Recent Articles from the 2008 Critical Care Literature by otvrKE6

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									  Critical Care 2008
    Articles that Should
   Change Your Practice




         Michael Winters, MD, FACEP FAAEM
Assistant Professor of Emergency Medicine and Medicine
     Associate Director, Combined EM/IM Program
 Co-Director, Combined EM/IM/Critical Care Program
       University of Maryland School of Medicine
                  Baltimore, Maryland
Objectives
At the conclusion of this presentation, the participant will be able to:
     Identify key articles from the 2008 literature that change the delivery of
       critical care in the ED
     Discuss the information presented and how emergency physicians can
       incorporate into their daily practice

Post-Intubation Care
Bonomo JB, Butler AS, Lindsell CJ, Venkat A. Inadequate provision of postintubation
anxiolysis and analgesia in the ED. AJEM 2008;26:469-72.
         Emergency physicians (EP) intubate and mechanically ventilate patients on a
daily basis. Often, intubated patients remain in the emergency department (ED) for
exceedingly long hours awaiting an ICU bed. As a result, care of the intubated patient
falls to the EP. An important component in the care of these critically ill patients is the
provision of adequate analgesia and anxiolysis. Mechanical ventilation, along with the
procedures that many of the patients require, can be extremely painful and
uncomfortable. The consequences of inadequate anxiolysis and analgesia can be
disastrous in the care of these challenging patients.
         The authors of the current study hypothesized that many patients receiving
mechanical ventilation in the ED receive inadequate doses of analgesics and anxiolytics.
As such, they performed a retrospective cohort study of intubated patients in their single,
Level-1, university-affiliated ED. Inclusion criteria were patients who were > 18 years of
age, received rapid sequence intubation, remained in the ED for > 30 minutes after
intubation, and survived to hospital admission. All patients in the study received
etomidate for induction and succinylcholine for paralysis. Lorazepam or midazolam
were used for anxiolysis, whereas fentanyl was used for analgesia. Adequacy of
anxiolysis was determined a priori as a minimum dose of lorazepam of 0.77 mg/h or a
minimum dose of midazolam of 4.2 mg/h. Adequacy of analgesia was defined as a
minimum dose of fentanyl of 35 mcg/h.
         One hundred seventeen patients were included in the study. The majority of
patients were male (61.5%) with an average ED length of stay of 4.2 hours. Only 29 of
117 patients received adequate analgesia. The remaining 88 patients received either
inadequate (26/117, 22%) or no analgesia (62/117, 53%). Only 30 patients (25.6%)
received adequate anxiolysis. The remaining 87 patients received either inadequate
(48/117, 41%) or no anxiolysis (39/117, 33.3%). Unfortunately, only 4 patients (3%)
received adequate amounts of both analgesics and anxiolytics. Of 70 patients receiving
vecuronium for post intubation paralysis, only 3 (4%) received adequate doses of both
analgesics and anxiolytics. This would suggest that many of these patients were aware of
their surroundings yet unable to respond.
         Although this study suffers from the limitations of a retrospective review, the
findings suggest that the ED management of analgesia and anxiolysis in intubated
patients is inadequate. Given the potential for patient awareness, and the noxious stimuli
of mechanical ventilation, it is imperative to ensure your intubated patients have received
appropriate amounts of analgesic and anxiolytic medications.




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Noninvasive Ventilation
Gray A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J. Noninvasive
ventilation in acute cardiogenic pulmonary edema. NEJM 2008;359:142-51.
         Acute cardiogenic pulmonary edema (ACPE) is a leading cause of hospitalization
each year in the US. The ED presentation of ACPE can often be dramatic. For those not
responding to initial therapy, noninvasive positive pressure ventilation (NPPV) can be
used to avert intubation and the complications associated with mechanical ventilation. In
ACPE, NPPV improves oxygenation, reduces the work of breathing, and increases
cardiac output through reductions in afterload. Numerous trials and meta-analyses have
reported that NPPV improves symptoms, improves respiratory rate and heart rate,
decreases intubation, and improves mortality in patients with ACPE. Currently, there is
no evidence to suggest a mortality difference between continuous positive airway
pressure (CPAP) or bilevel positive airway pressure (BiPAP).
         The current trial, Three Interventions in Cardiogenic Pulmonary Oedema (3CPO),
is an open, randomized, controlled, parallel-group trial conducted in 26 EDs across the
UK between July 2003 and April 2007. Patients were randomly assigned in a 1:1:1 ratio
between three treatment groups: standard oxygen therapy, CPAP, and BiPAP. Patients
assigned to standard oxygen therapy received supplemental oxygen to maintain oxygen
saturations above 92%. For the group receiving CPAP, CPAP was initiated at 5 cm H2O
and titrated to a maximum of 15 cm H2O. BiPAP was started at an inspiratory pressure
(IPAP) of 8 cm H2O and an expiratory pressure (EPAP) of 4 cm H2O, and titrated to a
maximum IPAP of 20 cm H2O and EPAP of 10 cm H2O. All patients received assigned
therapy for a minimum of 2 hours. Inclusion criteria were age > 16 years, a clinical
diagnosis of ACPE, chest x-ray evidence of ACPE, a respiratory rate > 20 breaths per
minute, and a pH < 7.35. At 1 and 2 hours after initiation of assigned therapy, patients
underwent repeat arterial blood gas, pulse, respiratory rate, oxygen saturation, blood
pressure, and rated their degree of dyspnea on a visual analog-scale. The primary end
point between NPPV and standard oxygen therapy was death within 7 days after
initiation of therapy. The primary end point for comparison between CPAP and BiPAP
was death within 7 days or endotracheal intubation within 7 days.
         Although the authors report 1069 patients were randomized, 1046 started the
assigned therapy. The majority of patients in all three groups were elderly (average age
78), female (56%), and were tachycardic, tachypneic (33 bpm), hypertensive, acidotic
(pH 7.22), and hypercapnic. Approximately 90% of patients in all three groups received
nitrates and diuretics as part of the standard treatment regimen.
         Overall, there was no significant difference in 7-day mortality for patients
receiving NPPV compared to standard oxygen therapy. In addition, there was no
significant difference in 7-day mortality or rates of endotracheal intubation between the
CPAP and BiPAP groups. NPPV was associated with statistically significant reductions
in dyspnea, heart rate, acidosis, and hypercapnia. These differences, however, were very
small. The authors conclude that NPPV had no short term mortality benefit when
compared with standard oxygen therapy.
         The 3CPO trial conflicts with prior publications that have reported decreased
intubation rates and improved mortality in patients with ACPE managed with NPPV.
Criticisms of this study include an older patient population and higher baseline mortality
rates, yet low rates of intubation (less than 3% in all patient groups). Since so few

