Controversies in Critical
Care
David A. Schulman, MD, MPH
Chief, Pulmonary and Critical Care Medicine,
Emory University Hospital
Training Program Director, Pulmonary and Critical
Care Medicine
Emory University School of Medicine
Topics to be covered in
this session
1. What are the indications for non-invasive ventilation in the
acute setting?
2. What are the common organisms causing ventilator
associated pneumonia, and what is recommended first line
therapy?
3. Which patients benefit from corticosteroids in sepsis?
4. What should be the target glucose in the ICU and how best
can it be achieved?
5. Which patients with sepsis should be given drotrecogin alfa?
6. What is the role of vasopressin in the septic patient?
Topic 1: The Role of Non-Invasive
Ventilation in Respiratory Failure
• COPD
– Fourteen study meta-analysis showed
• Decreased mortality (RR 0.52)
• Decreased need for intubation (RR 0.41)
• Decreased length of hospital stay (-3.24 days)
– Important to implement early in course
– Not just for severe failure!
Ram, FS, et al, “Non-invasive positive pressure ventilation for treatment of
respiratory failure due to exacerbations of COPD.” Cochrane Database, 2004 (3).
Which patients and when?
• Patients with pH>7.30 enrolled in one RCT
– Poorly tolerated therapy
– No differences in any clinically relevant
outcomes (including LOS and need for tube)
• When compared with mechanical
ventilation, NPPV yields similar outcomes
after failure of maximal medical Rx
Keenan, SP, et al, “Non-invasive positive pressure ventilation in patients with milder COPD exacerbations.”
Respiratory Care, 2005; 50(5):610-616.
Conti, G, et al, “Noninvasive vs. conventional mechanical ventilation in patients with COPD after failure of
medical treatment in the ward.” Intensive Care Med, 2002; 28(12): 1701-7.
Other disease states responsive to
NPPV
• Cardiogenic pulmonary edema
– Some data suggest CPAP may be better than NPPV,
with one study showing increased MI rates
• Pneumonia
– Assuming no problems with secretion handling
– Again, CPAP may be better than bilevel pressure
Peter, JV, et al, “Effect of NIPPV on mortality in patients with acute
cardiogenic pulmonary edema.” Lancet, 2006; 367(9517): 1155-1163.
Confalonieri, M., et al, “Acute respiratory failure in pts with severe
CAP.” AJRCCM 1999; 160 (1585-91).
Who shouldn’t receive NPPV?
• Patients with significant MS impairment
(GCS<11)
• APACHE > 28
• Profound tachypnea
• No improvement in acidosis after 1-2 hours
of therapy
Confanlonieri, M., et al, “A chart of failure risk for noninvasive
ventilation in patients with COPD exacerbation.” Eur Respir J.,
2005; 25(2):348-55..
Who shouldn’t receive NPPV?
• Patients with significant MS impairment
(GCS<11)
• APACHE > 28
• Profound tachypnea
• No improvement in acidosis after 1-2 hours
of therapy
Confanlonieri, M., et al, “A chart of failure risk for noninvasive
ventilation in patients with COPD exacerbation.” Eur Respir J.,
2005; 25(2):348-55..
Who shouldn’t receive NPPV?
•
•
•
•
•
Cardiopulmonary arrest
Upper GI bleed
Vasopressor dependence
Upper airway / facial trauma
Inability to handle secretions
What to start and how to start it
• CPAP clearly improves oxygenation, whereas
bilevel pressure better for muscular fatigue and
hypercapnia
– Start CPAP at 5 cm of water pressure and titrate to
patient comfort / tolerance and oxygenation
– Start bilevel pressure at 10/5 cm of water pressure
and titrate to comfort / work of breathing
assessment
• Can also use pCO2 to follow, but requires serial ABG
Soroksky, A, et al, “A pilot prospective randomized placebo-controlled trial
of bilevel PAP in acute asthmatic attack.” Chest, 2003; 123(4): 1018-25.
Topic 2: The Treatment of
Ventilator-Associated Pneumonia
• Guidelines divide patients into two separate
groups
– No risk factors for multi-drug resistant
pathogens
– Known risk factors
ATS / IDSA Guidelines for the management of adults with HAP, VAP and HCAP,
AJRCCM, 2005; 171: 388.
