Major Case Presentation Septic Shock
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  • Once the bacteria invades the host, inflammatory mediators are produced which causes damage to the host tissue and activation of leukocytes. The balance to control the inflammatory mediators are lost and therefore a systemic inflammatory response develops which in turn converts the infection into sepsis, severe sepsis or septic shock. The key proinflammatory mediator is the tumor necrosis factor-α (TNF-α),interleukin-1 (IL-1), and interleukin-6 (IL-6) . The TNF-áa) is considered the primary mediator of sepsis. Once the TNFáa) is activated, it leads to the activation of IL-1 and IL-6. The TNFá also contributes to the production of Thrombaxane A2, and prostaglandins, which causes vascular endothelial damage, capillary leak, vasodilation, microvascular thrombi formation. Which in turn lead to disseminated intravascular coagulation and acute kidney injury.

Major Case Presentation Septic Shock Major Case Presentation Septic Shock Presentation Transcript

  • Pharmacotherapy of Septic Shock
    Munzur Morshed, Pharm D. candidate 2011Arnold & Marie Schwartz College of Pharmacy and Health SciencesNorth Shore- Long Island Jewish Health SystemInfectious Diseases-Advanced Pharmacy Practice
  • Case Presentation
    IMA is a 59 Y/O female, who recently had a left urethral stent placed in her left ureter two weeks ago, came to the
    emergency room complaining of left-sided flank pain for 1-2 days. Patient was noted to have vomiting for one
    day, with symptoms of headache, and anxiety. Patient had no hx. of URI, possible kidney stone is suspected.
    Patient was admitted to the ICU with septic shock secondary to left pyelonephritis, hypoxia and HOTN. Her BP
    did not respond to the fluids given in the ER. Patient is currently intubated and is monitored on the ventilator.
     
    Past Medical/Surgical history: Patient had a left urethral stent placed a few weeks
     
    Family Hx: Patient has a family history of DM and CAD.
    Allg: NKA
    Meds on admission:IV Norepinephrine 2MG/250mL;Normal Saline 1000 ML; Lovenox 40MG SQ QD; Primaxin 500MG IVPB Q6H, Flagyl 1500 mg IVPB q6H STAT, Merrem 500mg IVPB Q8H, Regular Insulin Sliding Scale, Sodium Bicarb 7.5% 44.6MEQ, Gentamicin 100 MG IVPB one/time STAT, Protonix IVPB 40 mg PO q6h; Tylenol with Codeine #3 -1T PO Q4H PRN
    PE: Temp 102.6, Pulse 114, RR 18, BP 79/50,
    Laboratory Findings: WBC 20.6, Hg 8.5, Na 131, K 2.6, Cl 2.6, CO2 24, BUN 17, Scr 1.5, Glucose 217, Ca 6.5,
    Lactate 5.2, AST/ALT 61/91, MAP 59.67, PH 7.19, HCO3 17
    Urinalysis: Protein 150, Blood Urine- Large, Leuko Ester- Moderate, Nitrites (+), WBC 10-25, Bacteria-many
    Microbiology Blood Culture: Gram (-) Rods in aerobic Bottle.
    Urine Culture: Greater than 100,000 CFU/ML Pseudomona Less than 10,000 CFU/ML of other organism
    Diagnosis: Septic Shock and Pyelonephritis secondary to Stent placement
  • Introduction
    • What is shock?
    • Life threatening state, decrease in tissue perfusion of blood supply
    • Characterized by lack of nutrient and O2 rich blood to the organs resulting in inadequate perfusion
    • Vital Signs
    • HR < 20 or > 150 bpm
    • SBP < 80 mmHg, decrease by at least 40mmHg
    • MAP < 60 mmHg
    • DBP > 120 mmHg
    • RR > 35 breaths/min
    • pH < 7.1 or >7.7
    • low urine output (<0.5ml/kg/hr ) and confusion or loss of consciousness
  • Types of Shock
    • Hypovolemic Shock
    • Loss of blood volume (plasma + RBCs)
    • External-surgery or trauma
    • Internal-GI bleeding
    • Cardiogenic Shock
    • Hearts inability to pump appropriate amount of blood
    • Decreased Cardiac Output
    • Septic Shock- Discussed in detail
    • Obstructive Shock
    • Subtype of Hypovolemic Shock
    • Increase pressure of the jugular vein distended jugular vein
    • Neurogenic Shock
    • Injury of the spine
    • Loss of cardiac nerve fibers from the sympathetic nerve fibers at T1-T4 resulting in profound bradycardia
    • Diaphoretic Skin
    • Anaphylactic Shock
    • Angioedema like reaction
    • Large Eruptions or bumpy skin
    • Edema, Massive Swelling
    • Constricted Airways; Swollen throat; Breathlessness and cough
    • Weak or rapid pulse
  • What is Septic Shock?
