Continuous infusions of lorazepam, midazolam, and propofol for sedation of the critically ill surgery trauma patient: a prospective, randomized comparison

OBJECTIVE: To compare the efficacy, safety, and cost of continuous infusions of lorazepam, midazolam, and propofol in a critically ill trauma/surgery patient population. DESIGN: A prospective, randomized, nonblinded, single center. SETTING: A 16-bed intensive care unit. PATIENTS: A total of 30 ventilated patients who were 18-70 yrs of age and required pharmacologic sedation. Patients with renal and/or liver failure, a history of alcohol abuse, a head injury, or in a coma were excluded. INTERVENTIONS: Patients were randomized by block design to receive lorazepam, midazolam, or propofol. Initial boluses and infusion rates were as follows: lorazepam 0.05 mg/kg, then 0.007 mg/kg/hr; midazolam 0.05 mg/kg, then 0.003 mg/kg/hr; and propofol 0.25 mg/kg, then 0.06 mg/kg/hr. Sedation was assessed and agents titrated every 5-10 mins to achieve > or =2 and <5 on the modified Ramsay scale. Once adequate response was achieved, agents were titrated to maintain the desired level of sedation. MEASUREMENTS AND MAIN RESULTS: Maintenance doses of lorazepam 0.02+/-0.01 mg/kg/hr, midazolam 0.04+/-0.03 mg/kg/hr, and propofol 2.0+/-1.5 mg/kg/hr achieved the desired level of sedation 68%, 79%, and 62% of the time, respectively. Oversedation occurred most often with lorazepam, compared with midazolam and propofol, at 14%, 6%, and 7% of the assessment times, respectively. Undersedation occurred most frequently with propofol compared with lorazepam and midazolam, at 31%, 18%, and 16% of the assessment times, respectively. The mean number of dosage changes per day was 7.8+/-4.3 for lorazepam, 4.4+/-2.9 for midazolam, and 5.6+/-6.0 for propofol (p = .91). Sedation costs per patient day (mean +/- SD) were $48+/-$76 (lorazepam), $182+/-$98 (midazolam), and $273+/-$200 (propofol) (p = .005). The potential savings, if all study patients had received lorazepam, is $14,208 compared with $8,808 if all received midazolam. CONCLUSIONS: The data suggest that lorazepam appears to be a cost-effective choice for sedation; however, oversedation may be problematic. Midazolam is the most titratable drug in our population, avoiding excessive oversedation or undersedation. Trauma patients may respond inadequately to propofol even at higher doses. Lorazepam may be the sedative of choice in critically ill trauma/surgery patients.     

A cost analysis of enterally administered lorazepam in the pediatric intensive care unit

OBJECTIVE: To determine the cost savings of replacing intravenous midazolam with enterally administered lorazepam in mechanically ventilated children who require long-term continuous sedation. DESIGN: Retrospective review of patients treated according to a preestablished pediatric intensive care unit (ICU) sedation protocol. SETTING: Twenty-six-bed pediatric ICU in a tertiary care children's hospital. PATIENTS: The records of 30 mechanically ventilated children were analyzed. The median age was 1.5 yrs and the median weight was 8.0 kg. Patients required continuous sedation for a total of 16 days (median). INTERVENTIONS: According to our pediatric ICU sedation protocol, midazolam infusion was continued until the hourly midazolam requirement was stable for at least 24 hrs. Thereafter, patients with a nasojejunal tube who were likely to require a minimum of three additional days of continuous sedation were transitioned from intravenous midazolam to enterally administered lorazepam. The goal in transitioning therapy was to titrate the lorazepam dose and reduce midazolam administration while maintaining an unchanged level of sedation. MEASUREMENTS AND MAIN RESULTS: The rate of midazolam administration was significantly (p<.05) reduced beginning on day 1 of lorazepam treatment. Midazolam was successfully discontinued in 24 (80%) patients in 3 days (median), and adequate and appropriate sedation was maintained with lorazepam monotherapy. Six patients in whom midazolam could not be discontinued experienced a 52% reduction in the rate of midazolam administration as a result of adding lorazepam. Total projected midazolam utilization was defined as the sum of midazolam administration before initiating lorazepam and the projected midazolam requirement after initiating lorazepam. Projected midazolam cost was calculated as the product of total projected midazolam utilization and midazolam acquisition cost. Actual expenditures for both midazolam and lorazepam were subtracted from the projected midazolam cost to calculate the estimated cost savings. Overall, midazolam utilization (in milligrams) was reduced by 46.7+/-27.6% (median 52). Total projected midazolam cost for the 30 patients was $90,771. The actual cost of midazolam and lorazepam combined was $47,867, resulting in a cost savings of $42,904. CONCLUSIONS: Transitioning from intravenous midazolam to enterally administered lorazepam in critically ill children who require long-term sedation results in significant cost savings. The oral formulation of lorazepam was convenient to use, inexpensive, and effective in maintaining a continuous and appropriate level of sedation once midazolam was discontinued.     

A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients

OBJECTIVE: To compare duration of mechanical ventilation for patients randomized to receive lorazepam by intermittent bolus administration vs. continuous infusions of propofol using protocols that include scheduled daily interruption of sedation. DESIGN: A randomized open-label trial enrolling patients from October 2001 to March 2004. SETTING: Medical intensive care units of two tertiary care medical centers. PATIENTS: Adult patients expected to require mechanical ventilation for >48 hrs and who required > or =10 mg of lorazepam or a continuous infusion of a sedative to achieve adequate sedation. INTERVENTIONS: Patients were randomized to receive lorazepam by intermittent bolus administration or propofol by continuous infusion to maintain a Ramsay score of 2-3. Sedation was interrupted on a daily basis for both groups. MEASUREMENTS AND MAIN RESULTS: The primary outcome was median ventilator days. Secondary outcomes included 28-day ventilator-free survival, intensive care unit and hospital length of stay, and hospital mortality. Median ventilator days were significantly lower in the daily interruption propofol group compared with the intermittent bolus lorazepam group (5.8 vs. 8.4, p = .04). The difference was largest for hospital survivors (4.4 vs. 9.0, p = .006). There was a trend toward greater ventilator-free survival for patients in the daily interruption propofol group (median 18.5 days for propofol vs. 10.2 for lorazepam, p = .06). Hospital mortality was not different. CONCLUSIONS: For medical patients requiring >48 hrs of mechanical ventilation, sedation with propofol results in significantly fewer ventilator days compared with intermittent lorazepam when sedatives are interrupted daily.     

A dose-ranging study of midazolam for postoperative sedation of patients: a randomized,double-blind,placebo-controlled trial

OBJECTIVE: To evaluate the dose range, efficacy, and safety of midazolam for induction of sedation of mechanically ventilated postoperative patients in the intensive care unit. DESIGN: A randomized, double-blind, placebo-controlled study. SETTING: Thirteen intensive care units in Japan. PATIENTS: We included 98 patients undergoing general surgery who were ASA physical status I-III. The following inclusion criteria were applied to the patients after surgery: under mechanical ventilation, sedation level 2 or 3 on the Ramsay Sedation Scale, and any pain level but 4 on the Pybus and Torda Pain Scale. MEASUREMENTS AND RESULTS: Of the 98 patients initially enrolled in the study, 95 patients received one of the study medications: placebo (n = 24), 0.015 mg/kg midazolam (n = 21), 0.03 mg/kg midazolam (n = 26), or 0.06 mg/kg midazolam (n = 24). Level of sedation was assessed by using the Ramsay Sedation Scale before and 10 mins after medication. The proportions of patients with sedation level 4 or deeper after medication were 4.3%, 14.3%, 52.0%, and 90.9% in the placebo and the midazolam 0.015 mg/kg, 0.03 mg/kg, and 0.06 mg/kg groups, respectively. Safety was assessed by routine monitoring of body functions and monitoring for adverse events. Although midazolam dose-dependently reduced mean systolic arterial pressure, the changes in this variable were small; only one or two patients in each treatment group had decreases in systolic arterial pressure of >20%. No clear dose dependency was found for changes in other body functions measured in the intensive care unit. CONCLUSION: The proportion of patients who achieved a satisfactory level of sedation increased with an increasing dose of midazolam. Intravenous bolus injection of midazolam also dose-dependently reduced mean systolic arterial pressure. This study indicated that, balancing sedative efficacy and safety, from 0.03 to 0.06 mg/kg of midazolam provides relatively safe sedation in postoperative patients.     

Propylene glycol accumulation associated with continuous infusion of lorazepam in pediatric intensive care patients

OBJECTIVE: To determine if propylene glycol accumulates in children receiving continuous lorazepam infusion and, if accumulation occurs, to determine if it is associated with significant laboratory abnormalities. DESIGN: Prospective study. SETTING: A tertiary care pediatric intensive care unit. PATIENTS: Eleven intubated pediatric intensive care patients receiving continuous lorazepam infusion for sedation. INTERVENTIONS: Propylene glycol accumulation was determined by comparing concentrations at baseline, after 48 hrs, and at end of therapy. Laboratory abnormalities were determined by comparing serum lactate and osmolar gap at baseline, after 48 hrs, and at end of therapy. Correlation between the cumulative dose of lorazepam received and the propylene glycol concentration measured at the end of therapy was determined. MEASUREMENTS AND MAIN RESULTS: Patients aged 1-15 months were studied. Lorazepam infusion rates ranged from 0.1 to 0.33 mg.kg.hr and lasted 3-14 days. Propylene glycol accumulated significantly in patients receiving continuous infusion of lorazepam. The propylene glycol concentration increased during the study from 86 +/- 93 microg/mL at baseline to 763 +/- 660 microg/mL at the end of the study ( p=.038). A statistically significant correlation between the cumulative dose of lorazepam received and propylene glycol concentration at the end of therapy was demonstrated ( r(2)=.65, p<.005). However, the propylene glycol accumulation was not associated with significant laboratory abnormalities. Neither serum lactate concentrations nor osmolar gap were significantly elevated over baseline. CONCLUSION: Propylene glycol accumulated significantly in pediatric intensive care patients receiving continuous lorazepam infusion, and propylene glycol concentration correlated with the cumulative lorazepam dose the patient received. However, significant laboratory abnormalities due to propylene glycol accumulation were not observed.     

Prolonged isoflurane sedation of intensive care unit patients with the Anesthetic Conserving Device

OBJECTIVE: To test the efficacy and patient safety of a new method for administering isoflurane for prolonged sedation in the intensive care unit. DESIGN: Randomized controlled trial. SETTING: Multidisciplinary university intensive care unit, January 2002 to July 2003. PATIENTS: Forty ventilator-dependent intensive care unit patients 18-80 yrs old, expected to need >12 hrs sedation. INTERVENTIONS: Patients were randomized to sedation with inhaled isoflurane via the Anesthetic Conserving Device or intravenous midazolam infusion. Study duration was 96 hrs or until extubation. MEASUREMENTS AND MAIN RESULTS: Primary end points were wake-up times from termination of sedative administration and proportion of time within a predefined desired interval on a sedation scale (Bloomsbury Sedation Score). Practical and patient-related complications with the Anesthetic Conserving Device were noted. Hemodynamic, hepatic, and renal side effects were monitored. Wake-up times were significantly shorter in the isoflurane group than in the control group (time to extubation [mean +/- sd] 10 +/- 5 vs. 252 +/- 271 mins, time to follow verbal command 10 +/- 8 vs. 110 +/- 132 mins). Proportion of time within the desired sedation interval was comparable between groups (isoflurane 54%, midazolam 59% of sedation time). Few minor practical problems with this new method for isoflurane administration were noted. No serious complications related to either sedative drug occurred. We found no hemodynamic, hepatic, or renal adverse effects related to either sedative protocol. CONCLUSIONS: Isoflurane via the Anesthetic Conserving Device is a safe and efficacious method for sedation in the intensive care unit, with short wake-up times after termination of administration. The Anesthetic Conserving Device allows easily titratable administration of isoflurane without costly equipment and can be safely managed by nursing staff.     

Sedation during mechanical ventilation: a trial of benzodiazepine and opiate in combination

OBJECTIVE: To compare the efficacy of continuous intravenous sedation with midazolam alone vs. midazolam plus fentanyl ("co-sedation") during mechanical ventilation. DESIGN: A randomized, prospective, controlled trial. SETTING: A ten-bed medical intensive care unit at a university hospital. PATIENTS: Thirty patients with respiratory failure who were expected to require >48 hrs of mechanical ventilation and who were receiving a sedative regimen that did not include opiate pain control. INTERVENTIONS: An intravenous infusion of either midazolam alone or co-sedation was administered by a nurse-implemented protocol to achieve a target Ramsay Sedation Score set by the patient's physician. Study duration was 3 days, with a brief daily "wake-up." MEASUREMENTS AND MAIN RESULTS: We recorded the number of hours/day that patients were "off-target" with their Ramsay Sedation Scores, the number of dose titrations per day, the incidence of patient-ventilator asynchrony, and the time required to achieve adequate sedation as measures of sedative efficacy. We also recorded sedative cost in U.S. dollars and adverse events including hypotension, hypoventilation, ileus, and coma. Compared with the midazolam-only group, the co-sedation group had fewer hours per day with an "off-target" Ramsay Score (4.2 +/- 2.4 and 9.1 +/- 4.9, respectively, p < .002). Fewer episodes per day of patient-ventilator asynchrony were noted in the co-sedation group compared with midazolam-only (0.4 +/- 0.1 and 1.0 +/- 0.2, respectively, p < .05). Co-sedation also showed nonsignificant trends toward a shorter time to achieve sedation, a need for fewer dose titrations per day, and a lower total sedative drug cost. There was a trend toward more episodes of ileus with co-sedation compared with midazolam-only (2 vs. 0). CONCLUSIONS: In mechanically ventilated patients, co-sedation with midazolam and fentanyl by constant infusion provides more reliable sedation and is easier to titrate than midazolam alone, without significant difference in the rate of adverse events.     

Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults

OBJECTIVES: The primary objective was to evaluate the relationship between high-dose lorazepam and serum propylene glycol concentrations. Secondary objectives were a) to document the occurrence of propylene glycol accumulation associated with continuous high-dose lorazepam infusion; b) to assess the relationship between lorazepam dose, serum propylene glycol concentrations, and propylene glycol accumulation; and c) to assess the relationship between the osmol gap and serum propylene glycol concentrations. DESIGN: Prospective, observational study. SETTING: Tertiary care, medical intensive care unit. PATIENTS: Nine critically ill adults receiving high-dose lorazepam (> or =10 mg/hr) infusion. INTERVENTIONS: Cumulative lorazepam dose (mg/kg) and the rate of infusion (mg.kg(-1).hr(-1)) were monitored from initiation of lorazepam infusion until 24 hrs after discontinuation of the high-dose lorazepam infusion. Serum osmolarity was collected at 48 hrs into the high-dose lorazepam infusion and daily thereafter. Serum propylene glycol concentrations were drawn at 48 hrs into the high-dose lorazepam infusion, and the presence of propylene glycol accumulation, as evidenced by a high anion gap (> or =15 mmol/L) metabolic acidosis with elevated osmol gap (> or =10 mOsm/L), was assessed at that time. MEASUREMENTS AND MAIN RESULTS: The mean cumulative high-dose lorazepam received and mean high-dose lorazepam infusion rate were 8.1 mg/kg (range, 5.1-11.7) and 0.16 mg.kg(-1).hr (-1)(range, 0.11-0.22), respectively. A significant correlation between high-dose lorazepam infusion rate and serum propylene glycol concentrations was observed (r =.557, p =.021). Osmol gap was the strongest predictor of serum propylene glycol concentrations (r =.804, p =.001). Propylene glycol accumulation was observed in six of nine patients at 48 hrs. No significant correlation between duration of lorazepam infusion and serum propylene glycol concentrations was observed (p =.637). CONCLUSION: Propylene glycol accumulation, as reflected by a hyperosmolar anion gap metabolic acidosis, was observed in critically ill adults receiving continuous high-dose lorazepam infusion for > or =48 hrs. Study findings suggest that in critically ill adults with normal renal function, serum propylene glycol concentrations may be predicted by the high-dose lorazepam infusion rate and osmol gap.     

Subcutaneous administration of fentanyl and midazolam to prevent withdrawal after prolonged sedation in children.

OBJECTIVE: To determine the efficacy of switching to subcutaneous fentanyl with or without midazolam to prevent withdrawal after prolonged sedation in children in the pediatric intensive care unit (PICU). DESIGN: Retrospective review of hospital records. SETTING: Tertiary care center, PICU. PATIENTS: The cohort for the study included patients who had received subcutaneous fentanyl with or without midazolam to prevent withdrawal after prolonged sedation in the PICU. MEASUREMENTS AND MAIN RESULTS: Subcutaneous fentanyl with or without midazolam was administered to nine patients ranging in age from 3 to 7 yrs (mean, 4.4 +/- 1.8 yrs) and ranging in weight from 11 to 31 kg (mean, 20.1 +/- 6.8 kg). All patients required prolonged administration of fentanyl with or without midazolam during mechanical ventilation for respiratory failure. The starting infusion rate for subcutaneous fentanyl varied from 5 to 9 microg/kg/hr (mean, 7.1 +/- 1.4 microg/kg/hr). Four patients also received subcutaneous midazolam at a rate of 0.15 to 0.3 mg/kg/hr (mean, 0.24 mg/kg/hr). Subcutaneous access was maintained for 3-7 days (mean, 5.7 +/- 1.4 days) in the nine patients. No problems with the subcutaneous access were noted during treatment. The fentanyl infusion was decreased by 1 microg/kg/hr every 12-24 hrs and the midazolam infusion was decreased by 0.05 mg/kg/hr every 12-24 hrs. No patient demonstrated signs of symptoms of moderate to severe withdrawal. CONCLUSION: The subcutaneous route provides an effective alternative to intravenous administration. It allows for gradual weaning from sedative/analgesic agents after prolonged sedation while eliminating the need to maintain intravenous access.     

Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam

BACKGROUND: We sought to compare the efficacy of midazolam versus dexmedetomidine for sedation during mechanical ventilation in infants and children. METHODS: We performed a prospective, randomized trial in a pediatric intensive care unit in a tertiary care center. Infants and children requiring mechanical ventilation underwent a continuous infusion of either midazolam (starting dose of 0.1 mg/kg/h) or dexmedetomidine (starting dose of either 0.25 or 0.5 microg/kg/h) with intermittent morphine, as needed. The efficacy of sedation was assessed using the Ramsay sedation scale, pediatric intensive care unit sedation score, and the tracheal suctioning score as well as bispectral monitoring. RESULTS: There were 10 patients in each group. Sedation as assessed by the clinical sedation scores and the bispectral index was equivalent in the 3 groups. There were 36 morphine boluses administered to the midazolam group versus 29 and 20 morphine boluses administered respectively to the 0.25 and 0.5 microg/kg/h dexmedetomidine groups (P = 0.02 for midazolam versus 0.5 microg/kg/h dexmedetomidine). Total morphine use (mg/kg/24 h) was 0.74 +/- 0.5, 0.55 +/- 0.38, and 0.28 +/- 0.12 in the midazolam and the two dexmedetomidine groups respectively (P = not significant for midazolam versus 0.25 dexmedetomidine, P = 0.01 for midazolam versus 0.5 dexmedetomidine). In the two dexmedetomidine groups, 5 of 6 patients who at some point had a Ramsay score of 1 were less than 12 months of age while only 1 was more than 12 months of age (P < 0.05). CONCLUSIONS: At a dose of 0.25 microg/kg/h, dexmedetomidine was approximately equivalent to midazolam at 0.22 mg/kg/h. At 0.5 microg/kg/h, dexmedetomidine provided more effective sedation as demonstrated by the need for fewer bolus doses of morphine, a decrease in the 24-hour requirements for supplemental morphine, as well as a decrease in the total number of assessment points with a Ramsay score of 1 (inadequate sedation) and the number of patients who had a Ramsay score of 1.     

Quantitative analysis of the relationship between sedation and resting energy expenditure in postoperative patients

OBJECTIVE: To analyze quantitatively the relationship between sedation and resting energy expenditure or oxygen consumption in postoperative patients. DESIGN: A prospective, clinical study. SETTING: An eight-bed intensive care unit at a university hospital. PATIENTS: Thirty-two postoperative patients undergoing either esophagectomy or surgery of malignant tumors of the head and neck who required mechanical ventilation and sedation for > or = 2 days postoperatively. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 133 metabolic measurements were performed. Ramsay sedation scale (RSS), body temperature, and the dose of midazolam were evaluated at the time of the metabolic cart study. All patients received analgesia with buprenorphine at a fixed dose of 0.625 microg x kg(-1) x hr(-1) continuously. Midazolam was used for induction and maintenance of intravenous sedation after admission to the intensive care unit. The initial dose was 0.04 mg x kg(-1) x hr(-1) and was adjusted to achieve a desired depth of sedation at 3, 4, or 5 on the RSS every 4 hrs. The degree of sedation was classified into three states: light sedation (RSS 2-3; n = 49), moderate sedation (RSS 4; n = 39), and heavy sedation (RSS 5-6; n = 45). RESULTS: With increasing the depth of sedation, oxygen consumption index (mL x min(-1) x m(-2)), resting energy expenditure index (REEI; kcal x day(-1) x m(-2)), and REE/basal energy expenditure (BEE) decreased significantly. Oxygen consumption index (mean +/- SD), REEI, and REE/BEE were 151 +/- 18, 1032 +/- 120, and 1.29 +/- 0.17 in the light sedation, 139 +/- 22, 947 +/- 143, and 1.20 +/- 0.16 in the moderate sedation, and 125 +/- 16, 865 +/- 105, and 1.13 +/- 0.12 in the heavy sedation, respectively. CONCLUSION: An increase in the depth of sedation progressively decreases in oxygen consumption index and REEI in postoperative patients.     

Reversal of midazolam sedation with flumazenil.

OBJECTIVE: To demonstrate the efficacy of flumazenil in reversing the sedative action of midazolam in ventilated intensive care patients. DESIGN: Prospective, double-blind randomized study. SETTING: ICU of a tertiary, university-affiliated teaching hospital. PATIENTS: Thirty ICU patients requiring artificial ventilation for greater than 12 hrs were studied. INTERVENTIONS: All patients received a midazolam infusion for sedation. Twenty-nine patients received supplementary narcotics. At the end of the sedation period, either flumazenil or placebo was administered to all the patients in a double-blind, randomized fashion, and the effects were observed. MEASUREMENTS AND MAIN RESULTS: Sedation levels were measured hourly during the infusion; at the end of the infusion; and at 5, 15, 30, 60, and 120 mins after cessation of the midazolam infusion. Midazolam concentrations in serum were measured at the time of cessation of the midazolam infusion and at 30, 60, and 120 mins later. Reversal of sedation was observed in 14 of 15 patients who received flumazenil, and resedation occurred in seven of these patients. Reversal was not seen in any of the patients who received placebo. Midazolam serum concentrations were similar in both groups. CONCLUSION: Flumazenil in a dose of 0.15 mg is a safe drug that reverses the sedative effect of midazolam.     

Bispectral index-guided sedation with dexmedetomidine in intensive care: a prospective,randomized, double blind,placebo-controlled phase II study

OBJECTIVE: To compare dexmedetomidine vs. placebo with respect to the amount of additional propofol and morphine used for bispectral index-guided sedation and analgesia in mechanically ventilated, intensive care patients after surgery. DESIGN: Prospective, randomized, double blind, placebo-controlled, phase II clinical trial. SETTING: General surgical and cardiac surgical intensive care units. PATIENTS: Thirty patients scheduled for major surgery requiring mechanical ventilation for a minimum of 6 hrs were included in the study. INTERVENTIONS: Patients were assigned randomly to receive either dexmedetomidine (loading infusion, 6.0 microg x kg(-1) x hr(-1) for 10 mins; maintenance infusion, 0.1-0.7 microg x kg(-1) x hr(-1)) or placebo after intensive care unit admission. MEASUREMENTS AND MAIN RESULTS: Sedation was guided by using the electroencephalographic parameter bispectral index, a new noninvasive method to estimate the level of sedation. We aimed at maintaining bispectral index ranges between 60 and 70 during mechanical ventilation before starting weaning, 65 and 95 during weaning, and 85 to 95 postextubation. Additional sedative and analgesic medication was given (propofol and morphine) as clinically indicated and within the previously mentioned bispectral index ranges. Patients receiving dexmedetomidine required significantly less propofol during mechanical ventilation (0.87 +/- 0.21 vs. 1.52 +/- 0.30 mg x kg(-1) x hr(-1); p <.01) and weaning (0.17 +/- 0.06 vs. 0.62 +/- 0.21 mg x kg(-1) x hr(-1); p <.001) to maintain the target bispectral index range. During study drug administration, morphine requirements for dexmedetomidine-treated patients were reduced by 58% (p =.05). Hemodynamic stability during weaning and after extubation was better maintained in patients receiving dexmedetomidine. CONCLUSIONS: Dexmedetomidine reduced propofol requirements and improved hemodynamic stability during bispectral index-guided intensive care unit sedation.     

Withdrawal from lorazepam in critically ill children

BACKGROUND: Sedatives are used in critically ill children to facilitate mechanical ventilation. Although tolerance and withdrawal are associated with use of sedatives, information about withdrawal from benzodiazepines in children is limited. OBJECTIVE: To document the occurrence of lorazepam withdrawal in critically ill children and identify predictors for the development of withdrawal. METHODS: This prospective, investigational, open-label study enrolled pediatric patients receiving a continuous infusion of lorazepam for at least 72 hours. The lorazepam dosage was tapered in a uniform fashion over 6 days by decreasing the total daily dose by 50% every other day on 3 occasions; it was then discontinued. The occurrence of withdrawal from lorazepam was determined by pediatric intensive care unit attending physicians based on clinical judgment. Patients were assessed for withdrawal twice daily beginning 48 hours after the initiation of the lorazepam taper. Assessments were continued for 72 hours after lorazepam discontinuation or until the patient experienced withdrawal, whichever came first. Patient demographic, sedative dosing, and lorazepam serum concentration data were collected to identify risk factors for withdrawal. RESULTS: Twenty-nine patients completed the study. They received lorazepam for a median duration of about 21 days, and withdrawal occurred in 7 patients. There were no significant differences in demographic variables, lorazepam dosage or other sedative therapy, or lorazepam serum concentrations between patients with withdrawal and those without withdrawal. No predictors of withdrawal were identified. CONCLUSIONS: Withdrawal occurred in 24% of critically ill children receiving long-term sedation from lorazepam. Risk factors for withdrawal are unknown.     

Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients

OBJECTIVE: To determine the pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. DESIGN: Prospective population pharmacokinetic study. SETTING: Pediatric intensive care unit. PATIENTS: Twenty-one pediatric intensive care patients aged between 2 days and 17 yrs. INTERVENTIONS: The pharmacokinetics of midazolam and metabolites were determined during and after a continuous infusion of midazolam (0.05-0.4 mg/kg/hr) for 3.8 hrs to 25 days administered for conscious sedation. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken at different times during and after midazolam infusion for determination of midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations via high-performance liquid chromatography-ultraviolet detection. A population analysis was conducted via a two-compartment pharmacokinetic model by the NPEM program. The final population model was used to generate individual Bayesian posterior pharmacokinetic parameter estimates. Total body clearance, apparent volume distribution in terminal phase, and plasma elimination half-life were (mean +/- sd, n = 18): 5.0 +/- 3.9 mL/kg/min, 1.7 +/- 1.1 L/kg, and 5.5 +/- 3.5 hrs, respectively. The mean 1-OH-midazolam/midazolam ratio and (1-OH-midazolam + 1-OH-midazolam-glucuronide)/midazolam ratio were 0.14 +/- 0.21 and 1.4 +/- 1.1, respectively. Data from three patients with renal failure, hepatic failure, and concomitant erythromycin-fentanyl therapy were excluded from the final pharmacokinetic analysis. CONCLUSIONS: We describe population and individual midazolam pharmacokinetic parameter estimates in pediatric intensive care patients by using a population modeling approach. Lower midazolam elimination was observed in comparison to other studies in pediatric intensive care patients, probably as a result of differences in study design and patient differences such as age and disease state. Covariates such as renal failure, hepatic failure, and concomitant administration of CYP3A inhibitors are important predictors of altered midazolam and metabolite pharmacokinetics in pediatric intensive care patients. The derived population model can be useful for future dose optimization and Bayesian individualization.     

Pharmacoeconomic assessment of propofol 2% used for prolonged sedation

OBJECTIVE: To demonstrate that the use of propofol 2% is comparable to propofol 1% in effectiveness and in the wake-up time used for prolonged sedation. DESIGN: Open-label, case cohort study with a cohort of historical controls, phase IV clinical trial. SETTING: Medical and surgical intensive care unit (ICU) in a community hospital. PATIENTS: Fifty-one consecutive patients (medical, surgical, and trauma) admitted to our ICU requiring mechanical ventilation for >24 hrs. METHODS: All patients received propofol 2% (1-6 mg.kg-1.hr-1, starting with the lowest dose) and morphine chloride (0.5 mg.kg-1.24 hrs-1). A 4-5 level of sedation (Ramsay scale) was recommended. When weaning was indicated clinically, sedation and analgesia were interrupted abruptly, mechanical ventilation was discontinued, and the patient was connected to a T-bridge. OUTCOME MEASUREMENTS: Inability to attain the desired level of sedation with the highest dose rate of proposal, and hypertriglyceridemia >500 mg/dL, were considered therapeutic failure. The time between discontinuation of mechanical ventilation and extubation was measured. Those variables, as well as different items related to ICU cost, were compared between the study group and two historical groups sedated with propofol 1% and midazolam. RESULTS: The duration of sedation was 122.4 +/- 89.2 (sd) hrs for the propofol 2% group. The frequency of hypertriglyceridemia was 3.9% and 20.4% for the propofol 2% and the propofol 1% groups, respectively (p =.016). Therapeutic failure rates were 19.6% and 33.4% for the propofol 2% and propofol 1% groups, respectively (p =.127). The lower frequency of hypertriglyceridemia was associated with a higher number of patients reaching weaning. Weaning time was similar in the two propofol groups, 32.3 hrs ($1,744) for the propofol 2% group vs. 97.9 hrs ($5,287) for the midazolam group. Cost of sedation was $2.68 per hour for the midazolam group and $7.69 per hour for the propofol group. There was a favorable cost-benefit ratio for the propofol group, attributable to the shorter weaning time, although benefit was less than expected because higher doses of propofol 2% than propofol 1% were required during the first 48 hrs (p <.05). CONCLUSIONS: The new propofol 2% preparation is an effective sedative agent and is safe because of the low frequency of associated hypertriglyceridemia. The shorter weaning time associated with the use of propofol 2% as compared with midazolam compensates for its elevated cost. The economic benefit of propofol 2% is less than expected because higher doses of propofol 2% than propofol 1% are required over the first 48 hrs.     