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patients were actually intubated, definitive conclusions regarding the effects of NPPV on
intubation rates cannot be made.
        A primary goal in the ED management of ACPE is to relieve dyspnea and
improve respiratory distress. Clearly, NPPV is useful for improving dyspnea, improving
respiratory distress, and improving physiologic variables. As a result, NPPV should still
be considered a component to the ED management of ACPE. Further studies are
required to clarify the discordance in mortality between this study and multiple prior
studies.

Intracerebral Hemorrhage
Mayer SA, Brun NC, Begtrup MSc, Broderick J, Davis S, et al. Efficacy and safety of
recombinant Activated Factor VII for acute intracerebral hemorrhage. NEJM
2008;358:2127-37.
         Intracerebral hemorrhage (ICH) accounts for approximately 10% to 15% of all
strokes, yet has the highest morbidity and mortality, with up to 40% of patients dying
within 30 days. Aside from age, size, location, intraventricular extension, and GCS,
hematoma expansion has been shown to be an independent determinant of morbidity and
mortality. Hematoma expansion is reported to occur in up to 70% of patients within the
first several hours of the ICH. Recent research has focused on therapies to limit
hematoma expansion. One therapy is recombinant human activated Factor VII (rFVIIa).
Excitement regarding this medication stems from a single, manufacturer sponsored, phase
2 trial that demonstrated rFVIIa significantly reduced hematoma expansion and improved
patient mortality.
         The FAST trial (Factor Seven for Acute Hemorrhagic Stroke), is the follow up
manufacture sponsored, phase 3 trial performed to confirm the findings of their previous
phase 2 study. The current study is a multi-center, randomized, double-blind, placebo-
controlled trial conducted at 122 sites in 22 countries. Patients had to be at least 18 years
of age with a spontaneous ICH documented by computed tomography (CT) within 3
hours of symptom onset. Important exclusion criteria included GCS < 5 at presentation,
secondary ICH (trauma, arteriovenous malformation), current anticoagulant therapy,
thrombocytopenia, disseminated intravascular coagulation, previous disability from
CVA, or a thromboembolic event < 30 days prior to symptom onset. The primary end-
point was disability or death defined by a modified Rankin score of 5 or 6 at day 90. The
modified Rankin score evaluates global disability and handicap and ranges from 0 to 6.
A score of 5 indicates a patient who is bed-bound and incontinent, whereas a score of 6
indicates death.
         Of 8,886 patients screened, 821 underwent randomization and received placebo,
20 mcg/kg of rFVIIa, or 80 mcg/kg of rFVIIa. Treatment had to start within 1 hour of the
baseline CT and no more than 4 hours after symptom onset. Patients then underwent a
repeat CT at 24 hours and 72 hours to evaluate for hematoma expansion. Of note, the
majority of the patients in this study were Caucasian males, older than 65 year of age
with deep gray matter ICHs.
         As reported by the trial investigators, rFVIIa did reduce hematoma expansion at
24 hours compared to placebo. In the placebo arm, 26% of patients had hematoma
growth, whereas only 11% of patients who received 80 mcg/kg of rFVIIa had hematoma
expansion. In addition, the investigators report that the reduction in hematoma growth

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was even greater in those treated in less than 2 hours from onset of symptoms. However,
there was no significant difference in total hematoma volume or edema volume at 72
hours. More importantly, mortality at 90 days did not differ between placebo and the
treatment groups. In fact, a higher percentage of patients who received 80 mcg/kg of
rFVIIa had a worse outcome than compared with placebo. Furthermore, there was an
absolute increase of 5% in the frequency of arterial thromboembolic serious events (MI,
ischemia CVA) in the group receiving 80 mcg/kg of rFVIIa.
        This phase 3 trial failed to demonstrate improved 90 day mortality in patients with
spontaneous ICH who received rFVIIa. Although hematoma expansion was reduced at
24 hours in the rFVIIa groups, total lesion volume and edema volume at 72 hours
remained unchanged. Although rFVIIa has been used in a variety of clinical settings, the
results of this study indicate that it does improve mortality in patients with spontaneous
ICH. Given the expense of the drug and lack of benefit, this should not be a drug used in
the ED to treat patients with spontaneous ICH.

