Controversies in Hospital Medicine: Critical Care Vasopressors, Steroids, and Insulin Therapy Douglas Fish, Pharm.D. Professor of Pharmacy, University of Colorado Denver Clinical Specialist in Critical Care/Infectious Diseases University of Colorado Hospital What are the appropriate roles of dopamine, norepinephrine, and vasopressin in the management of patients requiring vasopressor therapy? Case: Vasopressors 58 y.o. man with multiple medical problems admitted to hospital for treatment of communityacquired pneumonia and sepsis Started on ceftriaxone/azithromycin, administered fluids for hypotension (MAP = 55 mm Hg) Remains hypotensive despite adequate fluid resuscitation (CVP = 11 mm Hg) Vasopressors to be initiated for refractory hypotension Which of the following should be initially started? A. Dopamine B. Norepinephrine C. Vasopressin D. Norepinephrine + Vasopressin
Vasopressors for Septic Shock Maintain MAP 65 mm Hg (Grade 1C) Norepinephrine and dopamine are the initial vasopressors of choice (Grade 1C) Epinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shock (Grade 2C) Vasopressin 0.03 units/min may be subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone Do not use low-dose dopamine for renal protection (Grade 1A) Dellinger RP, et. al. Crit Care Med 2008, 36: 296-327. Comparison of Dopamine and Norepinephrine in the Treatment of Shock Multicenter, randomized trial evaluated 1679 patients receiving either dopamine ( 20 mcg/kg/ min) or norepinephrine ( 0.19 mcg/kg/min) as first-line vasopressor therapy Primary outcome: 28-day mortality No significant difference in mortality rates was seen between DA and NOR groups (52.5% vs. 48.5%, P = 0.10) Subgroup analysis showed higher rates of death with DA among patients with cardiogenic shock (P = 0.03) More arrhythmic events among DA-treated patients (24.1% vs. 12.4%, P <0.001) DeBacker D et al. NEJM 2010;362:779-789.
Vasopressin and Septic Shock Trial (VASST) Multicenter, randomized, double-blind study investigating vasopressin 0.01-0.03 units/min vs. norepinephrine as add-on therapy Primary Hypothesis: Low dose vasopressin decreases 28-day mortality compared to norepinephrine Secondary Hypothesis: Beneficial effects of vasopressin more pronounced in patients with more severe septic shock ( 15 µg/min NE) Patients: severe septic shock with NE 5 mcg/min for 6/24 hrs VASST: Kaplan-Meier Survival Curve All Patients Log-rank statistic p = 0.27 day 28 p = 0.10 day 90 VASST: Kaplan-Meier Survival Curve More Severe Shock Log-rank statistic p = 0.77 day 28 p = 0.92 day 90
VASST: Kaplan-Meier Survival Curve Less Severe Shock Log-rank statistic p = 0.05 day 28 p = 0.03 day 90 VASST Interpretations Efficacy: Low dose vasopressin (0.03 U/min) plus NE similar to NE alone in septic shock Safety: Low dose vasopressin plus NE similar in safety to NE alone Subgroup: Vasopressin plus NE may decrease mortality vs. NE alone in less severe septic shock Post-hoc analysis also suggests that vasopressin may reduce progression to renal failure and need for RRT in patients at high risk of AKI (Gordon AC et al. Intensive Care Med 2009; published online 10/20/99.) Case: Vasopressors 58 y.o. man with multiple medical problems admitted to hospital for treatment of communityacquired pneumonia and sepsis Started on ceftriaxone/azithromycin, administered fluids for hypotension (MAP = 55 mm Hg) Remains hypotensive despite adequate fluid resuscitation (CVP = 11 mm Hg) Vasopressors to be initiated for refractory hypotension Which of the following should be initially started? A. Dopamine B. Norepinephrine C. Vasopressin D. Norepinephrine + Vasopressin
