Monday, August 4, 2008

July Journal Club

Wow. July already. The new Interns have jumped in full speed, and the 2's and 3's are making smooth transitions to their new roles.

Since I hosted this month, I make no comments on the quality of the food, though it seemed to disappear fairly quickly, so I assume it was palatable.

Two interesting, and controversial, topics this time around.

1) "Safety and Clinical Effectiveness of Midazolam versus Propofol for Procedural Sedation in the Emergency Department: A systematic Review," Hohl, CM, et. al. Academic Emergency Medicine 15(1) January 2008

A meta-analysis comparing the safety and efficacy of two commonly used medications for emergency department procedural sedation.

Design:
A systematic review of randomized controlled trials (RCTs) as well as observational studies that either directly compared or used either propofol or midazolam for emergency department procedural sedation. Articles were found by searching multiple medical databases as well as the indices of three major emergency medicine journals. All abstracts were manually reviewed by one of the investigators, and the following were excluded: commentaries, reviews, surveys, editorials, case reports, letters, and pediatric studies. The investigators identified 4 head-to-head RCTs, 9 RCTs using either agent, and 15 observational studies which were analyzed. The primary outcome was defined as the proportion of major adverse events (death, disability, hospital admission, prolonged ED stay, intubation, and vomiting with aspiration pneumonitis) and the secondary outcome was the mean difference in the proportion of patients successfully sedated so the procedure could be completed. The studies were evaluated for quality and heterogeneity by the investigators.

Results:
Overall, the quality of the included studies was not great. There was poor reporting of methods, and no consistent dose of the study drugs. Minor adverse events were not constantly reported by the studies, and could not be easily analyzed. Overall estimates of major adverse events were as follows:
Midazolam: 0/847 patient exposures (CI 0% - 0.45%)
Propofol: 1/2,453 patient exposures (CI 0.01% - 0.23%)
Regarding the secondary outcome of procedural sedation success, combined data indicated a non-significant trend towards greater success with propofol. The authors conclude that based on the limited available published data, both agents appear safe and effective for procedural sedation, but there is definitely room for a large, well designed randomized controlled trial.

Discussion points:
Overall, the group agreed that multiple agents are reasonable choices for emergency department procedural sedation. We discussed the two different types of sedation: moderate (where airway reflexes are preserved) and deep (where airway reflexes are lost) and how different situations may cause for different levels of sedation. We discussed both the advantages and disadvantages of the commonly used versed/fentanyl regimen, including the need for escalating doses and the easy availability of reversal agents. We also discussed some of the benefits and pitfalls of propofol, including its brief duration of action and its potential to cause hypotension. Finally, we discussed the use of etomidate (at half-dose for sedation) and ketamine for select populations. It is vitally important to know what is available in you clinical setting, and to be comfortable with any drug you want to use.

The upshot:
In the right hands, it is likely that many of the available procedural sedation agents are safe and effective. Knowledge and preparation are key, and practitioners must be familiar with the dose, time of onset, and duration of activity of any medications they are going to uses, as well as with the use of applicable reversal agents (thanks to Dr. Berger for this excellent point). In other words, know what you are going to use and how to use it before you push your meds!

Also, remember that the quality of studies which go into a meta-analysis determine the qulaity of the results that come out.


2) The CORTICUS study: "Hydrocortisone Therapy for Patients with Septic Shock," Sprung, CL, et. al. NEJM 358(2) January 10, 2008

A large, randomized study designed to identify the role of IV steroids in patients with septic shock. The issues raised by this study are EXTREMELY complex and controversial, and I will do my best to summarize them here.

Design:
Randomized, double-blind, placebo-controlled study at 52 participating ICUs comparing IV dexamethasone 50 mg every 6 hours for 5 days followed by a taper to placebo. Inclusion criteria "were clinical evidence of infection, evidence of a systemic response to infection, and the onset of shock within the previous 72 hours (as defined by a systolic blood pressure of <>a need for vasopressors for at least 1 hour) and hypoperfusion or organ dysfunction attributable to sepsis." Listed "exclusion criteria included underlying disease with a poor prognosis, a life expectancy of less than 24 hours, immunosuppression, and treatment with long-term corticosteroids within the past 6 months or short-term corticosteroids within the past 4 weeks." (Emphasis added by me - you'll see why later) The primary outcome measure was defined as death at 28 days in corticotropin non-responders. Secondary outcomes included "rates of death at 28 days in patients who had a response to corticotropin and in all patients, the rates of death in the ICU and in the hospital, the rates of death at 1 year after randomization, a reversal of organ system failure (including shock), and the duration of the stay in the ICU and the hospital."

Results:
499 patients were enrolled as compared to the estimated 800 needed to detect a statistically significant difference in the primary outcome. (Enrollment was topped early. Is this large enough?) There was no significant difference in the primary outcome of death at 28-days in corticotrpoin non-responders (39.2% with hydrocortisone, 36.1% in placebo). No significant difference was identified in mortality rate at any other measured time point in the study.

A number of interesting findings were identified in post-hoc analysis of the study data, some of which are listed below. Remember that post-hoc analyses are always somewhat suspect as these were NOT outcomes the study was designed to detect, but rather results derived by manipulating the patient groups and data variables:
1) Increased 28 day death rate for those given etomidate in both the steroid and placebo group.
2) Earlier reversal of shock in the hydrocortisone group
3) 11.2% reduction in mortality from steroids in patients with hypotension despite 24 hours of vasopressor therapy

Discussion points:
A number of potential problems were identified with this study, including substantial differences between the design and population of this and earlier steroid studies. First, the mortality rate and disease severity of the patients in CORTICUS was substantially lower than that in earlier studies which showed a significant mortality benefit. Second, in the present study, patients could receive steroids up to 72 hours after identification of septic shock, as opposed to 8 hours in the earlier study. Also, patients in the previous studies, patient needed to be in shock refractory to vasopressors to receive steroids, which was not a requirement in CORTICUS (and this sub-group had improved mortality in CORTICUS). Finally, patients who received steroids within the last 4-8 weeks were excluded in CORTICUS. One wonders whether this included patients who received them as a part of EGDT in the ER prior to admission.

The point about etomidate increasing mortality is something that has been discussed extensively in the literature recently. Please read the recent Clinical Controversies the July Annals of Emergency Medicine for two well presented perspectives. I think this question has yet to be answered.

The upshot:
The role of steroids in the treatment of septic shock remains as controversial as ever. There is likely a role for patients who remain hypotensive despite vasopressor therapy, but we have likely not yet identified the ideal target population. Keep your eyes peeled for upcoming studies re0evaluating the role of EGDT which may give us some better answers.

No comments: