Perner A et al. Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis N Engl J Med 2012; 367:124-134. This multicenter, double-blind, randomized trial compared the use of Hydroxyethyl Starch (a low molecular weight, low hydroxyethyl-to-glucose ratio product “Tetraspan”) and Ringer’s Acetate (similar to Lactated Ringer’s) for fluid resuscitation in adults admitted to the ICU with severe sepsis. Lower molecular weight compounds with a lower “substitution ratio” (hydroxyethel groups to glucose ratio) in these solutions have not been studied significantly in the setting of sepsis.

The primary outcome was death or renal replacement therapy at 90 days. Of 1211 eligible patients 804 were randomized and 798 were ultimately followed in the outcomes analysis. The two groups were well matched in characteristics. The Starch group was more likely to have met the primary outcome of death or renal replacement therapy at 90 days (51% mortality for the Starch group vs 43% for the Ringer’s group, (95% CI 1.01-1.36 with p = 0.03)). Only 1 person from each group was on renal replacement therapy (“RRT”, in this case dialysis) at day 90 (i.e., the difference in the primary outcome between the two groups was from death).

Pertinent secondary outcomes include no statistically significant difference in death at Day 28 and a significant increase in the need for RRT in the Starch group (22% vs 16% (CI 1.01-1.80, p = 0.04).

I thought it was an interesting article because this is a debate that seems to have somewhat passed and then become revisited as our ability to synthesize or modify starches and proteins has improved. No doubt the military in particular will continue to investigate this topic in pursuit of a fluid that can provide volume expansion more efficiently than isotonic fluid administration (which would affect us managing prehospital patients who may have been resuscitated with a starch or colloid compound). At this time this article will not change my clinical practice.

- Cotton 

Andolfatto G, Abu-Laban RB, Zed PJ, et al. Ketamine-Propofol Combination (Ketofol) Versus Propofol Alone for Emergency Department Procedural Sedation and Analgesia: A Randomized Double-Blind Trial.  Ann Emerg Med. 2012;59:504-512. This study is a randomized, double-blind trial with a primary objective of determining whether a 1:1 mixture of ketamine and propofol (ketofol) for ED procedural sedation in patients aged 14 years or older results in a reduction of adverse respiratory events as compared to propofol alone for procedural sedation.  This single-center study was based in the emergency department in one community teaching hospital in Vancouver, British Columbia.  Patient inclusion criteria included requirement for procedural sedation as defined by the treating emergency physician, aged 14 years or older, and American Society of Anesthesiology class 1 to 3 status.  Patients were excluded if they were unable to give informed consent, were pregnant, or had a known allergy to either study medication.  Fifty percent of the ED nurses were trained in the preparation of the study medications, and drew up study medications in identical 20-ml syringes.  The propofol-only syringes contained 20 ml of propofol at 10 mg/ml and the ketofol syringes contained 10 ml of propofol 10 mg/ml and ketamine 10 mg/ml.  Administration of medications was based on a predefined weight-based protocol.  Subjects received an initial dose of 0.075 ml/kg of study medication (either 0.75 mg/kg propofol or 0.375 mg/kg each of ketamine and propofol).  At every one-minute interval after the initial dose was given, the treating physician reassessed the patient’s level of sedation with the Ramsay Sedation Scale, and administered another 0.0375 ml/kg of the study medication if the sedation score was less than five. 

