Prevention of hypotension associated with the induction dose of propofol: A randomized controlled trial comparing equipotent doses of phenylephrine and ephedrine Farhan M, Hoda MQ, Ullah H – J Anaesthesiol Clin Pharmacol

Background and Aims: Propofol, the most commonly used intravenous (IV) anesthetic agent is associated with hypotension on induction of anesthesia. Different methods have been used to prevent hypotension but with variable results. The objective of this study was to evaluate efficacy of equipotent doses of phenylpehrine and ephedrine in preventing the hypotensive response to the induction dose of propofol.
Material and Methods: One hundred thirty five adult patients were randomised to one of the study groups: “propofol-saline (PS),” “propofol-phenylephrine (PP)” or “propofol-ephedrine (PE)” by adding study drugs to propofol. Anesthesia was induced with a mixture of propofol and the study drug. Patients were manually mask-ventilated for 5 min using 40% oxygen in nitrous oxide and isoflurane at 1%. A baseline mean arterial pressure (MAP) was recorded prior to induction of anesthesia. Systolic, diastolic and mean blood pressure and heart rate were recorded every minute for up to 5 min after induction. Hypotension was defined as a 20% decrease from the baseline MAP.
Results: There were no significant demographic differences between the groups. Overall incidence of hypotension in this study was 38.5% (52/135). Rate of hypotension was significantly higher in group PS than group PP (60% vs. 24.4% P = 0.001) and group PE (60% vs. 31.1% P = 0.005). In contrast, a significant difference in rate of hypotension was not observed between groups PP and group PE.
Conclusion: In equipotent doses, phenylephrine is as good as ephedrine in preventing the hypotensive response to an induction dose of propofol.

Dexmedetomidine Use in the ICU Are We There Yet?


Background Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an alpha-2 agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.

MethodsObjective: The objective was to determine the efficacy of dexmedetomidine versus midazolam or propofol (preferred usual care) in maintaining sedation, reducing duration of mechanical ventilation, and improving patients’ interaction with nursing care.

Design: Two phase 3 multicenter, randomized, double-blind trials were conducted.

Setting: The MIDEX (Midazolam vs. Dexmedetomidine) trial compared midazolam with dexmedetomidine in ICUs of 44 centers in nine European countries. The PRODEX (Propofol vs. Dexmedetomidine) trial compared propofol with dexmedetomidine in 31 centers in six European countries and two centers in Russia.

Subjects: The subjects were adult ICU patients who were receiving mechanical ventilation and who needed light to moderate sedation for more than 24 hours.

Intervention: After enrollment, 251 and 249 subjects were randomly assigned midazolam and dexmedetomidine, respectively, in the MIDEX trial, and 247 and 251 subjects were randomly assigned propofol and dexmedetomidine, respectively, in the PRODEX trial. Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials were employed.

Outcomes: For each trial, investigators tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were the ability of the patient to communicate pain (measured by using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol (midazolam, n = 233, versus dexmedetomidine, n = 227; propofol, n = 214, versus dexmedetomidine, n = 223) population.

Results Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% confidence interval (CI) 0.97 to 1.18), and dexmedetomidine/propofol ratio in time at target sedation was 1.00 (95% CI 0.92 to 1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours, interquartile range (IQR) 67 to 337) versus midazolam (164 hours, IQR 92 to 380;P = 0.03) but not with dexmedetomidine (97 hours, IQR 45 to 257) versus propofol (118 hours, IQR 48 to 327; P= 0.24). Patient interaction (measured by using VAS) was improved with dexmedetomidine (estimated score difference versus midazolam 19.7, 95% CI 15.2 to 24.2; P <0.001; and versus propofol 11.2, 95% CI 6.4 to 15.9; P <0.001). Lengths of ICU and hospital stays and mortality rates were similar. Dexmedetomidine versus midazolam patients had more hypotension (51/247 [20.6%] versus 29/250 [11.6%]; P = 0.007) and bradycardia (35/247 [14.2%] versus 13/250 [5.2%]; P <0.001).

Conclusions Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved the ability of patients to communicate pain compared with midazolam and propofol. Greater numbers of adverse effects were associated with dexmedetomidine.