Kinetics and dynamics of lorazepam during and after continuous intravenous infusion

OBJECTIVE: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. METHODS: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. RESULTS: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. CONCLUSION: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.     

Sedation in the critically ill ventilated patient: possible role of enteral drugs

Objective Sedation by the enteral route is unusual in intensive medicine. We analysed the feasibility/efficacy of long-term enteral sedation in ventilated critically ill patients.Design Prospective interventional cohort study.Setting General ICU.Patients and participants Forty-two patients needing ventilation and sedation for at least 4 days.Interventions At admission, sedation was induced with propofol or midazolam. Enteral hydroxyzine (± enteral lorazepam) was added in all patients within the second day. Intravenous drugs were gradually withdrawn, trying to maintain only enteral sedation after the initial 48 h. Analgesia was provided with continuous IV fentanyl.Measurements and results Sedation level was assessed evaluating, on a daily basis, patients compliance to the invasive care and comparing observed vs planned Ramsay scores three times a day. Excluding the first 2 days of patient-stabilisation and fast titration of sedation level, 577 days with ventilatory support were analysed. In 460 days (79.7%) total enteral sedation was given. This percentage rose to 94.2% when the requested Ramsay was 2 (347 days). Daily sedation was judged as adequate in 82.8% of days of total enteral sedation. Thirty-one patients had total enteral as the exclusive route of sedation.Conclusions After 24–48 h, enteral sedation may replace, totally/in part, IV sedation in ventilated patients. Total enteral sedation easily fits the target when a Ramsay score 2 is planned. When a deeper sedation is needed, a mixed regimen is effective and lowers IV drug dosages. No side effects were reported.     

Midazolam and 2% propofol in long-term sedation of traumatized critically ill patients: efficacy and safety comparison

OBJECTIVE: We proposed to compare the efficacy and safety of midazolam and propofol in its new preparation (2% propofol) when used for prolonged, deep sedation in traumatized, critically ill patients. We also retrospectively compared 2% propofol with its original preparation, 1% propofol, used in a previous study in a similar and contemporary set of patients. DESIGN: A prospective, randomized, unblinded trial (midazolam and 2% propofol) and a retrospective, contemporary trial (2% propofol and 1% propofol). SETTINGS: A trauma intensive care unit in a tertiary university hospital. PATIENTS: A total of 63 consecutive trauma patients, admitted within a period of 5 months and requiring mechanical ventilatory support for >48 hrs, 43 of whom (73%) suffered severe head trauma. We also retrospectively compared the 2% propofol group with a series of patients in whom 1% propofol was used. INTERVENTIONS: For the prospective trial, we randomized two groups--a midazolam group with continuous administration of midazolam at dosages 0.1-0.35 mg/kg/hr, and a 2% propofol group with continuous infusion at dosages 1.5-6 mg/kg/hr. Equal dosages of analgesics were administered. Similar management protocols were applied in the 1% propofol group, used in the retrospective analysis with 2% propofol. MEASUREMENTS AND MAIN RESULTS: Epidemiologic and efficacy variables were recorded. Hemodynamic and biochemical variables were also monitored on a regular basis. Neuromonitoring was also performed on those patients with head trauma. Sedation adequacy was similar and patient behavior after drug discontinuation was not different in either prospective group (midazolam and 2% propofol). Hemodynamic or neuromonitoring variables were also similar for both groups. Triglyceride levels were significantly higher in the 2% propofol group compared with the midazolam group. A higher number of therapeutic failures because of sedative inefficacy was seen in the 2% propofol group compared with the midazolam group, especially during the first sedation days. When comparing 2% propofol and 1% propofol, a significantly higher number of therapeutic failures because of hypertriglyceridemia were found in the 1% propofol group, as opposed to a major number of therapeutic failures because of inefficacy, found in the 2% propofol group. CONCLUSIONS: Propofol's new preparation is safe when used in severely traumatized patients. Its more concentrated formula improves the lipid overload problem seen with the prolonged use of the previous preparation. Nevertheless, a major number of therapeutic failures were detected with 2% propofol because of the need for dosage increase. This fact could be caused by a different disposition and tissue distribution pattern of both propofol preparations. New studies will be needed to confirm these results.