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  • Most normal cells have two copies of the HER2 gene and small amounts of HER2 protein on their surfaces (Hynes and Stern, 1994).
    For reasons not currently known, cells may produce many copies of the HER2 receptor, a condition known as overexpression.
    HER2 protein overexpression is associated with increased cell division and a high rate of tumor growth. It may also be associated with transformation to the cancer cell phenotype (Kraus et al, 1987; DiFiore et al, 1987; Hudziak et al, 1987).
    HER2 protein overexpression has been reported in malignancies other than breast cancer, including
    ovarian cancer (Slamon et al, 1989)
    gastric cancer (Yonemura et al, 1991)
    colon cancer (Holzmann et al, 1992)
    endometrial cancer (Hetzel et al, 1992; Saffari et al, 1995)
    lung cancer (Kern et al, 1993; Pastorino et al, 1993)
    salivary gland cancer (Press et al, 1994)
    pancreatic cancer (Peiper et al, 1997)
    prostate cancer (Ross et al, 1997; Zhang et al, 1998)
    The significance of HER2 protein overexpression in these cancers is not yet known.
  • Rivers et al conducted a randomized, non-blinded trial of standard therapy vs early, goal-directed therapy (EGT) in patients with SIRS criteria and systolic blood pressure (BP) 90 mm Hg unresponsive to 20 mL/kg of crystalloids, or a lactate 4 mmol/L.
    Two hundred and sixty-three patients met the entry criteria and were randomized to either standard therapy (n=133) or EGT (n=130).
    Patients were monitored by vital signs, laboratory data, cardiac monitoring, pulse oximetry, urinary catheterization, arterial and central venous catheterization.
    Standard therapy was administered by protocol with critical care consultation and consisted of measures to maintain a CVP of 8-12 mm Hg, MAP 65 mm Hg, and UOP of 0.5 mL/kg/hr.
    Patients randomized to EGT received an oximetric central venous catheter (CVC) capable of measuring SVO2 and were treated early in the emergency department according to protocol for at least 6 hours before they were transferred to the first available inpatient bed.
    Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
  • Patients treated with EGT received approximately 1.5 liters of fluids during the first 6 hours (3500 vs 5000 mL). In addition, patients treated with EGT received significantly more RBC transfusions (64.1% vs 18.5%).
    There were no significant differences in vasopressor support during the first 6 hours; however, the EGT group received significantly more vasopressors after 7 hours than did the standard group. While less than 1% of the standard group was treated with an inotrope, almost 14% of the EGT groups received dobutamine.
    Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
  • Patients treated with EGT had a significant mortality benefit while in the hospital (30.5% vs 46.5%; P=0.009), at 28 days (33.3% vs 49.2%; P=0.01), and at 60 days (44.3% vs 56.9%; P=0.03).
    There were no significant differences in the two groups in the mean duration of vasopressor therapy, mean duration of mechanical ventilation, or the mean length of stay.
    The number needed to treat (NNT) with EGT to prevent one death was calculated to be 6 to 8 patients.
    Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
  • This slide illustrates the study design of the combination of hydrocortisone and fludrocortisone on mortality in septic shock study. A short corticotropin stimulation test was performed in all patients by intravenously injecting 0.25 mg of tetracosactrin; blood samples were taken immediately before the test (T0) and 30 (T30) and 60 (T60) minutes afterward, and then the patients were randomized to steroids or placebo.
    Annane D. Effects of the combination of hydrocortisone (HC) -fludrocortisone (FC) on mortality in septic shock [abstract]. Crit Care Med 2000;28(suppl):abstract 63.
  • A total of 299 patients were included (placebo: 149, intervention: 150). Of these, 229 were non-responders; a response was seen in the remainder. At baseline, the two groups had similar demographic characteristics, severity scores, biochemical, hormonal and microbiological variables.
    Treatment with this regimen produced a 30% decrease in the risk of death in patients with septic shock. This effects reflects treatment benefits in septic shock patients who are nonresponders to ACTH. However, the use of steroids for this indication has not been approved by the FDA.
    Annane D. Effects of the combination of hydrocortisone (HC) -fludrocortisone (FC) on mortality in septic shock [abstract]. Crit Care Med 2000;28(suppl):abstract 63.