There were 284 patients randomized, with 142 patients in each group.  The primary outcome was the number and proportion of patients experiencing a respiratory adverse event as defined by the Quebec Criteria.  Secondary outcomes included sedation consistency, total medication dosage, sedation efficacy, induction time, procedure time, sedation time, recovery time, and the incidence of adverse events.  The two groups were similar in demographic characteristics and procedures performed.  With regards to the primary outcome, there were no differences in adverse respiratory events, with 43 (30%) patients receiving ketofol and 46 (32%) of the patients receiving propofol (p=.80) having an adverse event including oxygen desaturation, central apnea, partial or complete upper airway obstruction or pulmonary aspiration.  Three ketofol patients and one propofol patient received bag-valve mask, but no patient in either group required oral airway placement or endotracheal intubation.  Sedation consistency was better in the ketofol group with 65% having a RSS <5 during procedure or requiring repeated dosing during procedure, versus 93% of the propofol group (p=.001).  Sedation efficacy was similar in the two groups, defined as no patient recollection of the procedure and no adverse event resulting in abandonment of procedure or prolonged ED observation.  Physician, nurse and patient satisfaction scores were similar for propofol and ketofol.  Other secondary outcomes were similar between the two groups.  Limitations of the study include variability in treating physicians’ threshold for intervention in airway events.  Also, the variety of procedures had differing requirements for analgesia, with no protocol for varying the weight-based dosing schedule.  In conclusion, the use of ketofol has been touted recently as a superior procedural sedation agent due to its purported decreased risk of respiratory adverse events.  However, this study, which is the largest RCT to date does not demonstrate a significant improvement in the rate of adverse respiratory events in patients receiving ketofol versus propofol for procedural sedation.

- Stephani 

Nishijima et al. Utility of platelet transfusion in adult patients with traumatic intracranial hemorrhage and preinjury antiplatelet use: A systematic review.  J Trauma, 2012;72(6):1658-1663. Studies have shown that patients with preinjury antiplatelet use are at increased risk of mortality after blunt head trauma and traumatic ICH (tICH).  This review sought to address the question of whether adults with preinjury oral antiplatelet use and tICH, does urgent transfusion of platelets within 24 hours of injury improve patient-oriented outcomes such as mortality or neurologic outcomes, compared with no platelet transfusion? 

Study investigators targeted peer-reviewed RCTs or observational studies that compared platelet vs no platelet transfusion, though only 5 retrospective studies were found to meet inclusion criteria and meta-analysis was not done secondary to study heterogeneity.  Anti-platelet agents under consideration were aspirin, clopidogrel, ticlodipine, prasugrel and ticagrelor due to their oral, long-acting nature.  Inclusion criteria included adults 18 years and older with tICH diagnosed by CT or MRI.  Primary outcomes were all cause mortality and neurologic outcome.  Secondary outcomes were transfusion related morbidities. 

Of the 5 studies felt to meet inclusion criteria, 2 directly addressed the primary question.  The largest study by Downey et al, which was the only one to report dosing information (6 U concentrated platelets), 29/166 patients receiving platelet transfusion and 27/162 patients not receiving platelets died in hospital for a relative risk of 1.04.  Patients on warfarin in this study were not excluded though controlling for this did not change outcomes.  Of the other studies, Washington et al looked at platelet transfusion (unknown dose and timing) in patients with minor (GCS > 13) TBI.  Patients requiring surgical intervention and with coagulopathy were excluded, though no mortality benefit was seen with platelet transfusion.  Two other studies by Ivascu et al and Ohm et all showed trends toward increased mortality (RR 2.12 and 2.42 respectively) in platelet transfusion groups though neither study reported warfarin use.  The Ohm study has the advantage of being the only study of these 5 to report timing of dose within the first 24 hrs of tICH.  Only one study reviewed by Wong et al. showed improved morality for patients receiving platelet transfusion (RR 0.21), with a very large number of patients having received transfusion relative to the no transfusion cohort.  Unfortunately, there was not enough data presented to address the investigators other primary outcome of neurologic outcome or secondary outcomes of transfusion related morbidities. 

Major problems with the included studies in terms of addressing the paper’s major research questions include lack of studies relevant to the research question, confounding variables such as other anti-coagulants such as warfarin, lack of data on timing and volume of platelet transfusions, or adequate documentation of neurologic outcome.   This article is strong evidence that there is no EBM to support the practice of platelet transfusion in patients with tICH.  However, it must be noted that the preponderance of evidence does not weigh heavily on the side that it may be harmful, so it is likely to remain a practice largely at the discretion of the provider.  Unfortunately, studies meeting inclusion criteria were not prevalent or uniform enough to enable a meta-analysis of the data, which would provide a stronger basis for clinical decision making.  Clearly, this is a topic that would benefit greatly from a RCT. 

- Clingan