    • Massive Systemic infection associated with arterial hypotension that is refractory to fluid resuscitation
    • It is a systemic inflammatory Response syndrome
    • Criteria must include the following (2 out of 4)
    • WBC >12K or <4K or >10% bands
    • Temperature > 38C or < 36C
    • Heart rate > 90bpm
    • Respiratory Rate > 22 breaths/min
    • PaCO2 < 32mmHg
    • Systemic Infection- Any etiology
    • Bacterial- Presence of Bacteria in the bloodstream
    • Fungemia- Presence of Fungus in the Bloodstream
  • Epidemiology
    Defined by site of infection
    Respiratory Tract (21%-68%)
    Intraabdominal Space (14%-22%)
    Urinary Tract (14%-18%)
    Pathogens
    Gram-Positive bacteria (40% of patients)
    Gram-Negative bacteria (38% of patients)
    Fungi (17%)
  • Pathogens
    Gram-Positive Bacterial Sepsis
    Gram-Negative Bacterial Sepsis
    Most predominant in Septic Shock
    Staph. Aureus
    Strep. Pneumoniae
    Coagulase-Negative Staphylococci
    Enterococcus
    Strep. Pneumoniae- Mortality rate of more than 25%
    Staph. Epidermidis- related to infected intravascular device
    Severity depends on underlying comorbidites
    Fatal Prognosis
    Acute Leukemia
    Aplastic Anemia
    Burn Injury- >70& BSA
    Non-fatal prognosis
    Diabetes Mellitus
    Chronic Renal Insufficiencies
    Most predominant
    Escherichia coli
    Pseudomonas aeruginosis
  • Pathogens Cont…
    Anaerobes and miscellaneous bacterial Sepsis
    Fungal Sepsis
    Low risk organism but can occur
    Usually seen with other common pathogens in sepsis
    Meningococci, gonococci, rickettsiae, chlamydiae, spirochetes
    • Rate of the infection doubled since the 2000
    • Most Common pathogens
    • Candida Albicans ( Most Dominant)
    • Candida Glabrata
    • Candida Tarapsilosis
    • Candida Tropicalis
    • Candida Krusei
    • Risk factors of fungal-sepsis
    • Abdominal Surgery
    • Poorly controlled Diabetes Mellitus
    • Broad-spectrum Antimicrobials
    • Corticosteroids
    • Foley
    • Central Venous Catheter
  • Pathophysiology
  • Clinical Presentation
  • Prognosis
    • Increase mortality rate in a step-wise approach
    • SIRSSepsisSevere Sepsis Septic Shock
    • Higher mortality rates with co-morbidities
    • Advanced age
    • COPD
    • HIV
    • Pseudomonas Infection
    • Failing Organs
    • Ex. From 2 to 4 organs Increase mortality from 54% to 100%.
    • Elevated serum Lactate->4 mmol/L- Increase mortality as high as 89%
  • Goals of therapy
    Identify the source of infection.