What are the current recommendations for use of corticosteroids in the management of patients with sepsis? Case: Steroids The 58 y.o. male in the previous case was started on norepinephrine Hypotension persists despite high-dose norepinephrine and continued administration of fluids Vasopressin is added, and the initiation of steroids is also being considered What would be the most appropriate choice regarding the use of steroids in this patient? A. Steroids should not be used due to lack of benefit B. Perform an ACTH stimulation test and check results prior to steroid administration C. Perform an ACTH stimulation test and give steroids while waiting for results D. Administer steroids without performing an ACTH test Sepsis Cascade Pro-inflam. Mediators Inflammation Anti-inflam. Mediators Thrombin Thrombomodulin Infection Coagulation TF Endothelial Injury TAFI t-pa PAI-1 inhibits stimulates or activates Fibrinolysis
Potential Benefits of Exogenous Corticosteroids Reverse adrenal insufficiency and overcome corticosteroid resistance Directly and indirectly inhibit NF-κB to: reduce inflammation and restore cytokine homeostasis reduce production of NO and increase adrenergic receptor density Inhibit late inflammation to reduce production of direct vasodilators (PGE 1 and prostacyclin) Patients with Relative Adrenal Insufficiency (77%) Patients Without Relative Adrenal Insufficiency (23%) 28-day Mortality N=114 N=115 N=36 N=34 Low-dose Steroids Placebo Annane, D. JAMA, 2002; 288:868 CORTICUS: Comparisons with the Annane Study Annane JAMA 2002;288:862-71 CORTICUS NEJM 2008;358:111-24 Adrenal Insufficiency (%) 76.6% 46.7% 28-Day Mortality (%) All Patients Adrenally Sufficient Adrenally Insufficient 28-Day Shock Reversal (%) All Patients Adrenally Sufficient Adrenally Insufficient Median Time to Shock Reversal, days All Patients Adrenally Sufficient Adrenally Insufficient * p < 0.05 PL: 61% vs. HC: 55% * PL: 53% vs. HC: 61% PL: 63% vs. HC: 53% * PL: 43% vs. HC: 55% * PL: 53% vs. HC: 50% PL: 40% vs. HC: 57%) * PL: 9 vs. HC: 7 * PL: 7 vs. HC: 9 PL: 10 vs. HC: 7 * PL: 32% vs. HC: 34% PL: 29% vs. HC: 29% PL: 36% vs. HC: 39% PL: 74% vs. HC: 80% PL: 77% vs. HC: 85% PL: 70% vs. HC: 76% PL: 5.8 vs. HC: 3.3 * PL: 5.8 vs. HC: 2.8 * PL: 6 vs. HC: 3.9 *
Corticosteroids for Sepsis Consider hydrocortisone for adult septic shock when hypotension responds poorly to adequate fluid resuscitation and vasopressors (Grade 2C) ACTH stimulation test is not recommended to identify the subset of patients with septic shock who should receive hydrocortisone (Grade 2B) Steroid therapy may be weaned once vasopressors are no longer required (Grade 2D) Hydrocortisone dose should be 300 mg/day (Grade 1A) Dellinger RP, et. al. Crit Care Med 2008, 36: 296-327. Case: Steroids The 58 y.o. male in the previous case was started on norepinephrine Hypotension persists despite high-dose norepinephrine and continued administration of fluids Vasopressin is added, and the initiation of steroids is also being considered What would be the most appropriate choice regarding the use of steroids in this patient? A. Steroids should not be used due to lack of benefit B. Perform an ACTH stimulation test and check results prior to steroid administration C. Perform an ACTH stimulation test and give steroids while waiting for results D. Administer steroids without performing an ACTH test What is the most appropriate goal for blood glucose values in critically ill patients?
