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CRITICAL CARE PHARMACOLOGY LITERATURE UPDATE 
This monthly review of select articles has been compiled and prepared as a service to the members of the Clinical Pharmacy and Pharmacology (CPP) Section of the Society of Critical Care Medicine (SCCM). The content below is for information purposes only, and is intended to highlight recent articles that may be of interest to the CPP membership. Though some core content from the publications is presented, the reader is encouraged to review the selected articles in full for additional detail in order to fully interpret the study Contents 

Predictors of Initial Nontherapeutic Anticoagulation with 
Unfractionated Heparin in ST­Segment Elevation 
Myocardial Infarction. 
Cheng S, Morrow DA, Sloan S et al. Circulation 2009; 119: 1195-1202.

Unfractionated heparin (UFH) is the anticoagulant of choice in the treatment of ST
segment elevated myocardial infarction (STEMI). Weight based dosing nomograms have
improved the safety and efficacy, but there still exists a wide degree of variation in
attaining therapeutic goals. Data from The Enoxaparin and Thrombolysis Reperfusion
for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction
(ExTRACT-TIMI) 25 trial evaluated which patient characteristics influence the
achievement of a therapeutic aPTT as well as the associated risk of bleeding with a
markedly high aPTT (aPTT > 2.75 times control) or a recurrent thrombotic event with a
markedly low aPTT (aPTT < 1.25 times control). UFH was dosed according to the
American College of Cardiology/American Heart Association (ACC/AHA) weight based
algorithm and was administered for a least 48 hours. Significant variation in aPTT values
were seen and were more likely to be elevated in lower weight elderly female patients
with elevated creatinine. The increased risk of markedly high anticoagulation was 14%
for each decade increase in age (p=0.001), 46% if the patient were female (p<0.001),
19% for each 10kg decrease in weight (p<0.001) and 8% for an increase of serum
creatinine by 0.2mg/dl (p=0.006). Additionally, markedly low anticoagulation was
independently associated with decreasing age and increasing weight. When high or low
aPTT occurred there was a 2-fold increased risk of TIMI major or minor bleeding or
fatal/nonfatal recurrent MI by 48 hours, respectively. These data suggest that additional
factors in addition to weight should be considered when dosing UFH in STEMI patients.
The incidence and nature of adverse events during 
pediatric sedation/anesthesia with propofol for 
procedures outside the operating room: a report from the 
Pediatric Sedation Research Consortium 
Cravero JP, Beach ML, Blike GT, et al. Anesth Analg 2009; 108(3): 795-804

The use of propofol for pediatric sedation outside of the operating room (OR), although
controversial, has been embraced by emergency medicine specialists and pediatric
intensivists due to its rapid onset, effectiveness, and short duration. To date, studies
assessing use in the pediatric population have been underpowered to evaluate safety. To
better study sedation in pediatric patients, the multicenter Pediatric Sedation Research
Consortium, a prospective registry of pediatric sedation/anesthesia, was developed. The
primary objective of the study was to evaluate registry data to determine the rate of
adverse events and unplanned airway interventions with propofol use outside of the OR.
88,227 cases were eligible for evaluation, and of these 49,836 (56%) utilized propofol as
the primary sedative. A majority of cases were supervised by a pediatric intensivist
(48.8%) or an emergency medicine physician (36%) and the primary procedures
identified were radiology (60%), hematology/oncology (14%), and gastrointestinal (11%). The most frequently reported co-administered medications included opioids (10.2%) and midazolam (7.6%). There were 2,950 total complications reported (1,170 pulmonary complications). Desaturation (154.5/10,000 cases) was the most frequent complication, followed by airway obstruction (93.2/10,000 cases) and inadequate anesthesia (85/10,000 cases). There were no deaths and 2 cardiac arrest cases which responded quickly to treatment. Authors conclude the incidence of serious adverse events was low, but there is a significant risk of events with the potential of causing harm if timely intervention is not anticipated and available. Interaction of vasopressin infusion, corticosteroid 
treatment, and mortality of septic shock 
Russell JA, Walley KR, Gordon AC, et al. Crit Care Med 2009;37:811-818.

The answer to whether there is an interaction between corticosteroids and vasopressin is
unclear, and the investigators of this trial set out to address this controversial subject.
This is a post hoc analysis of patients enrolled in the Vasopressin in Septic Shock Trial
(VASST, NEJM 2008; 358:877-87), comparing treatment with vasopressin (AVP) to
norepinephrine (NE) in septic shock. Russell et al further classified patients into
subgroups of corticosteroid treatment (defined as corticosteroid administration for a
minimum of 1 day out of the 28-day study period) or no corticosteroid treatment. A
significant reduction in 28-day mortality, the primary outcome, was found in the steroid
plus AVP group (n = 295, 35.4%) when compared to the steroids plus NE group (n =
293, 44.7%, p = 0.03). Similarly, a trend to more days free of organ dysfunction was
noted in the steroids plus AVP group. An opposing pattern of outcomes was seen in non-
steroid treated patients, in which AVP-treated patients exhibited a trend toward increased
mortality and more organ failures versus NE patients. As hypothesized, the response to
AVP based on corticosteroid use (logistic regression interaction statistic) was statistically
significant (p = 0.008). Although the exact mechanism of interaction is unclear, previous
studies have suggested steroids may increase AVP mRNA, improve hemodynamic
responsiveness, have no effect, or even decrease AVP gene expression. In the current
study, AVP levels were nearly doubled in patients receiving steroids. In summary,
because this is a post hoc substudy and steroid use was not controlled nor defined a
priori, these results suggesting improved outcomes with corticosteroid administration
with AVP are simply hypothesis-generating. Additional studies to delineate a potential
cause/effect relationship and mechanism of interaction are warranted before applying the
findings clinical practice.
Feasibility of implementing a reduced fasting protocol for 
critically ill trauma patients undergoing operative and 
nonoperative procedures 
Pousman RM et al. J Parenter Enteral Nutr. 2009; 33:176-80.