  • Transcript

    • 1. ASSESSMENT OF THE PATIENT WITH A LOW BLOOD PRESSURE Peter E. Morris, MD, FACP, FCCP Pulmonary & Critical Care Medicine Wake Forest University School of Medicine Winston Salem, NC
    • 2. ASSESSMENT OF THE PATIENT WITH A LOW BLOOD PRESSURE What is an abnormal blood pressure? HYPOVOLEMIA HYPOTENSION SHOCK ADEQUATE PERFUSION
    • 3. BLOOD PRESSURE GOAL MAP vs Systolic? MAP = 60-70 mmHg Systolic = >90
    • 4. CEREBRAL PERFUSION PRESSURE (CPP) MAP-ICP = CPP •65-5 = 60 mmHG •<60 ↑ risk of brain ischemia •and neuronal damage
    • 5. Normal Hypertensive Relative CBF (Autoregulation) 50 100 150 200 MAP
    • 6. SHOCK • Cardiogenic • Neurologic • Distributive • Hypovolemic
    • 7. SHOCK • Preshock —known as warm shock or compensated shock • homeostatic mechanisms rapidly compensate for diminished perfusion • Despite a 10 percent reduction in total effective blood volume, a previously healthy adult may be asymptomatic • Tachycardia, peripheral vasoconstriction, modest decrement in systemic blood pressure
    • 8. SHOCK • Shock — During this stage, regulatory mechanisms are overwhelmed - signs and symptoms of organ dysfunction appear: tachycardia, tachypnea, metabolic acidosis, oliguria, cool and clammy skin. • A 20 to 25 percent reduction in effective blood volume
    • 9. REASONS FOR SHOCK •Hemorrhage •Myocardial dysfunction (cardiomyopathy, ischemia, pharmacologic, toxic, valvular) •Circulatory obstruction (pulmonary embolus, cardiac tamponade, pneumothorax)
    • 10. •Hypovolemia (gastrointestinal [GI], insensible losses) •Central sympathetic disruption (Drug overdose) •Arteriovenous fistula (cont’d) REASONS FOR SHOCK
    • 11. Vascular Endothelial Cell Dysfunction/Disruption •Sepsis (bacterial, viral, fungal) •Anaphylaxis •Dyshemoglobinemia (carbon monoxide, methemoglobinemia) •Cellular poisons (cyanide sulfur, iron, lithium) •Traumatic or massive tissue destruction •Heat shock, Hypothermia REASONS FOR SHOCK
    • 12. Compensatory reflexes may be more prominently demonstrated in young adults. Considerable variability exists at extremes of age Most notably, younger individuals are able to maintain normal blood pressure until cardiovascular decompensation is imminent Age Variation
    • 13. FOR MOST** ACUTELY HYPOTENSIVE PTS: if PULMONARY EDEMA (-) then FLUID CHALLENGE IS AN APPROPRIATE FIRST RESPONSE
    • 14. FLUID CHALLENGE? BOLUS OF FLUID? 1. HOW MUCH? 2. HOW FAST? 3. LENGTH OF TUBING 4. DIAMETER OF CATHETER 5. LENGTH OF CATHETER 6. PRESSURE BAGS
    • 15. LOW URINE OUTPUT DEHYDRATION INTRAVASCULAR VOLUME HYPOTENSION A Spectrum of Severity
    • 16. DURING RESUSCITATION REMEMBER TO MONITOR: MENTAL STATUS VITAL SIGNS (MAP - O2 SATS) URINE OUTPUT SKIN PERFUSION (LACTATE)
    • 17. SHOCK RESUSCITATION • Golden Rule – early 1960s Parkland Hospital, Dallas TX First hour post-trauma – attention to blood pressure improves outcome • Traditionally, Internal Medicine-trained critical care practitioners: – Never heard of Golden Rule? – Fear of Volume resuscitation? 2o Fear of CHF or Intubation?