    Control the source of infection
    Eradicate the infection
    Provide adequate hemodynamic support and tissue perfusion
    Prevent continued organ failure, complications, and/or mortality
    Provide supportive care during the length of stay in the ICU
  • Therapeutic Alternatives
    Interventions/therapies-Must be accomplished within the first 6 hours
    Cultures
    Antibiotics within 1 hour
    Measure a serum lactate
    Achieve a CVP = 8-12 mmHg
    MAP > 65 mmHg
    Maintain urine output ≥0.5 mL/kg/hr
    Achieve a ScvO2 ≥70%
  • Diagnosis and Identification of Pathogens
    • Determine the source of the infection
    • Systemic Complication
    • Recent Travel history
    • Animal Exposure
    • Use of antimicrobials
    • Two sets of Blood samples
    • Peripheral Vein- Culture in an aerobic and an-aerobic environment
    • Cather-related suspecting
    • Two sets of blood culture
    • Catheter Hub
    • Peripheral Vein
    • Abdominal infections- Fluid Collections by imaging studies
    • Lumbar Puncture- in cases of mental alteration, severe headache, or a seizure
  • Hemodynamic Monitoring
    • Mean Arterial Pressure(MAP)- Systemic Vascular Resistance x Cardiac Output
    • MAP greater than 50mmHG-Goal
    • MAP less than 50 decrease coronary and cerebral blood flow
    • Monitor Continuously- Arterial Catheter in the Radial Artery
    • Central Venous Catheter
    • Placed in 3 veins-Triple Lumen
    • Internal Jugular Vein-Neck
    • Subclavian Vein- Chest
    • Femoral Vein- Groin
    • Measures the central venous oxygen saturation- ScvO2, Central Venous Pressure (CVP)
    • Goal CVP = 8-12 mmHg during fluid resuscitation
    • Goal CVP = 12-15mmHg-in presence of mechanical ventilation
  • Hemodynamic Monitoring cont…
    • Central Venous Catheters
    • Depends on CO, Oxygen demand, SaO2 and Hemoglobin
    • Goal SaO2 = >70% in shock
    • Lower Value Inadequate O2 oxygen delivery to tissue and high extraction by tissue
    • Lactate
    • Metabolic product of Pyruvate increase production in anaerobic conditions
    • Goal= 0.5 – 2.2 mmol/L
    • Better correlation with outcomes
  • Treatment Recommendations
  • Antimicrobial Therapy
    •  Empiric parenteral aggressive antimicrobial therapy is a MUST
    • Selection of the antimicrobial depends on
    • Suspected site of infection
    • The most likely pathogens
    • Community acquired or Hospital Acquired
    • Immune status of the patient
    • Institution susceptibility profile of the ABX
    • Re-asses the regimen 48-72 hours laterSwitch to narrow spectrum based on culture and susceptibility
    • Cases of Pseudomonas, Neutropenia, severe sepsis - Combination therapy is imminent
  • Empiric Antimicrobial Therapy
  • Empiric Antimicrobial Therapy
  • Antifungal Therapy
    • Choice of therapy depends upon
    • Fungal Species
    • Presence of Liver and Kidney dysfunction-Elimination
    • Prior Exposure to anti-fungal agents
    • Treatment of Choice-
    • Amphotericin B based preparations
    • Fluconazole, Itraconazole
    • Fluconazole plus Amphotericin B
    • Voriconazole- Fluconazole resistant isolates
    • Caspofungin- Potent against all Candida Species
    • Initial Empiric Therapy-
    • parenteral amphotericin B or caspofungin
    • Better activity against Resistant fungal speicies, non-albicans; neutropenic and critically-ill patients
  • Duration of Therapy
    Variable- Site of infection
    Neutropenic- continue therapy until afebrile for 72 hours and no longer neutropenic
    Normal host with sepsis- 7 to 10 days
    Host with Fungal infection- 10 to 14 days
    Step-Down from parenteral to oral therapy
    Hemodynamically Stable
    Afebrile for 48 to 72 hours
    Normal WBC count
    Able to take PO medications
  • Fluids
    Significant Fluid Requirements due to
    Peripheral Vasodilation
    Capillary Leakage
    Mechanism of action
    Increasing left ventricular preload  maximize cardiac output restore tissue perfusion decrease in serum lactate level
    Titrate over time based on mental status,HR, BP, UOP
    Choice of Agents Crystalloids vs. Colloids
  • Fluids cont…
    Intravenous Fluids
    Dextrose- Not a crystalloid, used for uncomplicated dehydration caused by water deficit
    Crystalloids
    Freely cross the semi-permeable membrane and form crystals
    Colloids
    Increased molecular weight= Increased retention time
    Cannot pass through the semi-permeable membrane
    Eventually will leak through the membrane (e.g. 60% of albumin shifts to interstitium by day 3-5)
  • Crystalloids vs. Colloids
  • Crystalloids vs. Colloids Cont…
  • Inotropes
    Improves Cardiac Output
    Must be on board if failed therapy with fluids
    Increase risk of atrial, ventricular arrhythmias
    Increases demand of Myocardial O2 in pt.s with CAD-Caution.