In the ongoing effort to reduce time to target attainment of post-procedure nutrition goals,
an observational study conducted at Vanderbilt University has demonstrated that
reducing fasting times prior to selected procedures in trauma patients is associated with a
trend toward faster achievement of nutrition goals. Researchers compared a group of 41
mechanically ventilated trauma patients prior to the implementation of a reduced fasting
protocol (control) to 34 patients post-implementation (intervention). Control patients
went through fasting periods of at least eight hours pre-procedure; the protocol called for
small bowel feeds up until the procedure or gastric feeds halted 45 minutes prior.
Patients were eligible for participation if they were undergoing: orthopedic surgery of an
extremity that did not require prone positioning; tracheostomy; percutaneous feeding tube
placement; otolaryngeal or ophthalmologic surgery; or invasive, non-operative
procedures like bronchoscopies and inferior venacaval filter placement. Intervention
patients went a median of 29.5 hours without nutrition as compared to 38 hours in the
control group (p = 0.07). Protocol patients reached nutrition goals in a median of 4.5
days versus 7 days in the control group (p = 0.20). While they had not conducted a
formal power analysis prior to the study, the study’s authors determined that they would
have needed a total sample of 700 patients to detect the difference they observed in the
study’s primary outcome, total volume of enteral nutrition post-procedure, with 80%
power. There were two episodes of hypoglycemia (blood glucose < 70 mg/dL) in the
intervention group and none in the control group (p = 0.03); otherwise, there were no
differences between groups in complication rates. The study’s place in the literature is
one of hypothesis generation, and the authors caution against applying their findings in
the absence of controlled clinical trials.
Abbreviated Infusion of Eptifibatide after Successful 
Coronary Intervention: The BRIEF­PCI (Brief Infusion of 
Eptifibatide Following Percutaneous Coronary 
Intervention) Randomized Trial 
Fung AY, Saw J, Starovoytov A, et al. JACC 2009; 53(10): 837-848

Eptifibatide given as a bolus dose followed by an 18 hour infusion was shown in the
ESPRIT trial to decrease the composite endpoint of death, myocardial infarction (MI) and
target vessel revascularization at 6 months. The BRIEF-PCI study was designed to
compare the usual extended infusion with an abbreviated two hour infusion. Both groups
received the standard bolus dose. After randomizing 624 patients with acute coronary
syndromes who were undergoing non-emergent PCI, the two hour infusion was found to
be non-inferior in terms of the incidence periprocedural ischemic myonecrosis and a 30
day composite outcome of MI, death, and target vessel revascularization. In addition, the
18 hour infusion was found to be associated with a higher risk of major bleeding (1% vs
4.2%). The investigators concluded that patients who undergo non-emergent successful
PCI, and who do not have certain risk factors (recent STEMI, visible thrombus,
unprotected left main intervention, or unsuccessful PCI), do not benefit from an
eptifibatide infusion beyond 2 hours after PCI. In addition, the use of the shorter infusion
minimizes risk of bleeding and reduces costs associated with eptifibatide treatment. The
authors comment that the abbreviated infusion may allow for shorter hospital stay as
well. Because this abbreviated infusion is limited to non-emergent PCI, it is unlikely to
have a large impact in the critical care environment.
Methemoglobinemia related to local anesthetics:  A 
summary of 242 episodes  
Guay J. Anesth Analg. 2009; 108:837-45.
 