Anderson CS, Huang YH, Wang JG, Arima H, Neal B, Peng B, et al. Intensive blood
pressure reduction in acute cerebral haemorrhage Trial (INTERACT): a randomized
pilot trial. Lancet Neurol 2008;7:391-99.
         Over 1 million patients per year worldwide experience an intracerebral
hemorrhage (ICH). Most patients with an ICH either die or are left with severe
neurologic deficits. In recent years, research has indicated that early hematoma growth is
a significant predictor of patient morbidity and mortality. Controversy continues as to the
contribution of elevated blood pressure to hematoma expansion. To date, non-
randomized studies suggest that lowering of severe hypertension may limit hematoma
growth, and ultimately improve morbidity and mortality from an ICH. Unfortunately,
current recommendations for blood pressure management in the setting of an ICH are
based primarily on expert opinion.
         The authors of the current study performed a multicenter, open, randomized trial
comparing an intensive blood pressure reduction strategy to the American Heart
Association guideline for blood pressure reduction in ICH. Patients were enrolled from
44 sites in China, Australia, and South Korea. Patients included in the study had to be >
18 years of age, have a spontaneous ICH confirmed by CT, have an elevated systolic
blood pressure between 150 – 200 mm Hg, and able to undergo randomization and
treatment within 6 hours of the onset of the ICH. Important exclusion criteria included a
clear indication for intensive lowering of blood pressure (systolic blood pressure > 200
mm Hg or encephalopathy), a clear contraindication to acute lowering of blood pressure
(severe cerebral artery stenosis or renal failure), clear evidence that the ICH was
secondary to a structural abnormality (aneurysm or arteriovenous malformation), use of a
thrombolytic agent, a Glascow Coma Scale of 3 – 5, or an ischemic stroke within 30
days.
         Four hundred four patients were enrolled in this study. The majority of patients
were male (65%), from China (95%), had a history of hypertension (74%), and had an
ICH located in the basal ganglia or thalamus (82%). For patients randomized to the
intensive blood pressure lowering group, the goal was to achieve a systolic blood
pressure (SBP) of 140 mm Hg within 1 hour of randomization and to maintain this for 7
days or until discharge. For patients in the AHA guideline group, the goal was to

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maintain a target SBP of 180 mm Hg. The primary efficacy endpoint was the
proportional change or growth in hematoma volume during the first 24 hours after
randomization. The primary clinical endpoint was the combination of death and
dependency at 90 days. Secondary endpoints were absolute and substantial growth of the
hematoma plus any intraventricular extension.
        In the intensive blood pressure lowering group, 42% achieved the target SBP goal
of 140 mm Hg in the first hour, with 66% achieving this goal within 6 hours. The
majority of patients had blood pressure control using continuous intravenous infusions.
The most common medications used to lower blood pressure were urapidil, frusemide,
and phentolamine. Only a small proportion of patients in the intensive group (20%) and
the guideline group (14%) had control of SBP by bolus injection alone. The authors
report that the proportional mean increase in hematoma at 24 hours was 36.3% in the
AHA guideline group and only 13.7% in the intensive control group. The absolute
difference, however, was only 1.7 ml. Importantly, there were no statistically significant
differences between the groups in terms of 90-day rates of death or dependency.
Limitations of the study include the unblinded administration of medications, the average
severity of ICH was mild, and the overall lower mortality of patients in this study
compared to other trials of ICH.
        Blood pressure control in ICH remains controversial. It has been theorized that
acute lowering of blood pressure can limit expansion of the hematoma, a significant
predictor of patient morbidity and mortality. Despite acutely lowering blood pressure to
near normal values in this study, only a small absolute decrease (1.7 ml) in hematoma
expansion was observed. This reduction in hematoma growth did not impact patient
mortality.

Acute Ischemic Stroke
Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis
with alteplase 3 to 4.5 hours after acute ischemic stroke (ECASS III—European
Cooperative Acute Stroke Study) NEJM 2008;359:1317-1329.
         Thrombolysis using tissue plasminogen activator (tPA) for patients with acute
ischemic stroke (AIS) continues to be debated in the emergency medicine and critical
care literature. Since the 1995 publication of the National Institute of Neurological
Disorders and Stroke (NINDS) Trial, tPA is approved for the treatment of patients with
AIS presenting within 3 hours of symptom onset. The authors of the current study state
that subsequent analyses of the NINDS study, as well as data from other trials using tPA
for AIS, suggest that the benefit of tPA may occur in patients treated up to 4.5 hours after
symptom onset.
         ECASS III is a double-blind, prospective, randomized, placebo-controlled study
to test the efficacy of tPA given between 3 to 4.5 hours after symptom onset in patients
with AIS. Inclusion criteria were age between 18 and 80 years, acute ischemic stroke,
onset of symptoms between 3 and 4.5 hours, and the presence of symptoms for at least 30
minutes with no improvement prior to treatment. Important exclusion criteria were
intracranial hemorrhage, unknown time of symptom onset, NIHSS stroke score > 25,
rapidly improving symptoms, blood pressure > 185/110 mm Hg, thrombocytopenia, oral
anticoagulant therapy, and symptoms suggestive of a subarachnoid hemorrhage despite a
normal CT. The primary endpoint of the study was disability at 90 days. Secondary