    Dobutamine
    Milrinone, Nesiritide- Not used in Septic Shock
  • Inotropes cont…
    Dobutamine
    b-adrenergic inotropic agent
    b1 > b2 ≥ a1
    Vasodilatation due to stimulation of the Beta receptor
    Can be an add on to nor-epinephrine in sepsis
    2.5-5 mcg/kg/min
  • Vasopressors
    Must be on board if failed therapy with fluids
    Considered when Systolic BP < 90mmHg, MAP <60-65mmHg
    Titrate slowly to achieve MAP w/o impairing SV
    Norepinephrine, Dopamine, Epinephrine, Phenylephrine
  • Vasopressors cont…
    Norepinephrine(Levophed)
    First line agent for septic shock
    Stimulates a1,2 > b1
    Increases MAP by vasoconstriction on peripheral vascular beds
  • Vasopressors cont…
    Dopamine
    Activity against D1,2,a1 and b2 activity-Dose related
    1-3 mcg/kg/min-D1,2
    For treatment or prevention of AKI
    3-10 mcg/kg/min- D1, b1
    >10-20 mcg/kg/min- a1, b1
    Vasoconstriction AND increase MAP
    May depress ventilation, worsen hypoxemia, inhibit GH secretion and T-Cell proliferation
  • Vasopressors cont…
    • Epinephrine (Adrenaline)
    • nonspecific a and b-adrenergic agonist
    • significant peripheral vasoconstriction- Last line therapy for refractory shock
    • 1-10 mcg/min
    • Phenylephrine (Neosynephrine)
    • selective a1-agonist
    • Rapid onset, short duration, and primary vascular effects, and it is least likely to produce tachycardia
    • Limitted use- preferred in tachyarrhythmia
  • Tight Glucose Control
    Intensive Insulin Therapy
    Hyperglycemia causes phagocyte dysfunction, worsens ischemia, increases platelet activation, increases production of pro-inflammatory cytokines (Il-6, TNF-a)
    Target Goal- <140-180mg/dL (NICE SUGAR study)
    Desired Goal- < 150 mg/dL
    Regular Insulin 100 units in 100ml NS, start at 3 units/hr, check FSBS q1hr
  • Corticosteroids
    Indications
    Diagnosis of Critical Illness related corticosterioid insufficiency
    Random Cortisol < 10mcg/dL
    D Total serum Cortisol <9mcg/dL
    Refractory Septic Shock
    SBP <90mmHg for >1 hour despite fluid resuscitation, inotropes, vasopressors
    Hydrocortisone 200-300 mg/day IV divided q6-q8h ± fludrocortisones 50mcg PO daily x 7 days
  • Drotrecogin
    • Recombinant Human Activated Protein C (rhAPC)
    • Inhibits Coagulation, reduces inflammation
    • Clinical Trial- Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)
    • Reduced Mortality by 24.7% in those who received rhAPC
    • Current recommendations
    • APACHE II score ≥25, sepsis-induced multiple organ failure, septic shock, or
    • Sepsis-induced ARDS and with no absolute contraindication related to bleeding risk
    • Recommend avoid rhAPC if APACHE II < 20 or one organ failure 
  • DVT Prophylaxis
    Pharmacologic Approach
    Unfractionated Heparin
    Low Molecular Weight Heparin
    Fondaparinux
    Avoid if kidney function is impaired
    Non-Pharmacologic Approach if high risk for bleeding
    Graduated Compression Stockings (GCS)
    Intermittent Pneumatic Compression (IPC)
  • DVT Prophylaxis
    Patient Considerations
    UFH or LMWH preferred first-line
    Consider LMWH for highest risk
    E.g. Spinal Cord Injury, Trauma, Surgery
    Consider GCS or IPCs if C/I to pharmacologic prophylaxis
    Severe Risk- E.g.- Shock, Septic
    UFH or LMWH + GCS or IPC
  • Stress-Ulcer Prophylaxis
    • Pharmacologic Approach
    • Proton Pump Inhibitors (PPIs)
    • Greater acid-suppression (less evidence)
    • First line for patients with upper GI bleed
    • Histamine-2 receptor antagonists (H2RAs)
    • Most Evidence
    • Sucralfate-Sucrose octasulfate, Aluminum Hydroxide
    • Patient Considerations