Risk Factors for MDR Pathogens
• Antibiotic therapy in prior 3 months
• In-hospital X 5+ days currently, or 2+ days in
prior 3 months
• High frequency of abx resistance locally
• Immunosuppressed state
• SNF resident
• Chronic dialysis
• Contact of an MDR patient
• Open wound
ATS / IDSA Guidelines for the management of adults with HAP, VAP and HCAP,
AJRCCM, 2005; 171: 388.
Treatment options for low-risk
patients
• Ceftriaxone
• Levofloxacin, moxifloxacin or ciprofloxacin
• Ampicillin / Sulbactam
ATS / IDSA Guidelines for the management of adults with HAP, VAP and HCAP,
AJRCCM, 2005; 171: 388.
Treatment options for high-risk
patients
• Cephalosporin with antipseudomonal
activity (cefepine or ceftazidime)
• Imipenem or meropenem
• β -Lactam + β-Lactamase inhibitor PLUS
an antipseudomonal fluoroquinolone (levo
or ciprofloxacin) or aminoglycoside
• Add vancomycin or linezolid if MRSA is of
high incidence locally (10%+, in my
opinion)
ATS / IDSA Guidelines for the management of adults with HAP, VAP and HCAP,
AJRCCM, 2005; 171: 388.
Follow-up treatment
• If clinically improved:
– Cultures negative – consider stopping antibiotics
– Cultures positive – Narrow antibiotics, total Rx 7 days
target
• If not clinically improved:
– Cultures negative – Search for other dx, reculture
– Cultures positive – Adjust abx therapy, look for other
site of infection
ATS / IDSA Guidelines for the management of adults with HAP, VAP and HCAP,
AJRCCM, 2005; 171: 388.
Topic 3: Corticosteroid
Administration in Septic Shock
• Data demonstrated an association between
outcomes and serum cortisol levels in septic patients
– Higher baseline cortisol predicted worse outcomes
– A positive response to ACTH predicted a good
outcome
• Most clearly documented benefit was in shock
reversal
Winter, W., et al, “Hydrocortisone improved hemodynamics and fluid requirements in
surviving, but not non-surviving, severely burned patients.” Burns, 2003; 29:717-20.
Figure 2 and Figure 3, page 727, Briegel J, Forst H, Haller M, et al. Stress doses of
hydrocortisone reverse hyperdynamic septic shock: A prospective, randomized, doubleblind, single-center study. Crit Care Med 1999; 27:723-732
Corticosteroid Administration in
Septic Shock
• Practice-changing trial:
– Three hundred patients with septic shock refractory to
vasopressors
– Tested for adrenal responsiveness with ACTH
• Non-responders identified by <9 point response
– Administered glucocorticoid and mineralocorticoid
supplementation regardless of results
– Primary outcome was 28-day survival
Annane, D., et al, “Effect of treatment with low doses of hydrocortisone and
fludrocortisone in patients with septic shock.” JAMA, 2002: 288(7), 862-871
Annane, D., et al, “Effect
of treatment with low doses
of hydrocortisone and
fludrocortisone in patients
with septic shock.” JAMA,
2002: 288(7), 862-871.
CORTICUS
• Randomized controlled trial of 500 patients
– Hydrocortisone 50 mg q6 hours X 5 days, followed by
a 6 day taper versus placebo
– No difference in 28-day mortality among all subjects
(34.3% vs 31.5%, p=0.51)
– No difference in 28-day mortality among RAI patients
(39.2% vs 26.1%, p=0.69)
– Shorter duration of shock with steroids
– Increased risk of hyperglycemia (SS), recurrent sepsis
(NS) and recurrent shock (SS) in active therapy
subjects
Sprung, CL, et al, “Hydrocortisone therapy for patients
with septic shock.” NEJM 2008; 358:111-24.
Annane vs. CORTICUS
• Annane’s trial
– Subjects had more frequent use of etomidate
(24%)
• Higher incidence of relative adrenal insufficiency
than in CORTICUS
– Subjects had a higher average dose of pressors
at enrollment
– Used fludrocortisone
So where are we with this?
• More unclear than ever
• Current advisory is to implement a
combination of hydrocortisone and
fludrocortisone if a patient remains
hypotensive with presumed septic shock for
more than an hour after administration of
appropriate fluids and pressors
• Clearly will reverse shock sooner
Surviving Sepsis Guidelines: 2008 update, Crit Care
Medicine, January, 2008.
Should patients without relative
adrenal insufficiency be excluded
from therapy?
