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): 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):

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): Confalonieri, M., et al, “Acute respiratory failure in pts with severe CAP.” AJRCCM 1999; 160 ( ).

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):

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):

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):

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.

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 Topic 3: Corticosteroid Administration in Septic Shock Winter, W., et al, “Hydrocortisone improved hemodynamics and fluid requirements in surviving, but not non-surviving, severely burned patients.” Burns, 2003; 29:

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, double- blind, single-center study. Crit Care Med 1999; 27:

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 Corticosteroid Administration in Septic Shock Annane, D., et al, “Effect of treatment with low doses of hydrocortisone and fludrocortisone in patients with septic shock.” JAMA, 2002: 288(7),

Annane, D., et al, “Effect of treatment with low doses of hydrocortisone and fludrocortisone in patients with septic shock.” JAMA, 2002: 288(7),

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:

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? Surviving Sepsis Guidelines: 2008 update, Crit Care Medicine, January, 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

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:

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: Suematsu, Y, et al, Heart and Vessels, 2000; 15: Muhlestein, JB, et al, Am Heart J, 2003; 146:

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 – mg/dl Van Den Berghe, G., et al, “Intensive insulin therapy in critically ill patients.” NEJM, 2001; 345:

Van den Berghe, G., et al, “Intensive insulin therapy in critically ill patients.” NEJM, 2001: 345, Relative mortality reduction (after adjustment) of 32%, p <0.04 (8% → 4.6%) Similar benefits in hospital mortality, infection, renal failure and neuropathy

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:

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:

Risk of hypoglycemia in Leuven studies Leuven I % → 5.1% Leuven II % → 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 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

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 28- days PROWESS trial Bernard, G.R., et al, “Efficacy and safety of recombinant human activated protein C for severe sepsis.” NEJM, 2001: 344(10),

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 ADDRESS trial Abraham, E, et al, “Drotrecogin alfa for adults with severe sepsis at low risk of death.” NEJM, 2005; 353:

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 RESOLVE trial Nadel, S, et al, “Drotrecogin alfa (activated) in children with severe sepsis.” Lancet, 2007; 369:

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? Concerns about PROWESS

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 Summary of Controversies over Activated Protein C

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).

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: – available at survivingsepsis.org, accessed March 4, 2007 The role of vasopressin

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) VASST trial (unpublished)

“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/m 2 ) The role of vasopressin 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!