    • Thrombocytopenia- Consider PPI
    • More gastric acid suppression may lead to Clostridium Difficile- associated diarrhea, pneumonia
    • PPIs are the most common cause of interstitial nephritis
    • Sucralfate may clog feeding tubes 
  • Management
    • Early goal directed therapy
    • Reach the following endpoints w/in 6 hours of onset
    • CVP=8-12mmHg, (or 12-15 if mechanically ventilated)
    • MAP ≥65mmHg, UOP ≥0.5mL/kg/hr
    • ScvO2 >70%
    • Fluid challenges with crystalloids 1000mL or colloids 300-500mL over 30 min
    • Target CVP= 8-12mmHg or (12-15 if mechanically ventilated)
    • Begin Broad-Spectrum ABX w/in 1 hour
    • Consider most likely pathogens and fungal infections based on suspected source of infection
    • Skin and Soft tissue
    • Intra-Abdominal
    • Respiratory
    • Urinary Tract
  • Management cont…
    • Vasopressors to maintain MAP ≥ 65mmHg
    • Administer centrally
    • NE or DA are first line
    • NE-1st line
    • Phenylephrine, Epinephrine, Vasopressin- Last line
    • Use epinephrine if blood pressure unresponsive to first line
    • Do not use low dose DA for renal protection
    • If ScvO2 target not reached with fluids, transfuse packed RBCs to hematocrit ≥ 30% and/or dobutamine infusion
    • Corticosteroids
    • Refractory Septic Shock
    • SBP <90mmHg for >1 hour despite fluid resuscitation, vasopressors
  • Management Cont…
    rhAPC
    Use if APACHE II ≥ 25 or multiple sepsis-induced organ failure if no C/I
    Avoid if APACHE II <20 or one organ failure
    Analgesia, sedation protocols titrated to predetermined endpoints
    DVT prophylaxis with UFH and LMWH
    Head of the bed elevation >30-45 degree angle
    SUP with PPI or H2RA
    Glycemic control with intensive insulin therapy
  • Conclusion
    • Septic Shock- Systemic Infection of any etiology
    • It is a goal directed therapy
    • Must Achieve the following parameters within the first 6 hours
    • Measured Serum Lactate
    • CVP= 8-12mmHg
    • MAP > 65mmHg
    • urine output ≥0.5 mL/kg/hr
    • ScvO2 ≥70%
    • Provide Supportive therapy
    • Treat the systemic infection
    • Monitor closely for efficacy and toxicity
  • Case Presentation
    IMA is a 59 Y/O female, who recently had a left urethral stent placed in her left ureter two weeks ago, came to the
    emergency room complaining of left-sided flank pain for 1-2 days. Patient was noted to have vomiting for one
    day, with symptoms of headache, and anxiety. Patient had no hx. of URI, possible kidney stone is suspected.
    Patient was admitted to the ICU with septic shock secondary to left pyelonephritis, hypoxia and HOTN. Her BP
    did not respond to the fluids given in the ER. Patient is currently intubated and is monitored on the ventilator.
    Past Medical/Surgical history: Patient had a left urethral stent placed a few weeks
     
    Family Hx: Patient has a family history of DM and CAD.
    Allg: NKA
    Meds on admission:IV Norepinephrine 2MG/250mL;Normal Saline 1000 ML; Lovenox 40MG SQ QD; Primaxin 500MG IVPB Q6H, Flagyl 1500 mg IVPB q6H STAT, Merrem 500mg IVPB Q8H, Regular Insulin Sliding Scale, Sodium Bicarb 7.5% 44.6MEQ, Gentamicin 100 MG IVPB one/time STAT, Protonix IVPB 40 mg PO q6h; Tylenol with Codeine #3 -1T PO Q4H PRN
    PE: Temp 102.6, Pulse 114, RR 18, BP 79/50,
    Laboratory Findings: WBC 20.6, Hg 8.5, Na 131, K 2.6, Cl 2.6, CO2 24, BUN 17, Scr 1.5, Glucose 217, Ca 6.5,
    Lactate 5.2, AST/ALT 61/91, MAP 59.67, PH 7.19, HCO3 17
    Urinalysis: Protein 150, Blood Urine- Large, Leak Ester- Moderate, Nitrites (+), WBC 10-25, Bacteria-many
    Microbiology Blood Culture: Gram (-) Rods in aerobic Bottle.