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endpoints included a score of 0 or 1 on the modified Rankin scale, a score of > 95 on the
Barthel Index, and score of 0 or 1 on the NIHSS and Glasgow Outcome Scales. Safety
endpoints were 90 day mortality, any intracranial hemorrhage, or symptomatic edema.
        A total of 821 patients were enrolled with 418 randomized to receive alteplase
and 403 randomized to receive placebo. Those in the alteplase group received 0.9 mg/kg
of medication administered intravenously. Baseline demographics of the two groups
were similar. The median time for alteplase administration was 3 hours and 59 minutes
compared to 3 hrs and 58 minutes for placebo. For the primary endpoint of 90 day
disability, 52.4% (219/418) of patients receiving alteplase had a favorable outcome
compared to 45.2% (182/403) of patients receiving placebo. Secondary endpoints also
seemed more favorable in the group receiving alteplase. Importantly, the incidence of
intracranial hemorrhage was significantly higher in the alteplase group. Twenty-seven
percent (113/418) of patient receiving alteplase were diagnosed with an intracerebral
hemorrhage compared to 17.6% (71/403) of placebo patients. Despite the discrepancy
between in incidence of intracerebral hemorrhage, there was no statistically significant
difference in mortality (7.7% alteplase vs. 8.4% placebo) between the two groups.
        The study populations had lower portions of patients with diabetics compared
with other large stroke study. They also excluded patients with both diabetes and
previous stroke from this study. More importantly, this study excluded patients with
National Institutes of Health Stroke Scale (NIHSS) > 25 or patients with stroke involving
more than one third of the middle cerebral artery territory on the imaging study.
Therefore, the efficacy and safety data of alteplase from this study can‟t be generalized to
the severe stroke patients.
        The key message from this study is not that you have more time to relax in your
emergency department to treat these patients with ischemic stroke. It still remains true
that the earlier you administer the thrombolytic for ischemic stroke with no
contraindications, the better the outcome is. For example, treatment with alteplase is
nearly twice as efficacious when administered within the first 1.5 hours after the onset of
stroke compared to 1.5 – 3 hours window group. However, the result of this trial opens a
door to thrombolytic treatment for patients who failed to show up to ED within 3 hours
window. In summary, ED physicians should consider alteplase treatment in patients with
ischemic stroke with NIHSS < 25 and no other contraindications up to 4.5 hours from the
stroke symptoms onset. However, there should be no delay of door to needle time in
order to maximize the benefit of the treatment.

Martin-Schild S, Hallevi H, Albright KC, Khaja AM, Barreto A, Gonzales NR, et al.
Aggressive blood pressure-lowering treatment before intravenous tissue plasminogen
activator therapy in acute ischemic stroke. Arch Neurol 2008;65(9):1174-8.
        Thrombolytic therapy with tissue plasminogen activator (tPA) has been used in
the treatment of acute ischemic stroke (AIS) since the publication of the National
Institute of Neurological Disorders and Stroke Trial. Guidelines that advocate the use of
tPA for AIS state the medication should not be given to patients with sustained blood
pressures > 185/110 mm Hg. It is believed that severe hypertension increases the risk of
hemorrhagic transformation following administration of tPA. Although the association
between hemorrhagic transformation and severe hypertension is weak, current guidelines
recommend blood pressure reduction to levels < 185/110 mm Hg prior to tPA.

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        The authors of this single center, open, retrospective, nonrandomized,
observational study sought to evaluate the safety of blood pressure reduction before tPA
therapy in patients with AIS. Inclusion criteria included all patients who received tPA
and blood pressure reduction with either labetalol or nicardipine between January 2004
and December 2006. Patients treated with other antihypertensive medications, those
treated after the recommended 3-hour window, or patients treated with adjuvant
intraarterial tPA were excluded. The primary end points were adverse events, discharge
disposition, and modified Rankin score at discharge. Adverse events were defined as
symptomatic intracranial hemorrhage, all grades of hemorrhagic transformation, and
neurologic deterioration. Neurologic deterioration was not further defined.
        A total of 178 patients were treated with tPA during the study period. Fifty
patients received medications to lower blood pressure to < 185/110 mm Hg before
administration of tPA. Twenty-six of 50 patients received labetalol alone, whereas 42
required nicardipine in addition to labetalol or nicardipine alone. Patients who received
antihypertensives had higher mean National Institutes of Health Stroke Severity (NIHSS)
scores and higher rates of hypertension. Although not statistically significant, patients
receiving antihypertensive medications had a trend towards increased hemorrhagic
transformation (20% vs. 12%) and increased neurologic deterioration (18% vs. 13%).
Patients who had more aggressive blood pressure reduction with nicardipine had a higher
likelihood of neurologic deterioration (25%) and death (12.5%).
        Citing the absence of statistical differences between those treated with
antihypertensives and those who received no blood pressure medications, the authors
incorrectly assert that blood pressure reduction „may not be harmful”. Importantly, this
study is a retrospective chart review of a single center‟s experience with tPA. Without a
comparison group, the claim that aggressive blood pressure reduction may be safe prior
to tPA cannot be supported. In fact, those that received aggressive blood pressure
reduction had higher rates of neurologic deterioration and death.
        Blood pressure management in patients with AIS is challenging. Current
guidelines recommend the use of antihypertensive medication to lower blood pressure to
< 185/110 mm Hg prior to tPA administration. In this study, aggressive blood pressure
reduction using intravenous nicardipine resulted in a non-significant trend towards higher
rates of neurologic deterioration and death.

Sepsis
Sprung CL, Annane D, Keh D, Moreno R, Singer M, et al. Hydrocortisone therapy for
patients with septic shock. NEJM 2008;358:111-24.
        Corticosteroid therapy for patients with septic shock seems to change favor every
couple of years. In the first publication of the Surviving Sepsis Campaign Guidelines,
steroids were given a favorable recommendation based largely upon the results of one
multicenter, randomized, controlled trial. In that study, the authors reported a reduction in
the likelihood of death in patients who did not respond to the corticotropin stimulation
test and were given both hydrocortisone and fludrocortisone.
        The current study is from the CORTICUS Study Group and is a multicenter,
randomized, double-blind, placebo-controlled study conducted in 52 ICUs from March
2002 to November 2005. Enrolled patients had to have clinical evidence of infection, a
systemic response to infection, organ dysfunction attributable to sepsis, and the onset of

