hospital.
Nonparametric data were analyzed with Mann–Whitney U tests.These data are presented as median values (with 25th and 75thpercentiles). Nominal data were analyzed by chi-square analysiswith Yates' continuity correction or by Fisher's exact test,as appropriate. Kaplan–Meier survival analysis14 and Coxproportional-hazards analysis15 were used to assess the effectsof daily interruption of the sedative infusion on the durationof mechanical ventilation and on the length of stay in the intensivecare unit and in the hospital. Cox proportional-hazards analysiswas used to assess differences between the intervention groupand the control group after adjustment for base-line variables,including age, sex, weight, APACHE II score, and type of respiratoryfailure (acute hypoxemic respiratory failure, such as that resultingfrom pulmonary edema or the acute respiratory distress syndrome;hypercapnic respiratory failure; or shock).16 All statisticaltests were two-sided.
Results
Patients
A total of 150 patients were enrolled in the study; 75 wererandomly assigned to the intervention group and 75 to the controlgroup. Seven patients in the intervention group and 15 in thecontrol group were excluded because either the endotrachealtube was removed or they died on the first or second day inthe intensive care unit. Thus, 68 patients in the interventiongroup and 60 in the control group were included in the analyses.The demographic characteristics, APACHE II scores, rate of useof permissive hypercapnia during ventilation, and diagnoseson admission to the intensive care unit were similar in thetwo groups (Table 2). In the intervention group, 37 patientsreceived midazolam and 31 received propofol, and in the controlgroup 29 received midazolam and 31 received propofol. Therewere no demographic differences between these subgroups in eithergroup (data not shown).
Table 2. Characteristics of the Study Patients on Admission to the Intensive Care Unit.
Outcomes
In 18 of the 60 patients in the control group, the sedativeinfusions were stopped temporarily on days other than the finalday of administration, and the percentage of days (other thanthe final day) on which the drugs were stopped ranged from 0to 54 percent. The daily interruption of sedative infusionsin the intervention group was associated with a significantdecrease in the duration of mechanical ventilation; the medianduration of mechanical ventilation in this group was 2.4 daysshorter than it was in the control group (Table 3). Mechanicalventilation was discontinued earlier in the intervention groupthan in the control group (relative risk of extubation, 1.9;95 percent confidence interval, 1.3 to 2.7; P<0.001) (Figure 1).The median length of stay in the intensive care unit inthe intervention group was shorter than it was in the controlgroup by 3.5 days (relative risk of discharge, 1.6; 95 percentconfidence interval, 1.1 to 2.3; P=0.02) (Figure 2). The lengthof stay in the hospital did not differ between the two groups(Table 3).
Table 3. The Duration of Mechanical Ventilation, Length of Stay in the Intensive Care Unit and the Hospital, and Doses of Sedative Drugs and Morphine, According to Study Group.
Figure 1. Kaplan–Meier Analysis of the Duration of Mechanical Ventilation, According to Study Group.
After adjustment for base-line variables (age, sex, weight, APACHE II score, and type of respiratory failure), mechanical ventilation was discontinued earlier in the intervention group than in the control group (relative risk of extubation, 1.9; 95 percent confidence interval, 1.3 to 2.7; P<0.001).
Figure 2. Kaplan–Meier Analysis of the Length of Stay in the Intensive Care Unit (ICU), According to Study Group.
After adjustment for base-line variables (age, sex, weight, APACHE II score, and type of respiratory failure), discharge from the intensive care unit (ICU) occurred earlier in the intervention group than in the control group (relative risk of discharge, 1.6; 95 percent confidence interval, 1.1 to 2.3; P=0.02).
Among the patients receiving midazolam, the total dose of thissedative was lower in the intervention group than in the controlgroup, as was the total dose of morphine (Table 3). In contrast,among the patients receiving propofol, there were no significantdifferences between the intervention and the control groupsin the total dose of propofol or the total dose of morphine.