    Urine Culture: Greater than 100,000 CFU/ML Pseudomonas Less than 10,000 CFU/ML of other organism
    Diagnosis: Septic Shock and Pyelonephritis secondary to Stent placement
  • Problem List
    • Septic Shock
    • Objective
    • Heart Rate >90bmp
    • RR >22bpm
    • WBC >12,000
    • Severe HOTN
    • Elevated Lactate
    • Gram (-) rods on blood culture
    • Pyelonephritis
    • Subjective
    • Flank abdominal pain
    • Vomiting/headache/anxiety
    • Objective
    • Urinary Stent
    • Moderate Esterase
    • Pyuria
    • WBC 10-50K
    • Urine Culture: Pseudomonas and other organism
    • Metabolic Acidosis
    • Objective
    • pH less than 7.35
    • HCO3 less than 22 mEq/L
  • Medication Critique
    • Pyelonephritis
    • Gentamicin- Good Choice
    • Primaxin and Merrem- Not the DOC; therapy duplication
    • Metabolic Acidosis
    • Sodium Bicarbonate 7.5%- Good Choice
    • Septic Shock
    • The patient is receiving the appropriate fluid therapy
    • Antibiotics
    • Gentamicin- Good Choice
    • Primaxin and Merrem- Therapy Duplication
    • Flagyl- No indication
    • Vasopressors
    • Norepinephrine-DOC
    • Supportive Care
    • Glucose Control
    • Regular Insulin- Good Choice
    • Stress Ulcer Prophylaxis
    • Protonix- Good Choice
  • Recommendations
    • Septic Shock
    • Continue IV Normal Saline
    • Antibiotics
    • Tobramycin IV 500mg Q36H
    • Pseudomonal Coverage
    • Maximizes concentration-dependent killing activity
    • Ceftazadime 1 gram IV q12h
    • Excellent Gram (-) infection plus Pseudomonal Coverage
    • Vasopressors
    • Norepinephrine 1-4mcg/kg/min IV
    • Increase by 1-4 mcg/kg/min titration to the desired effect
    • Supportive Care
    • Head of the bed elevation 30-45 degree angle
    • Analgesia
    • Fentanyl 200 mcg/hr IV
    • Glucose Control
    • Regular Insulin- Good Choice
    • Stress Ulcer Prophylaxis
    • Protonix 40 mg IVPB q6h- Good Choice
    • Agitation
    • Precedex- 0.4mcg/kg/hr via IV
    • DVT Prophylaxis
    • Lovenox 40 mg SQ QD plus Compression Stockings
    • High Risk Patient
  • Recommendations
    Pyelonephritis
    Antibiotics
    Tobramycin IV 500mg Q36H
    Pseudomonal Coverage
    Maximizes concentration-dependent killing activity
    Ceftazadime 1 gram IV q12h
    Excellent Gram (-) infection plus Pseudomonal Coverage
    Metabolic Acidosis
    Sodium Bicarbonate 7.5%- Good Choice
  • Monitoring Parameters
    Efficacy
    Serum Lactate- Goal less than 2.2mmol/L
    Central Venous Pressure-8-12 mmHg
    Mean Arterial Pressure- >65 mmHg
    Maintain urine output ≥0.5 mL/kg/hr
    a ScvO2 ≥70%
    Tobramycin
    Trough at 6-14 hours after the first dose
    CBC, WBC, LFT’s, symptoms of bleeding- everyday
    Urinalysis and Blood Culture
  • Monitoring Parameters
    • Toxicity
    • Aminoglycoside
    • Nephrotoxicty
    • Ototoxicity
    • Neuromuscular Blockade
    • HOTN
    • Ceftazadime
    • Anaphylaxis Reaction
    • Norepinephrine
    • Chest Pain
    • Palpitations
    • Extravasations
    • Toxicity
    • Fentanyl
    • Respiratory Depression
    • Precedex
    • Hypotension
    • Bradycardia
    • Regular Insulin
    • Hypoglycemia
    • Lovenox
    • Bleeding
    • Decrease Hemoglobin level
    • Protonix
    • Diarrhea
    • Melena
  • Thank You!
  • References
    Clinical Pharmacology-Gold Standard ( database online)2010.
    MICROMEDEX® Healthcare Series: Micromedex, Greenwood Village, Colorado
    DiPiro JT, Talbert RL, Hayes PE, Yee GC, Matzke GR, Posey Lm. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, N.Y.: Appleton & Lange Inc.2008. Chapter 123-Sepsis and Septic Shock