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shock within 72 hours (SBP < 90 mmHg despite fluids or vasopressors). Patients were
randomized to receive either hydrocortisone or placebo for 5 days. Doses were then
tapered over the next 6 days for a total duration of therapy of 11 days. A lack of response
to corticotropin was defined as an increase in cortisol of no more then 9 mcg/dL. The
primary end point of the study was the rate of death from any cause at 28 days in “non-
responders”. Some important secondary end-points included the rate of death at 28 days
in “responders”, time to reversal of shock, duration of ICU and hospital stay, and rates of
death at 1 year.
         Four-hundred ninety nine patients were enrolled in the study. Of these, 233 were
identified as “non-responders”. In this group, 125 were randomized to receive
hydrocortisone with 108 randomized to receive placebo. The demographic and clinical
characteristics of patients in each group were similar. Over 90% of patients in each
group were vented and all were receiving vasopressors, the most common being
norepinephrine. With respect to the primary outcome, there was no significant difference
in the rate of death at 28 days between the study groups. For the secondary end points,
there was also no significant difference in the rate of death in “responders”, duration of
ICU or hospital length of stay, or death at 1 year. The only difference that was found in
those receiving hydrocortisone was a reduction in the time to reversal of shock.
Importantly, this did not translate into improved mortality. Lastly, the authors reported
an increase in new episodes of sepsis and septic shock in those receiving hydrocortisone
but the absolute numbers are small.
         Investigators had planned to enroll 800 patients, however stopped at 499 due to
slow recruitment, termination of funding, and expiration of the study drug. In addition,
the mortality rate in the placebo group was lower than what would be expected. As a
result, the study is inadequately powered. In contrast to the Annane study, enrollment of
patients could be up to 72 hours after the onset of shock, raising the question of timing of
steroids administration. Furthermore, the majority of patients in this study were older,
Caucasian males who required emergency surgery. Importantly, patients who were
receiving long-term corticosteroids within the past 6 months, or short-term steroids
within the past 4 weeks were excluded. Typically, these are the patients we would give
stress dose steroids to during refractory shock.
         Although CORTICUS is underpowered, it is one of the largest trials to date on
corticosteroids in patients with septic shock. The results indicate that corticosteroid
therapy in this patient population of “non-responders” had no effect on mortality. Based
upon this study, the latest version of the Surviving Sepsis Campaign Guidelines has
downgraded their recommendation on corticosteroids. It appears that the pendulum
regarding steroids may now be swinging back in the negative direction.

Brunkhorst FM, Engel C, Bloos R, Meier-Hellmann A, Ragaller M, et al. Intensive
insulin therapy and pentastarch resuscitation in severe sepsis. NEJM 2008;358:125-139.
        The concept of “tight glucose control” in critically ill patients primarily began
with the Van de Berghe study published in 2001. In this study, investigators found a
reduction in mortality in critically ill patients whose glucose was maintained between 80
– 110 mg/dL. The benefit was primarily seen in cardiac surgery patients who had
multiple organ failure from sepsis. Furthermore, these patients were given a high glucose
challenge immediately after surgery, not a common practice. More recently, the same

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investigators evaluated medical ICU patients who had not undergone surgery nor
received a glucose challenge. In this latter study there was no benefit to intensive insulin
therapy.
        The current study is a multicenter, randomized, open-label study of both intensive
insulin therapy and hydroxyethyl starch in patients with severe sepsis. The study was
conducted from April 2003 to June 2005 in 18 multidisciplinary ICUs at academic
tertiary hospitals throughout Germany. The study was designed to detect a decrease in
mortality from 40% to 30% at 28 days. Enrolled patients had to have the onset of severe
sepsis or septic shock either 24 hours before ICU admission or less than 12 hours after
ICU admission. The primary end points were the rate of death from any cause at 28 days
and morbidity.
        The insulin arm of the study compared intensive insulin therapy to conventional
insulin therapy. In the conventional group, insulin was given when glucose values were
> 200 mg/dL, with the goal of maintaining glucose between 180 – 200 mg/dL. In the
intensive insulin group, insulin was given when glucose values were > 110 mg/dL, with
the goal of maintaining glucose between 80 – 110 mg/dL. Treatment ended at either
discharge from the ICU, death, or a total of 21 days of therapy were reached.
        Five hundred thirty seven patients were enrolled, 290 in the conventional insulin
group and 247 in the intensive insulin group. Baseline patient characteristics including
age, pre-existing co-morbidities, sites of infection, lab values, and hemodynamic
variables were similar between the groups. Total nutritional intake, including glucose,
was similar in both groups. Interestingly, the majority of patients had nosocomial
acquired infections and over 60% in both groups were given hydrocortisone. Overall,
there was no significant difference in the rate of death between the intensive and
conventional insulin therapy groups. Furthermore, there was no significant difference in
morbidity between the two groups. As one might expect, there was significantly more
hypoglycemic episodes in the intensive insulin therapy group (17% vs. 4.1%). Although
no deaths were attributable to hypoglycemia, there were more “life threatening” episodes
of hypoglycemia in the intensive insulin group. As a result of the increase in
hypoglycemic episodes the study was stopped early.
        Many EDs across the country are now developing, and implementing, sepsis
protocols primarily based upon the SSC Guidelines. Given the lack of mortality benefit,
marked increases in rates of hypoglycemia, and the resources required to monitor patients
receiving insulin infusions, intensive insulin therapy should not be a necessary
component to the ED management of patients with severe sepsis or septic shock.