Methemoglobin is produced when the iron bound to hemoglobin is oxidized, converting
it from its ferrous (Fe2+) to ferric form (Fe3+), making it incapable of oxygen transport.
Typically, methemoglobin levels are maintained around 1 to 2% by reduction to
hemoglobin with cytochrome b5 methemoglobin reductase and its cofactor, NADH. In
the presence of direct or indirect oxidizers, such as local anesthetics, production of
methemoglobin overwhelms the cytochrome reductase enzymatic system, leading to
accumulation and associated toxicities of methemoglobinemia, such as cyanosis, altered
mental status, respiratory distress, coma, and even death. This article reviewed 242
individual cases of local anesthetic-induced methemoglobinemia found in Pub Med from
1949 through 2007. Patient cases were included if the total dose of local anesthetic
utilized was 10 mg/kg of lidocaine using the following conversion factors: lidocaine = 1,
bupivacaine = 4, cocaine = 4, mepivacaine = 0.8, prilocaine =0.9, tetracaine = 4. The
main local anesthetics implicated in reported cases were benzocaine (66%), prilocaine
(28%), and lidocaine (5%). The wide inter-patient variability of response to the local
anesthetics makes cases of methemoglobin difficult to predict. The author recommends
avoiding benzocaine use in all patients due to the risk of methemoglobinemia induction
with as little as one spray. Avoidance of prilocaine may be necessary in infants less than
6 months-old, pregnant women, those with glucose-6-phosphate dehydrogenase (G6PD)
deficiency and patients receiving oxidizing drugs to reduce the incidence of
methemoglobinemia. Finally, lidocaine should be restricted to patients who are not
concomitantly receiving other oxidizing agents.
Continuous Infusion of Pantoprazole with Octreotide Does 
Not Improve Management of Variceal Hemorrhage 
Alaniz C, Mohammad RA, Welage LS. Pharmacotherapy 2009; 29(3):248-254

Hemorrhage is a major, life-threatening complication of gastroesophageal varices. As
such, this study proposed to assess the effectiveness of continuous infusion pantoprazole
on patient outcomes with the recommended therapy for control of active variceal
bleeding, octreotide. This was a retrospective cohort study which included 130 patients
with documented variceal hemorrhage, determined by EGD, between January 2002 and
June 2005. Patients were assigned to 1 of 2 groups; a continuous infusion (pantoprazole n=53) > 24 hours or a control group (octreotide alone n=3, octreotide with <24 hours pantoprazole n=24, or octreotide with intermittent acid suppression n=50). The primary outcome was the number of packed RBC’s transfused during hospitalization. Other outcomes included number of FFP, platelets, and cryoprecipitate transfused, endoscopic interventions, frequency of rebleeding, length of ICU stay, length of hospitalization and mortality rate. Authors found no significant difference in any outcome measures with the exception of FFP transfusion which was higher in the continuous infusion group (p=0.05). Patients most likely to benefit from pantoprazole infusion include those with bleeding from gastric varices, whereas most bleeding episodes in study patients were due to esophageal varices. Although no benefit was observed with continuous infusion of pantoprazole with octreotide in the treatment of varices, prospective studies are needed to better evaluate their role in this setting. A  clinical  evaluation  committee  assessment  of 
recombinant  human  tissue  factor  pathway  inhibitor 
(Tifacogin)  in  patients with  severe  community­acquired 
pneumonia 
Laterre P-F, Opal SM, Abraham E, et al. Critical Care 2009, 13:R36.

The coagulation-inflammation pathway continues to be a research target. The Phase III
OPTIMIST Trial determined that the inhibition of tissue factor pathway with tifacogin
resulted in no difference in 28 day all-cause mortality. Treatment benefit was found,
however, in a subset of patients with pneumonia and who did not receive heparin. The
purpose of the present study was to retrospectively determine the validity and
categorization (HAP or CAP) of the subgroup pneumonia cases from the OPTIMIST
Trial. Patients with CAP treated with tifacogin had lower 28-day all-cause mortality
compared to placebo (27.9% versus 32.7%, p=0.25). In a subset of patients with
microbiologic evidence of infection and no heparin administration, the difference
widened (29.3% versus 51.9%, p=0.02). Tifacogin treated patients had more bleeding
events, especially those on heparin. Results of this study reflect the high mortality
associated with severe CAP and the potential importance of the coagulation-inflammation
pathway, much like that seen in the PROWESS trial. This subgroup analysis is limited by
its retrospective nature, and that diagnosis of pneumonia could be made with subjective
evidence. This study is promising in that it specifies a subpopulation of sepsis, details that
the current drotrecogin alfa data lack. Until followup studies are performed, FDA
approval of tifacogin is unlikely based on the available data.
Recent Guidelines and Reviews of Interest 
American Society for Parenteral and Enteral Nutrition. Enteral Nutrition Practice
Recommendations.
J Parent Enteral Nutr 2009; 33(2):122-167
2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management
of Heart Failure in Adults. A Report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines.
Circulation 2009; 119: DOI 10.1161/CIRCULATIONAHA.109.192064
Antimicrobial Stewardship in the Intensive Care Unit.
Lawrence KL, Kollef MH. Am J Resp Crit Care Med 2009; 179:434-438

Contributors 
Emily Anderson, Pharm.D., BCPS (Wishard Memorial Hospital), Haley Goodwin, Pharm.D. (Medical University of South Carolina), Erin Koopman, Pharm.D., BCNSP (Mayo Clinic), Shawn Kram, Pharm.D., BCPS (Mayo Clinic), Deanna McMahon, Pharm.D., BCPS (University of Kentucky), Angela Plewa, Pharm.D., BCPS (John H. Stroger, Jr. Hospital of Cook County), Allison Schriever, Pharm.D. (Loyola University Medical Center), Charles Turck, Pharm.D., BCPS (University of Massachusetts), Peter Herout, Pharm.D. (EPI-Q, Inc.)

Source: http://scientiacme.org/pdfs/SCCM%20CPP%202010-03.pdf