Case: Insulin Therapy 34 y.o. male is admitted to ICU with multiple injuries after a motor vehicle accident Injuries include fractured pelvis, compound fractures of both femurs, fractured ribs, hepatic laceration Past medical history significant for Type I DM and hypertension (well controlled with medications) What is the most appropriate target value for blood glucose in this ICU patient? A. 80-110 mg/dl B. 110-150 mg/dl C. <180 mg/dl D. < 250 mg/dl Glycemic Control Important for Stress- Induced Hyperglycemia Potential benefits of aggressive glucose control: May exert anti-inflammatory effect during critical illness May protect against multiple organ dysfunction May decrease incidence of polyneuropathy May decrease hyperglycemia-mediated immune dysfunction May decrease hospital-acquired infections
15% 15% 10.9% Mortality (%) 10% 5% 0% n=783 n=765 Conventional 10% 5% 0% Conventional 7.2% Intensive Insulin n=783 n=765 Intensive Insulin van den Berghe G. N Engl J Med 2001;345:1359-1367. Other Benefits of Aggressive Insulin Therapy in SICU Patients In addition to significantly reduced mortality: 46% decrease in bloodstream infection 41% decrease in acute renal failure requiring dialysis or hemofiltration 50% decrease in number of RBC transfusions 44% decrease in critical-illness polyneuropathy van den Berghe G. N Engl J Med 2001;345:1359-1367. Intensive Insulin Therapy in the Medical ICU Prospective, randomized, controlled study patients Patients assigned to receive conventional insulin therapy vs. intensive insulin with goal blood glucose of 80-110 mg/dl 1,200 patients included in the intent-to-treat analysis: Intensive insulin therapy significantly reduced blood glucose levels but was not associated with reduction in mortality compared to placebo (37.3% vs. 40.0%, respectively; P=0.33) Other endpoints significantly reduced (new renal dysfunction, days on ventilator, days to ICU and hospital discharge) Mortality significantly reduced among patients in ICU for 3 days (52.5% vs. 43.0%, P=0.009) Mortality increased among patients in ICU <3 days (not statistically significant when adjusted for severity of illness) Van den Berghe G, et al. NEJM 2006;354:449-461.
The NICE-SUGAR Study (NEJM 2009;360:1283-1297) ICU patients randomized to receive insulin in order to achieve intensive control (IC, target blood glucose 81-108 mg/dl) or conventional control (CC, target BG <180 mg/dl) 6,022 evaluable patients with similar baseline characteristics 90-day mortality = 27.5% IC vs. 24.9% CC (OR 1.14, 95% CI 1.02 1.28; P = 0.02) Severe hypoglycemia = 6.8% IC vs. 0.5% CC (P <0.001) No significant differences in ICU LOS, hospital LOS, days of mechanical ventilation, days requiring renal replacement therapy Conclusion: intensive glucose control increased mortality among ICU patients Earlier SepNet study also showed significantly higher incidence of hypoglycemia and adverse effects among patients receiving intensive insulin therapy (target BG 80-110 mg/dl) Brunkhorst FM, et al. NEJM 2008;358:125-139. Case: Insulin Therapy 34 y.o. male is admitted to ICU with multiple injuries after a motor vehicle accident Injuries include fractured pelvis, compound fractures of both femurs, fractured ribs, hepatic laceration Past medical history significant for Type I DM and hypertension (well controlled with medications) What is the most appropriate target value for blood glucose in this ICU patient? A. 80-110 mg/dl B. 120-150 mg/dl C. <180 mg/dl D. < 250 mg/dl Summary Initial vasopressors for severe sepsis/septic shock: Norepinephrine most appropriate as first-line agent Dopamine equally effective but more adverse effects Vasopressin may be added in refractory patients Corticosteroids in sepsis: Appropriate in patients on vasopressors with refractory hypotension ACTH stimulation tests not routinely recommended Insulin therapy: <180 mg/dl recommended for most patients based on NICE-SUGAR study Many practitioners and Surviving Sepsis guidelines recommend <150 mg/dl Optimal goal still not entirely clear