Adrenal Insufficiency
Vinclair M, Broux C, Faure P, Brun J, Genty C, et al. Duration of adrenal insufficiency
following a single dose of etomidate in critically ill patients. Intensive Care Med
2008;34:714-9.
       Etomidate has become a favored first-line induction agent for intubation in the
emergency department. Given its excellent hemodynamic tolerance, etomidate is
especially useful in hemodynamically unstable patients. A known side effect of
etomidate is adrenal suppression, due to inhibition of 11β-hydroxylase, the enzyme that
converts 11β-deoxycortisol into cortisol. As a result, recent literature has raised concerns



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that etomidate may worsen patient outcomes in those with relative adrenal insufficiency,
namely those with septic shock.
         The current study is a prospective, observational study conducted in France from
October 2005 to January 2006. The purpose of the study was to assess the duration of
adrenal suppression following a single dose of etomidate, given either in the field or in
the emergency department for RSI. Importantly, patients with septic shock, or those with
preexisting adrenal insufficiency, were excluded from this study. To diagnose adrenal
insufficiency, the investigators measured total cortisol and 11β-deoxycortisol following a
high-dose cosyntropin stimulation test (250 mcg). Values were obtained at 12, 24, 48,
and 72 hours following etomidate administration. An accumulation of 11β-deoxycortisol
with a lack of cortisol rise was used to establish etomidate-related adrenal insufficiency.
         A total of 40 patients were included in this study. The majority of patients
required intubation as a result of either trauma or subarachnoid hemorrhage. At hour 12,
80% of patients fulfilled the investigators definition of etomidate-related adrenal
insufficiency, whereas by hour 48, only 9% met criteria. In addition, at hour 24, patients
with etomidate-related adrenal suppression required larger doses of norepinephrine that
those without adrenal inhibition. From their data, the authors conclude that a significant
proportion of patients without septic shock have adrenal suppression for at least 12 hours
following a single dose of etomidate. This effect, however, appeared reversible in that
most patients recovered adrenal function by hour 48. Finally, the authors recommend
that systemic steroid supplementation be considered during the first 48 hours in
hemodynamically unstable patients who have received etomidate for intubation.
         There are a number of limitations with this study. The most important limitation
is, perhaps, the authors‟ definition of etomidate-related adrenal insufficiency.
Diagnosing adrenal insufficiency in critically ill patients remains controversial. The
cosyntropin test (high- or low-dose) has many recognized limitations. In addition,
measurement of 11β-deoxycortisol is difficult because reference values for critically ill
patients are rare. The authors also chose to measure total serum cortisol, rather than the
more biologically active free serum cortisol. Lastly, data for all 40 patients at 72 hours
was not complete.
         This small, observational study found a high incidence of adrenal suppression for
at least the first 12 hours in unstable patients receiving etomidate for intubation.
Importantly, this study excluded patients with sepsis or septic shock. Given the limited
number of patients and the difficulty in defining adrenal insufficiency in the critically ill,
this study provides some interesting results and is hypothesis-generating. Their
recommendation for systemic steroid supplementation during the first 48 hours following
etomidate administration in unstable patients cannot be supported by this study.

Hildreth A, Mejia V, Maxwell RA, Smith PW, Dart BW, Barker DE. Adrenal suppression
following a single dose of etomidate for rapid sequence induction: A prospective
randomized study. J Trauma 2008;65:573-579.
        Etomidate is commonly used in the ED as an induction agent for rapid sequence
intubation (RSI) due to its rapid onset of action, minimal cardiovascular effects, lack of
histamine release, and short duration of action. Etomidate is known to inhibit 11-β-
hydroxylase, which catalyzes the conversion of deoxycortisol to cortisol, thereby
decreasing cortisol concentrations for up to 24 hours. To date, etomidate related adrenal

                            Winters ME. Critical Care 2008                                 11
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suppression has not been well studied in trauma patients. The purpose of this current
study was to assess adrenal insufficiency after a single dose of etomidate and its effect
within 24 hours on resuscitation, hospital length of stay, and patient mortality.
        This is a prospective, randomized, controlled, non-blinded study performed at a
single, Level 1 trauma center in Tennessee. Investigators compared the effect of
etomidate (0.3 mg/kg) and succinylcholine (1 mg/kg) vs. fentanyl (100 mcg), midazolam
(5 mg), and succinylcholine (1 mg/kg) for induction. Serum cortisol levels were drawn at
baseline and then 4 – 6 hours after intubation. An ACTH stimulation test was also
performed. Inclusion criteria for the study were adult trauma patients requiring RSI for
orotracheal intubation during the first 48 hours following injury. Exclusion criteria were
pregnancy, adrenal trauma, a history of adrenal insufficiency, a history of corticosteroid
use during the year prior to the study, current use of imidazole antifungal agents, and
current incarceration.
        Thirty patients were enrolled, with 18 randomized to etomidate and
succinylcholine, and 12 randomized to fentanyl, midazolam, and succinylcholine. The
majority of patients were male suffering from blunt trauma. Baseline characteristics,
including cortisol level, were similar between both groups. The post-intubation cortisol
levels were significantly different between groups (18.2 vs. 27.8 µg/dL, p < 0.05), as
were cortisol levels following ACTH stimulation. Hospital length of stay (13.9 +/- 9.5
days vs. 6.4 +/- 4.4 days, p=0.007), ICU length of stay (8.1 +/- 7.2 days vs. 3.0 +/- 2.4
days, P=0.011), and ventilator days (6.3 +/- 6.5 days vs. 1.5 +/- 0.8 days, P= 0.007) were
all significantly higher in patients who received etomidate.
        The current study suffers from several limitations. Primarily, the study is a non-
blinded study with a small number of patients. Furthermore, the investigators used total
cortisol levels as opposed to free cortisol levels, the biologically active form.
Resuscitation was performed at the discretion of the attending physician. As such, there
was no documentation of resuscitation guidelines or indications for transfusions. Though
not statistically significant, there was a trend toward higher injury severity in patients
receiving etomidate.
        The results of this study, as well as several others, indicate that etomidate does
indeed result in transient adrenal suppression. The clinical relevance of this suppression,
however, remains controversial. Given its limitations, this study suggests that etomidate
may be associated with both increased ICU and hospital length of stay in adult trauma
patients.
Abdominal Compartment Syndrome
Vidal MG, Weisser JR, Gonzalez F, Toro MA, Loudet C, Balasini C, et al. Incidence and
clinical effects of intra-abdominal hypertension in critically ill patients. Crit Care Med
2008;36:1823-31.
         Intra-abdominal hypertension (IAH) and abdominal compartment syndrome
(ACS) have been recognized as causes of increased morbidity and mortality in the
critically ill. Increased intra-abdominal pressure can decrease preload, increase afterload,
impair ventilation, decrease end-organ oxygen delivery, and decrease oxygen utilization.
Although initially believed to occur solely in patients with severe trauma, IAH and ACS
are common among both surgical and medical ICU patients. Risk factors for IAH and
ACS include massive fluid resuscitation, sepsis, ileus, gastroparesis, abdominal surgery,
acidosis, and coagulopathy.