Sedation is commonly used in the intensive care unit (ICU) to reduce patient discomfort, improve tolerance with mechanical ventilation, prevent accidental device removal, and reduce metabolic demands during respiratory and hemodynamic instability.[1,2]Continuous and deep sedation have been associated with increased risk of delirium, longer duration of mechanical ventilation, increased length of ICU and hospital stays, and long-term risk of neurocognitive impairment, post-traumatic stress disorder, and mortality.[3–7] Sedation interruption and protocolized sedation have been associated with decreased length of ICU stay and reduced duration of mechanical ventilation.[4,5] Whether combining sedation interruption and protocolized sedation improves outcome is controversial. Whereas some studies show a benefit,[6] others show no difference.[8]

Commonly used first-line sedative medications, including propofol and midazolam, and less commonly used medications, such as lorazepam, have many side effects. There exists wide intra- and inter-individual variability,[9] resulting in unpredictable drug accumulation with benzodiazepines.[10] Lorazepam is associated with propylene glycol-related acidosis and nephrotoxicity. Propofol causes hypertriglyceridemia, pancreatitis, and propofol-related infusion syndrome.[11,12] Dexmedetomidine is a potent alpha-2 adrenoceptor agonist with an affinity for the alpha-2 adrenoceptor that is eight times higher than that of clonidine.[13] Prior data suggest that dexmedetomidine reduced duration of mechanical ventilation and resulted in earlier extubation.[14,15] In critically ill patients, use of dexmedetomidine has been associated with lower risk of delirium and coma compared with propofol, lorazepam, and midzolam.[15,16] However, safety and efficacy of prolonged dexmedetomidine infusion in the ICU have not been evaluated.

The PRODEX (Propofol vs. Dexmedetomidine) and MIDEX (Midazolam vs. Dexmedetomidine) trials attempted to answer this question with higher doses of dexmedetomidine for longer duration when compared with propofol and midazolam in mechanically ventilated patients. Both studies provide important clinical evidence that dexmedetomidine is an effective sedative agent compared with propofol and midazolam. Use of dexmedetomidine is associated with easier communication with patients, better assessment of pain (from the perspective of the caregiver), reduced delirium, and decreased time to extubation as compared with propofol. However, this finding did not translate into reduction of length of ICU or hospital stay. Among the strengths of the study are that it was a well-conducted, large, multicenter, double-blind, randomized controlled study. The trial employed frequent sedation assessment, daily sedation stops, and a double-dummy design to reduce the risk of bias.

Several important limitations to the study deserve further consideration. The weaning from mechanical ventilation and criteria for extubation were not standardized. Spontaneous breathing trials were performed in only about half of the sedation stops, as compared with approximately 60% of those screened in the Awakening and Breathing Controlled trial.[6] Whereas the incidence of neurocognitive disorders, including delirium, anxiety, and agitation, was evaluated throughout the study, the long-term neurocognitive and functional outcomes with dexmedetomidine have not been examined. Sedation was assessed from the caregivers’ perspective only, and future studies should include the patients’ perspective of quality of sedation. Also, this study included only patients with light to moderate sedation; thus, these findings may not be applicable to patients requiring deep sedation. In the first 24 hours of the PRODEX trial, discontinuation of dexmedetomidine was more frequent because of a lack of efficacy. As acknowledged by the authors of the PRODEX and MIDEX trials, most clinicians and centers do not consider dexmedetomidine an equivalent alternative to propofol and midazolam for long-term sedation. These trials, nevertheless, reassure clinicians regarding the safety of dexmedetomidine in terms of higher doses over a long period of time.

Recent guidelines of the Society of Critical Care Medicine recommend using non-benzodiazepine agents, such as propofol or dexmedetomidine, over benzodiazepines as a first-line sedative agent, and dexmedetomidine in patients at risk for delirium that is not related to alcohol and benzodiazepine use.[11] The opioid-sparing[11] effect of dexmedetomidine may reduce opioid requirements in critically ill patients. The most common side effects of dexmedetomidine are hypotension and bradycardia, and this limits its use in patients who are dependent on their cardiac output, such as patients in the acute phase of shock.



In carefully selected critically ill patients receiving prolonged mechanical ventilation, dexmedetomidine is safe and may be preferred as an alternative non-benzodiazepine agent to maintain light to moderate sedation. However, long-term outcomes, including neurocognitive effects, and the safety of dexmedetomidine are unknown.


Propofol Procedural Sedation Is Safe.

No adverse outcomes occurred among 1000 adult propofol procedural sedation episodes.

To determine the safety of propofol for emergency department (ED) procedural sedation, researchers retrospectively applied a sedation adverse-event reporting tool to 1008 consecutive patients (age range, 15 to 97 years) who underwent procedural sedation at a single ED in the U.K. over a 5-year period. Sentinel events included oxygen saturation <75% for any length of time or <90% for more than 60 seconds, apnea lasting longer than 60 seconds, aspiration event, need for intubation, cardiovascular collapse, permanent neurologic disability, and death. Most patients were sedated for orthopedic procedures (77%) and cardioversion (9%). Monitoring included pulse oximetry, non-invasive blood pressure measurement, respiratory rate, and electrocardiography; nasal capnography was adopted near the end of the study period.

A total of 73 adverse events were reported: 11 sentinel, 34 moderate, 25 minor, and 3 minimal risk. Sentinel events included six episodes of prolonged hypotension (>60 seconds) requiring brief vasopressor support, and five episodes of hypoxia, all but one of which resolved with assisted ventilation. One patient with unstable ventricular tachycardia underwent cardioversion, vomited, and became hypoxic, necessitating intubation for airway protection and altered mentation. He was found to have a saddle pulmonary embolism and distal aortic thrombus; he survived to hospital discharge. No adverse outcomes related to procedural sedation were identified.