    • 18. 01/30/15 18 Sepsis: Defining a Disease Continuum SIRS – Temperature ≥38o C or ≤36o C – HR ≥90 beats/min – Respirations ≥20/min – WBC count ≥12,000/mm3 or ≤4,000/mm3 or >10% immature neutrophils SepsisSepsisInfectionInfection SevereSevere SepsisSepsis • Sepsis with ≥1 sign of organ failure – Cardiovascular (refractory hypotension) – Renal – Respiratory – Hepatic – Hematologic – CNS – Unexplained metabolic acidosis Shock Mechanical Ventilation Acute Dialysis
    • 19. Early Goal-Directed Therapy for Septic Shock • Randomized, non-blinded trial of traditional vs early goal-directed therapy (EGT) –Septic shock unresponsive to 20 mL/kg crystalloids, or –Lactate ≥4 mmol/L • Standard –CVP ≥8-12 mm Hg –Vasopressors for SBP ≤90 mm Hg –Maintain UOP ≥0.5 mL/kg/hr –MAP ≥65 mm Hg • Goal-directed –Above, plus –Patients monitored with CVP and SVO2 –If SVO2 <70% •RBCs until Hct ≥30% •If SVO2 still <70%, add dobutamine to dose of 20 Rivers E, et al. N Engl J Med 2001;345:1368-77.
    • 20. O2 Delivery & Uptake during Severe Sepsis • D-O2 = Cardiac Output x Hgb x O2 sat • V-O2 = Body’s uptake of oxygen • As blood circulates from arteries – capillaries – veins: oxygen content decreases • Response to increase tissue demand (exercise, illness) = ↑cardiac output, ↑ O2 extraction
    • 21. O2 Delivery & Uptake during Severe Sepsis • Crude estimate of O2 extraction is Arterial O2 sat minus Venous O2 sat • Normal arterial O2 sat = > 95% Normal mixed venous O2 sat = 75% • For Severe Sepsis Pt in shock: if mixed venous O2 sat = 50%, suspicion that tissue O2 needs may not be met
    • 22. Arterial Hemoglobin-O2 saturation Nl = 95% O2 content high Mixed venous hemoglobin-O2 saturation (SVO2) Nl = 70-75% O2 content low
    • 23. Arterial Hemoglobin-O2 saturation Nl = 95% O2 content high Mixed venous hemoglobin-O2 saturation (SVO2) <70% O2 content very low Flow-dependent O2 Uptake
    • 24. 0% 25% 50% 75% RBCs Dobutamine Traditional EGT EGT Pts Received More Fluids, RBCs and Dobutamine Rivers E, et al. N Engl J Med 2001;345:1368-77. Pressors Fluids in mL First 6 hours 0 1000 6000 2000 3000 4000 5000 Patients Receiving Treatment (%)
    • 25. 0 10 20 30 40 50 60 In-hospital mortality (all patients) 28-day mortality 60-day mortality Standard Therapy EGT Early Goal-Directed Therapy for Septic Shock • EGT* in patients with severe sepsis produced the following: – 42% ↓ in relative risk of in-hospital and 28-day mortality (P=0.009, P=0.01) – 33% ↓ in relative risk of death at 60 days (P=0.03) • NNT to prevent 1 event (death) = 6-8 *Aggressive resuscitation begun in emergency department. Rivers E, et al. N Engl J Med 2001;345:1368-77. Mortality(%)
    • 26. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock • Sponsoring Organizations: American Association of Critical-Care Nurses, American College of Chest Physicians, American College of Emergency Physicians, American Thoracic Society, Australian and New Zealand Intensive Care Society, European Society of Clinical Microbiology and Infectious Diseases, European Society of Intensive Care Medicine, European Respiratory Society, International Sepsis Forum, Society of Critical Care Medicine, Surgical Infection Society, • Crit Care Med 2004; 32:858–873
    • 27. 6 & 24 Hour Severe Sepsis BUNDLES • 6 Hour: – Dx – Lactate – Antibiotics – Fluids – CVP – MAP>65 – mvO2 sat • 24 Hour: – Glc<150 – Vent Plat Press<30 – APC considered – Adrenal Evaluation
    • 28. NUMBER OF ADMISSIONS November & December vs. March Group # Admissions November 110 December 108 218 March 130 130
    • 29. Number of patients with Severe Sepsis Group # Severe Sepsis November 27 December 25 March 45