• “Current data do not provide sufficient
evidence that low doses of corticosteroids
are harmful in patients without RAI and
sepsis.”
• Fludrocortisone is optional, unless
hydrocortisone is not being used as the
glucocorticoid
– No study of HC vs HC + FC planned for now
Surviving Sepsis Guidelines: 2008 update, Crit Care
Medicine, January, 2008.
Topic 4: The Controversy over
Glycemic Control
• Stress Diabetes
–
–
–
–
Peripheral insulin resistance
Increased insulin levels
Increased gluconeogenesis
Decreased glucose uptake by peripheral cells
Van Den Berghe, G., et al, “How does blood glucose control with insulin save lives in
intensive care?” J Clin Invest, 2004; 114:1187-1195.
Worsened outcomes due to
hyperglycemia
• Increase in mortality after MI
• Increase in mortality and delay in extubation s/p
cardiac surgery
• Increase in mortality, length of ICU stay, length of
hospital stay, infection rate, need for mechanical
ventilation in trauma patients
• Increase in mortality and worsened neurologic
function after stroke
Capes, SE, et al, Lancet, 2000; 355:773-8.
Suematsu, Y, et al, Heart and Vessels, 2000; 15: 214-20.
Muhlestein, JB, et al, Am Heart J, 2003; 146: 351-8.
Leuven I
• 1,548 subjects admitted to ICU after surgery
or trauma randomized to intensive vs.
standard glycemic control
– Patients enrolled only if expected to be in ICU
5+ days
– Target glucose – 80-110 mg/dl
Van Den Berghe, G., et al, “Intensive insulin therapy in
critically ill patients.” NEJM, 2001; 345: 1359-67..
Relative
mortality
reduction
(after
adjustment) of
32%, p <0.04
(8% → 4.6%)
Similar
benefits in
hospital
mortality,
infection,
renal failure
and
neuropathy
Van den Berghe, G., et al, “Intensive insulin therapy in
critically ill patients.” NEJM, 2001: 345, 1359-1367.
Leuven II
• 1,200 medical ICU patients enrolled
– Expected to stay in ICU 3+ days
– No significant change in hospital mortality
amongst all enrollees
– Decreased ventilator time, renal morbidity, ICU
LOS, and hospital survival amongst the
subgroup that actually stayed in the ICU 3+
days
Van den Berghe, G, et al, “Intensive insulin therapy in the medical
ICU.” NEJM, 2006; 354: 449-61.
VISEP
(Efficacy of Volume Substitution and Insulin Therapy in Severe
Sepsis)
• 2X2 study design
– Tested both glycemic control regimen and
resuscitation therapy (LR vs pentastarch)
• Intensive insulin therapy stopped at first
interim analysis for safety concerns
– 17% rate of severe hypoglycemia vs 4.1%
– No significant change in mortality
• Prior “Glucontrol” study had similar
problems
Brunkhorst, FM, et al, “Intensive insulin therapy and pentastarch
resuscitation in severe sepsis.” NEJM, 2008; 358: 125-39.
Risk of hypoglycemia in Leuven
studies
• Leuven I -- 0.8% → 5.1%
• Leuven II -- 3.1% → 18.7%
– More common amongst patients with sepsis
(which is more common in MICU than SICU)
• Why the differences between Leuven and
elsewhere?
– Single center vs. real world
Recommendations on glycemic
control in the ICU
• Most good-quality data support intensive insuling
therapy to achieve a BG < 110 mg/dl
• More impressive benefits amongst patients with
higher lengths of stay
• Can this be practically implemented without harm
in a multicenter trial?
• Some data that POC glucometers overestimate
plasma glucose
• Probably reasonable to target glucose levels of
80-150 mg/dl
NICE SUGAR
• Normoglycemia in Intensive Care Evolution
and Survival Using Glucose Algorhythm
Regulation
• Target BG < 150
• The best study acronym ever
Topic 5: The Controversy over
Drotrecogin Alfa in the Management
of Sepsis
• Endogenous anticoagulant
– Inhibits thrombosis and promotes fibrinolysis
• Conversion of protein C to APC impaired during
sepsis
• Reduced levels of APC in septic patients
associated with higher risk of death
• ? Mediates tissue damage with increased
formation / persistence of microvascular clots
PROWESS trial
• 1,690 patients with severe sepsis
randomized to APC or placebo
– Continuous infusion 24 mcg/kg/hr X 96 hours
– Primary outcome was all-cause mortality at 28days
Bernard, G.R., et al, “Efficacy and safety of recombinant human activated protein C
for severe sepsis.” NEJM, 2001: 344(10), 699-709.