Comment: Several patients with sentinel adverse events had significant underlying medical comorbidities. Fortunately, no patients suffered any adverse outcomes related to the procedural sedation, but this study reminds us that proper monitoring, including capnography, and careful patient selection are crucial to ensure the safety of this procedure. Patients at high risk for adverse events, such as those with significant cardiopulmonary comorbidity, and those with difficult airways should be evaluated for possible sedation in the operating room.


Source: Journal Watch Emergency Medicine


Routine Propofol Sedation Increases Risk During Colonoscopy.

In a large database study, anesthesia assistance was associated with an elevated risk for perforation, splenic injury, or aspiration pneumonia.


The use of anesthesiologist-administered propofol sedation for colonoscopy is increasing in the U.S. (JW Gastroenterol April 13 2012 and JW Gastroenterol Feb 17 2012). Propofol use during colonoscopy is associated with shorter recovery time and higher patient satisfaction but also an estimated 20% increase in health care costs. Whereas most studies on the use of propofol sedation during colonoscopy have focused on its economic cost, researchers now explore another possible disadvantage — increased risk for complications.

Using a database of linked U.S. Medicare and cancer registry data, investigators identified patients without cancer who underwent diagnostic colonoscopy between 2000 and 2009, assessed whether they received anesthesiology services, and determined whether they were hospitalized during the 30 days following colonoscopy for perforation, splenic injury, or aspiration pneumonia. Data on the type of anesthetic agent used were unavailable, but investigators assumed that anesthesiologist-administered propofol was used most often.

Of 165,527 colonoscopy examinations in 100,359 patients, 35,128 procedures (21.2%) were performed with anesthesia assistance. Complications of aspiration, perforation, or splenic injury occurred more frequently in patients who received anesthesia assistance than in those who did not (0.22% vs. 0.16%, P<0.001; odds ratio, 1.46; 95% confidence interval, 1.09–1.94). This difference was mostly attributable to the difference in risk for aspiration (0.14% vs. 0.10%; P=0.02). The risks for perforation and splenic injury were similar between groups. Other independent risk factors for these complications were older age, male sex, increased comorbidity, and undergoing the procedure in a hospital.

Comment: Although the overall rate of complications was very low, the use of anesthesia services for diagnostic colonoscopy resulted in a higher risk for complications. These findings might result in part from confounding if patients who received anesthesia assistance were sicker or more prone to complications and were chosen to receive anesthesia for those reasons. Also, the data were from a period when propofol was sometimes administered by trained nurses rather than anesthesiologists, and the relative safety of this approach compared to anesthesia-administered services cannot be determined. Finally, these findings might be more pronounced in the types of patients included in this trial (65 years old), and whether the observed increased risk is present in younger or more healthy patients remains to be determined.

Source: Journal Watch Gastroenterology


Capnographic Monitoring Reduces the Incidence of Arterial Oxygen Desaturation and Hypoxemia During Propofol Sedation for Colonoscopy: A Randomized, Controlled Study (ColoCap Study).

The aim of this randomized study was to determine whether intervention based on additional capnographic monitoring reduces the incidence of arterial oxygen desaturation during propofol sedation for colonoscopy.


Patients (American Society of Anesthesiologists classification (ASA) 1–3) scheduled for colonoscopy under propofol sedation were randomly assigned to either a control arm with standard monitoring (standard arm) or an interventional arm in which additional capnographic monitoring (capnography arm) was available. In both study arms, detection of apnea or altered respiration induced withholding propofol administration, stimulation of the patient, chin lift maneuver, or further measures. The primary study end point was the incidence of arterial oxygen desaturation (defined as a fall in oxygen saturation (SaO2) of ≥5% or <90%); secondary end points included the occurrences of hypoxemia (SaO2 <90%), severe hypoxemia (SaO2 ≤85%), bradycardia, hypotension, and the quality of sedation (patient cooperation and patient satisfaction).



A total of 760 patients were enrolled at three German endoscopy centers. The intention-to-treat analysis revealed a significant reduction of the incidence of oxygen desaturation in the capnography arm in comparison with the standard arm (38.9% vs. 53.2%; P<0.001). The numbers of patients with a fall in SaO2 <90% and ≤85% were also significantly different (12.5% vs. 19.8%; P=0.008 and 3.7 vs. 7.8%; P=0.018). There were no differences regarding the rates of bradycardia and hypotension. Quality of sedation was similar in both groups. Results of statistical analyses were maintained for the per-protocol population.



Additional capnographic monitoring of ventilatory activity reduces the incidence of oxygen desaturation and hypoxemia during propofol sedation for colonoscopy.

Source: American Journal of Gastroenterology.