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                                 MD ACEP 4/17/09
        The authors of the current study conducted a single-center, prospective cohort
study to determine the incidence of IAH in a mixed medical-surgical ICU population, and
to determine the association of IAH to outcome. All patients admitted to the ICU during
a 9 month period from November 2004 to July 2005 were included in the study, provided
their ICU length of stay was > 24 hours and they required bladder catheterization. Intra-
abdominal pressure was measured every 6 hours until death, discharge, or 7 days. The
primary endpoint of the study was hospital mortality.
        A total of 83 patients completed the study protocol. Twenty-six patients (31%)
had IAH on admission to the ICU and an additional 27 (33%) developed IAH during their
ICU stay. The occurrence of IAH for all patients totaled 64%. Patients with IAH were
more acutely ill, had more organ failure, more often mechanically ventilated, and had
higher hospital mortality rates (53% vs. 27%). Ten patients (12%) developed ACS, with
only 2 of these patients surviving. Interestingly, no patients with ACS underwent
surgical decompression, the recommend treatment for ACS.
        The current study suffers from several limitations. It is a single center,
prospective study including just 83 patients. An editorial to the study criticizes the
authors for using the wrong reference point for measurements, as well as an outdated
method of measuring intra-abdominal pressure. Finally, the fact that only 83 patients
were included during a 9 month period raises the question of whether this was truly a
cohort study or random sample.
        Despite the limitations of the current study, it highlights the fact that IAH and
ACS occurs in both surgical and medical ICU patients. At present, it is unclear whether
IAH and ACS are a cause of poor patient outcome, or simply a reflection of the severity
of illness. As ICU patients remain the ED awaiting an ICU bed, the emergency physician
must be aware of IAH and ACS. Current recommendations from the World Society of
the Abdominal Compartment Syndrome are to measure an intra-abdominal pressure,
using a Foley catheter, in at risk patients. ED patients at greatest risk are those with
sepsis and massive fluid resuscitation.

Hyperglycemia
Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically
ill adults. JAMA 2008;300(8):933-44.
         Hyperglycemia is associated with increased morbidity and mortality in critically
ill patients. The concept of “tight glucose control”, whereby blood glucose is maintained
between 80 – 110 mg/dL using an insulin infusion, began with the 2001 publication by
Van de Berghe. In this study, investigators reported a significant decrease in mortality for
cardiac surgery patients whose blood glucose was maintained between 80 – 110 mg/dL.
As a result of this publication, the Surviving Sepsis Campaign incorporated glucose
control into its recommendations for the treatment of patients with severe sepsis and
septic shock. In addition, the Institute for Healthcare Improvement, the Volunteer
Hospital Association, the American Association of Clinical Endocrinologists, and the
American Diabetes Association recommend tight glucose control for all critically ill
adults. Recent literature, however, challenges this treatment recommendation, indicating
a lack of benefit and suggesting a possible trend toward increased mortality with tight
glucose control.



                           Winters ME. Critical Care 2008                                13
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         The authors of the current study performed a meta-analysis of trials evaluating
tight glucose control. Inclusion criteria for this meta-analysis were: randomized,
controlled trials of critically ill adult ICU patients comparing an intervention group
(blood glucose goal of < 150 mg/dL using an insulin infusion) to a comparison group in
which patients received traditional care. The analysis was further restricted to trials in
which one-third or less of patients were diabetic and trials that used only insulin infusions
to tightly control glucose. The primary outcome was hospital mortality, defined as death
occurring during the hospital stay or within 30 days following admission. Secondary
outcomes included rates of septicemia, need for new dialysis, and rates of hypoglycemia.
Given the heterogeneity of critically ill patients, 2 subgroups were identified a priori;
glucose goal (maintaining tight glucose < 110 mg/dL vs. moderately tight glucose 111-
150 mg/dL) and ICU setting (surgical vs. medical vs. mixed medical-surgical).
         Twenty-nine randomized controlled trials were included in this meta-analysis
comprising 8432 patients. Most studies included were performed at single centers and
had relatively small numbers of patients. All trials had follow up rates of 80% or greater.
No significant difference was found in hospital mortality (21.6% vs. 23.3% for traditional
care). In addition, there was no significant difference in hospital mortality when
stratified by ICU setting or tight (23.2% vs. 25.2%) or moderately tight (17.3% vs. 18%)
glucose goal. Tight glucose control was, however, associated with a significant reduction
in septicemia (10.9% vs. 13.4% for traditional care). This effect appeared limited to
patients in the surgical ICU setting. No association was found between tight glucose
control and the new need for dialysis (11.2% vs. 12.1%). Importantly, tight glucose
control was associated with a 5-fold increase in hypoglycemia (13.7% vs. 2.5%).
         Similar to recent literature, this meta-analysis found no difference in hospital
mortality for hyperglycemic critically ill patients receiving intravenous insulin for tight
glucose control. The primary limitation of this meta-analysis is that it is dependent upon
the quality of the constituent trials. Many of the included trials varied with regard to
patient characteristics and insulin infusion protocols. Furthermore, bedside testing of
glucose in the critically ill can be inaccurate.
         Despite initial enthusiasm, tight glucose control does not appear to improve
hospital mortality for a heterogeneous population of critically ill patients. Importantly,
there is a significant, and substantial, increase in the incidence of severe hypoglycemia.
Given the lack of established benefit, the lack of an agreed standard for glycemic control,
varied insulin protocols, and the resource utilization needed to manage continuous insulin
infusions, tight glucose control is not recommended as an emergency department therapy.