ADDRESS trial
• 11,500 subjects judged to be at low risk of
death at enrollment (no other definition)
– Randomized to APC or placebo
– Primary outcome – 28-day mortality
• Study stopped after 2,613 enrolled given
small chance of showing benefit
– Increased serious bleeding risk in APC group
Abraham, E, et al, “Drotrecogin alfa for adults with severe sepsis at low risk of
death.” NEJM, 2005; 353:1332-1341.
RESOLVE trial
• Investigated the safety and efficacy of APC
in children
– Randomized to APC or placebo
– Primary outcome – CTCOFR (Composite time
to complete organ failure resolution)
• 28-day mortality too infrequent
• Study stopped after interval analysis
showed little chance of demonstrating
efficacy
Nadel, S, et al, “Drotrecogin alfa (activated) in children
with severe sepsis.” Lancet, 2007; 369: 836-43.
Concerns about PROWESS
• Trial protocol changed midstream
– 720 subjects in phase I
– 970 subjects in phase II
• Changes:
– Septic shock or severe sepsis, changed to severe sepsis
only
– Placebo changed from NS to 0.1% albumin
– Change in manufacturing process of the product
• The protocol change was not reported in the initial
manuscript
Concerns about PROWESS
• Before the protocol change:
– Activated protein C had no SS effect on 28-day
mortality (RR 0.94)
• After the protocol change
– RR 0.71
• Overall
– RR 0.81
• So if ADDRESS and RESOLVE were
stopped early, why wasn’t PROWESS?
Summary of Controversies over
Activated Protein C
• Still recommend its use if “significant” risk of
death exists (APACHE > 25, according to some)
and if risk of bleeding considered safe
– Exclusions clearly include recent surgery, GI bleeding,
intracranial trauma or thrombocytopenia (<30K)
• Major issues with its use
– Bleeding risk (1.4% increase in serious bleeding)
– Expense
• Need to hold infusion for two hours before
procedures
Topic 6: The Role of Vasopressin in
the Management of Hypotension
• AKA anti-diuretic hormone (ADH)
– Direct vasoconstrictor of systemic vasculature
• No clear inotropic or chronotropic effect
– Enhances the sensitivity of vasculature of other
vasopressure agents
– May cause mesenteric vasoconstriction
Ram, FS, et al, “Non-invasive positive pressure ventilation for treatment of
respiratory failure due to exacerbations of COPD.” Cochrane Database, 2004 (3).
The role of vasopressin
Circulating Vasopressin Levels in Septic Shock
Figure 2, page 1755 reproduced with permission from Sharshar T, Blanchard A, Paillard
M, et al. Circulating vasopressin levels in septic shock. Crit Care Med 2003; 31:1752-1758
– available at survivingsepsis.org, accessed March 4, 2007
VASST trial (unpublished)
• 779 subjects with septic shock on pressors
X 6+ hours and at least one new organ
dysfunction
– Randomized to NE or NE+VP
– No difference in 28-day mortality
– Amongst patients started on <15 mcg/min NE,
mortality better with addition of VP (26.5% vs
35.7%, p=0.05); persisted at 90 days (p=0.04)
• The opposite group in which they expected to find it
– More digital ischemic in VP group (p=0.06)
The role of vasopressin
• “Vasopressin… may be added to NE … with
antivipation of an effect equivalent to that of NE
alone.”
• Dosed at 0.03 units/minute
– DO NOT TITRATE!
• Use in patients with presumptive septic shock on a
“moderate dose” of another pressor… NOT AS A
FIRST AGENT!
– ? Use earlier than we thought
– Use with caution in patients with significant myocardial
dysfunction (CI < 2 lpm/m2)
Surviving Sepsis Guidelines: 2008 update, Crit Care
Medicine, January, 2008.
Controversies addressed
1. What are the indications for non-invasive ventilation in the
acute setting?
2. What are the common organisms causing ventilator
associated pneumonia, and what is recommended first line
therapy?
3. Which patients benefit from corticosteroids in sepsis?
4. What should be the target glucose in the ICU and how best
can it be achieved?
5. Which patients with sepsis should be given drotrecogin alfa?
6. What is the role of vasopressin in the septic patient?
Thank you for the invitation to
present, and for your kind
attention!