    • 30. HOURLY BLOOD PRESSURES – MAP – Severe Sepsis Patients Median (range) Mean (std dev) November & December (n = 50) 61.72 (46.89 – 110.33) 65.82 (12.96) March (n = 44) 67.11 (47.58 – 110.61) 71.08 (14.39) P = 0.0508 Non-order (n=30) 65.94 (47.58 – 110.61) 70.46 (14.55) Order (n=14) 68.72 (57.22 – 108.0) 72.40 (14.48) p = 0.6361*
    • 31. MAP 60 65 70 75 80 85 1 2 3 4 5 6 HOUR MAP NOV/DEC MARCH-NO ORDER MARCH - ORDER
    • 32. HOURLY VOLUME OF RESUSCITATION FLUID – Severe Sepsis Patients Median (range) Mean (std dev) November & December (n = 50) 424.58 (0 – 3489.50) 604.03 (626.25) P = 0.6889* March (n=44) 452.42 (1.67 – 1588.33) 569.71 (442.48) Non-order (n=30) 403.33 (1.67 – 1498.33) 444.87 (400.96) P = 0.0014** Order (n=14) 770.58 (130.0 – 1588.3) 837.23 (491.45) *no difference in average volume between Nov/Dec & March **significant difference in average volume between order and non-order March sepsis patients Note: t-test done on log volume
    • 33. ORDER SHEET USAGE AND ADMISSION SOURCE 14 of 45 (31.11%) of the March Severe Sepsis patients had the Order Sheet Order Sheet = No Order Sheet = Yes Emergency 15 (53.57%) 13 (46.43%) WFUBMC Clinic 1 (100%) 0 Outside Hospital 11 1 Outside Emergency 0 0 Other 2 0 29 (67.44%) 14 (32.56%)
    • 34. Chart Copy NORTH CAROLINA BAPTIST HOSPITAL PHYSICIAN ORDER FORM PHYSICIANS: All orders should be w ritten generically and using the Metric System; include the physician's signature, PRINTED name, ID Number, beeper number and the date/time. A generically and therapeutically alternative drug as approved by the P & T Committee may be dispensed unless the order is specifically designated "Dispense as Written" ." Form Approved by Medical Record Informatics Technology Committee: 02/05 FAX TITLE: SEVERE SEPSIS ORDER SET – ICU (ADULT) Page 1 of 4 Consider for use with suspicion of infection and at least one organ dysfunction DATE TIME (PLEASE CIRCLE OR CHECK APPROPRIATE ORDERS AND FILL IN BLANKS AS NEEDED) DIAGNOSIS: ALLERGIES: GOALS OF THERAPY Severe Sepsis 6 Hour Bundle - starts with timing of first organ dysfunction (Refer to Page 5 of Sepsis Bundle Algorithm for organ dysfunction definitions) MAP>65 mmHg CVP >8 mmHg Urine Output >0.5 cc/kg/hour Central venous oxygen saturation 70-80% Antibiotics initiated within 1 hour 1. Admit to ICU- see separate MICU admission orders 2. Baseline Labs- STAT (if not already done in the Emergency Department or on the Floor)  CBC with diff
    • 35. DIAGNOSIS: ALLERGIES: GOALS OF THERAPY Severe Sepsis 6 Hour Bundle - starts with timing of first organ dysfunction (Refer to Page 5 of Sepsis Bundle Algorithm for organ dysfunction definitions) MAP>65 mmHg CVP >8 mmHg Urine Output >0.5 cc/kg/hour Central venous oxygen saturation 70-80% Antibiotics initiated within 1 hour 1. Admit to ICU- see separate MICU admission orders 2. Baseline Labs- STAT (if not already done in the Emergency Department or on the Floor)  CBC with diff  CMP  ABG with lactate  PT/PTT  Random Serum Cortisol Level  Type and Screen 3. Line Placement- Consider (if not already done in the Emergency Department or the Floor)  Triple lumen central venous catheter (subclavian or internal jugular)  Continous central venous oxygen saturation triple lumen catheter (PreSep catheter)  Foley catheter with hourly urine meter bag  Thermister Foley 4. Cultures (if not already done in the Emergency Department or on the Floor)  Urinalysis and Culture  Blood Cultures X 2 (if central line present, may draw one from central line, one peripheral)  Sputum Culture and Gram Stain Other: CSF Pleural Fluid Peritoneal Fluid Wound Stool Other: _________ DATE: TIME:

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