Treggiari MM, Karir V, Yanez D, Weiss NS, Daniel S, Deem SA. Intensive insulin therapy
and mortality in critically ill patients. Crit Care 2008;12:R29.
         Intensive insulin therapy (IIT) to control hyperglycemia is currently a hot topic in
the critical care literature. Although there is no conclusive evidence that it is beneficial,
many organizations such as the Institute for Healthcare Improvement and the Volunteer
Hospital Administration support IIT in the treatment of critically ill patients. The authors
of the current study sought to evaluate the effect of IIT on a heterogeneous population
that included a mix of trauma, surgical, neurosurgical, and medical intensive care unit
patients. The study was conducted at a single, Level-1 trauma center and county hospital
in Seattle, Washington.

                           Winters ME. Critical Care 2008                                 14
                                 MD ACEP 4/17/09
        Overall, the outcomes of 10,456 patients were evaluated in the study. The
investigators divided the patient population into three cohorts. Period I included 2,366
patients from March 2001 to February 2002. During this time there was no specific
glycemic control protocol and the overall target blood glucose was between 120 – 180
mg/dL. Period II consisted of 3,322 patients from March 2002 to June 2003 with target
blood glucose values between 80 – 130 mg/dL. Finally, period III included 4,768 patents
between July 2003 and February 2005. Target glucose values for period III ranged
between 80 – 110 mg/dL. The investigators chose to follow 6 am blood glucose values
based on the reporting of two prior trials using IIT. The primary outcomes of the study
were ICU and hospital mortality. Secondary safety outcome measures included the
occurrence of moderate (< 65 mg/dL) and severe (< 40 mg/dL) hypoglycemia.
        As expected, the percentage of patients receiving insulin increased from 9% in
period I to 25% in period II to 43% in period III. The average 6 am glucose values for
periods I, II, and III were 144 mg/dL, 139 mg/dL, and 129 mg/dL. Thus, many of the
patients included in this study did not meet target glucose goals for their respective
period. Nonetheless, there was no change in either ICU or hospital mortality between
periods I, II, and III. Importantly, after the investigators adjusted for cofounding
variables, there was a trend toward higher mortality in patients receiving IIT during
period III. In addition, there was a significant increase in both moderate and severe
episodes of hypoglycemia between periods I and III.
        This study adds to the growing body of critical care literature demonstrating that
IIT for glycemic control does not improve patient mortality. Importantly, there is a
significant increase in rates of severe hypoglycemia. Until additional evidence is
reported, IIT should not be routinely used in the ED for critically ill patients.

Resuscitation
Bottiger BW, Arntz HR, Chamberlain DA, Bluhmki E, Belmans A, Danays T, et al.
Thrombolysis during resuscitation for out-of-hospital cardiac arrest. NEJM
2008;359:2651-62.
         Out-of-hospital cardiac arrest occurs in approximately 155,000 patients per year
in the United States. Almost 70% of these cases are caused by acute myocardial
infarction or pulmonary embolism. It is, therefore, a reasonable hypothesis that providing
thrombolytic therapy in such patients may improve clinical outcome.
         The current study is a prospective, double-blind, placebo-controlled study
involving 66 emergency medical service systems throughout Europe. The study was
designed to assess the efficacy of the thrombolytic medication tenecteplase in patients
with out-of-hospital cardiac arrest. Patients included in the study were adults with
witnessed out-of-hospital cardiac arrest who had initiation of advanced life support
within 10 minutes of collapse. Exclusion criteria were suspected non-cardiac origin of
arrest, known internal bleeding, neurologic impairment, known coagulation disorder,
pregnancy, institutionalization, and hypersensitivity to the medication. Open label
thrombolytic therapy was permitted in cases where pulmonary embolism was suspected
as the cause of cardiac arrest. The primary endpoint of the study was 30-day survival.
Secondary endpoints included survival to hospital admission, return of spontaneous
circulation, 24 our survival, survival to hospital discharge, and the neurologic outcome of
surviving patients.

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                                 MD ACEP 4/17/09
        A total of 1050 patients were enrolled in the study. Five hundred and twenty five
patients were randomized to receive tenecteplase and 525 were randomized to receive
placebo. Importantly, the data and safety monitoring board recommended discontinuing
the enrollment of patients with asystole due to the extremely low rate of survival. The
protocol was subsequently amended. Unfortunately, there was no statistically significant
difference in 30-day outcome between the tenecteplase group (14.7%) and the placebo
group (17%). None of the secondary outcomes were statistically different between the
groups. There was, however, a statistically significant increase in adverse events such as
intracranial hemorrhage in the tenecteplase group (2.7% vs. 0.4%).
         Despite the fact that the majority of cases of out-of-hospital arrest are due either
to acute myocardial infarction or pulmonary embolism, the empiric administration of
thrombolytic therapy did not improve outcomes in this study.




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