The percentage of days during which patients were awake whilereceiving a sedative infusion was greater in the interventiongroup than in the control group (85.5 percent vs. 9.0 percent,P<0.001). Fewer diagnostic tests to assess changes in mentalstatus were performed in the intervention group (6 CT scansof the brain) than in the control group (13 CT scans of thebrain, 2 MRI scans of the brain, and 1 lumbar puncture; P=0.02).Only 4 of the 16 tests in the control group and 3 of the 6 testsin the intervention group provided an explanation (e.g., intracranialhemorrhage) for the changes in mental status.
Only 7 patients in the intervention group never awakened duringtheir stay in the intensive care unit, as compared with 15 patientsin the control group (P=0.05). Of these patients, 6 in the interventiongroup and 13 in the control group died in a coma; the otherswere transferred to facilities equipped to provide long-termventilation. There were no significant differences between thetwo groups in the number of other adverse events (in the interventiongroup, two patients removed the endotracheal tube and one pulledout a central venous catheter; in the control group, four patientsremoved the endotracheal tube) (P=0.88). Seven patients in eachgroup were given cisatracurium (P=0.78), and five in each grouprequired noninvasive ventilation after extubation (P= 0.74).Twelve patients in the intervention group and 18 patients inthe control group required reintubation (P=0.17), and 12 and16, respectively, underwent tracheostomy (P=0.31). Nine patientsin the intervention group and 12 in the control group were transferredto a facility equipped to provide long-term ventilation (P=0.43).The in-hospital mortality rate did not differ significantlybetween the two groups (36.0 percent in the intervention groupand 46.7 percent in the control group, P=0.25), and care waswithdrawn from 24 and 25 patients, respectively (P= 1.00). Fifty-ninepercent of the patients in the intervention group were dischargedto their homes, as compared with 40 percent of the patientsin the control group (P=0.06).
When the primary end points of the study (the duration of mechanicalventilation, the length of stay in the intensive care unit,and the length of stay in the hospital) were evaluated accordingto whether midazolam or propofol was given, no significant differencesbetween the intervention and control groups were found (datanot shown). In the intervention group, the average number ofhours per day that patients received the sedative infusion was22.8 among those given propofol, as compared with 18.7 amongthose given midazolam (P=0.05).
Discussion
Sedatives are often given to patients who are receiving mechanicalventilation to alleviate their anxiety, decrease excessive oxygenconsumption, and facilitate nursing care.17 Administration ofthese drugs by continuous infusion offers a more consistentlevel of sedation than intermittent bolus administration andthus may improve patients' comfort.9 In our experience, sedationis often difficult with intermittent administration, and suchregimens can be taxing on nurses and can hamper other aspectsof patient care.17 However, a potential drawback to continuousinfusions is the accumulation of the drug and accompanying delaysin the improvement of mental status. We hypothesized that dailyinterruption of the sedative infusion would decrease these problems.
Care of critically ill patients is costly. In the United Statesin 1997, approximately $80.8 billion was spent on intensivecare,18 and about 10 percent of this amount was spent on drugs.19Ten to 15 percent of the drug costs resulted from the purchaseof sedative drugs.20 Thus, a conservative estimate of the yearlycost of sedative drugs administered in intensive care unitsin the United States, in 1997 dollars,21 is between $0.8 billionand $1.2 billion, and the costs may be higher than that if theuse of sedative drugs increases the duration of mechanical ventilationand the length of stay in the intensive care unit.
In this study, daily interruption of the infusion of sedativedrugs shortened the duration of mechanical ventilation by morethan 2 days and the length of stay in the intensive care unitby 3.5 days. Reducing the duration of mechanical ventilationwill probably cut costs — both monetary costs and thoserelated to complications of mechanical ventilation, such asventilator-associated pneumonia and barotrauma. Daily interruptionof the sedative infusion is a practical, cost-effective interventionthat can be readily performed by the nurses caring for patientsin the intensive care unit. The results of neurologic assessmentscan then be relayed to physicians, and infusions of sedativedrugs can be restarted and adjusted as needed by the nurses.Our results suggest that daily interruption of the sedativeinfusion provides acceptable sedation while minimizing adverseeffects.
In addition, in our study, daily interruption of the sedativeinfusion reduced the total dose of midazolam administered byalmost half. A trend toward the use of lower doses of benzodiazepineshas previously been reported13,22 and is at least partly relatedto the concomitant administration of opiates such as morphine.Benzodiazepines may enhance the analgesic effects of morphine,23and this synergism may decrease the doses of benzodiazepinesneeded to achieve adequate sedation. In our study, daily interruptionof the sedative infusion did not alter the doses of propofoladministered. The concentration of propofol in plasma declinesrapidly after administration is discontinued,24 and this isprobably the reason why the daily period of drug stoppage inthe intervention group was shorter among patients assigned topropofol than among those assigned to midazolam. Despite thisdifference, the patients were awake on more than 80 percentof days in both subgroups of the intervention group, and thispercentage did not differ according to the sedative agent used.In addition, there were no differences in the duration of mechanicalventilation or the length of stay in the intensive care unitwhen patients were grouped according to the sedative they received.
One drawback to continuous intravenous sedation is impairedmental status,8,25 which may prevent the early detection ofneurologic dysfunction resulting from new insults. Stoppingthe sedative infusion for a period during each day is a simpleway to improve clinicians' ability to perform daily neurologicexaminations. In our study, most of the diagnostic tests performedto assess changes in mental status were not helpful, but fewerof these tests were performed in the group in which the sedativeinfusion was interrupted each day than in the control group.Avoiding unnecessary diagnostic studies may reduce the rateof complications related to the transport of pa-tients26,27and may reduce costs.
The incidence of adverse events, such as removal of the endotrachealtube by the patient, was low and did not differ significantlybetween the intervention group and the control group. Becausesuch events were uncommon, the power of this study to detecta difference between the groups may not have been adequate.Nevertheless, the 5 percent overall rate at which patients removedthe endotracheal tube compares favorably with the rates of 10to 12 percent observed in previous studies.28,29 It is noteworthythat in no case did a patient in the intervention group removehis or her endotracheal tube during an interruption period.There were no differences between the groups in the proportionsof patients who needed paralytic drugs, noninvasive ventilation,tracheostomy, reintubation, or transfer to another facilityfor long-term ventilation, or in the proportion from whom carewas withdrawn. The percentage of patients successfully dischargedto their homes was greater in the group assigned to daily interruptionof infusions than in the control group.
This study has several limitations. We cannot be certain thatthe clinicians involved in patient care were completely unawareof the study-group assignments. We attempted to minimize thisproblem by not disclosing the end points of the study to theclinicians. In the case of some patients in the control group,the sedative infusions were periodically interrupted by theintensive care unit team. This practice may have interferedwith the detection of differences in outcome between the twogroups, since some patients in the control group thus receivedthe potentially beneficial intervention. This study involvedpatients receiving medical intensive care; whether our resultscan be extrapolated to other groups of critically ill patients(e.g., those receiving intensive care after surgery or trauma)is not clear. In addition, we monitored visible signs of physicaldiscomfort during interruptions of the sedative infusions. Whetherless obvious types of discomfort or psychological distress werepresent during the daily interruptions of the sedative infusionscannot be discerned from this study.
In conclusion, daily interruption of the infusion of sedativedrugs is a safe and practical approach to treating patientswho are receiving mechanical ventilation. This practice decreasesthe duration of mechanical ventilation, the length of stay inthe intensive care unit, and the doses of benzodiazepines used.It also improves the ability of clinicians to perform dailyneurologic examinations and reduces the need for diagnosticstudies to evaluate unexplained alterations in mental status.
We are indebted to the nurses in the medical intensive careunit at the University of Chicago for helping to make this studypossible.
Source Information
From the Department of Medicine, Section of Pulmonary and Critical Care (J.P.K., A.S.P., J.B.H.), and the Department of Anesthesia and Critical Care (M.F.O., J.B.H.), University of Chicago, Chicago.
Address reprint requests to Dr. Hall at the University of Chicago, Department of Medicine, Section of Pulmonary and Critical Care, MC 6026, Chicago IL 60637, or at jhall{at}medicine.bsd.uchicago.edu.
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50 mm Hg) was also recorded. The paralytic drug cisatracurium was given to patients with the acute respiratory distress syndrome or status asthmaticus whose ventilation was deemed ineffective while they were receiving the sedative infusions. 
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