1. 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

2. 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

4. Life threatening state, decrease in tissue perfusion of blood supply

5. Characterized by lack of nutrient and O2 rich blood to the organs resulting in inadequate perfusion

6. Vital Signs

7. HR < 20 or > 150 bpm

8. SBP < 80 mmHg, decrease by at least 40mmHg

9. MAP < 60 mmHg

10. DBP > 120 mmHg

11. RR > 35 breaths/min

12. pH < 7.1 or >7.7

14. Loss of blood volume (plasma + RBCs)

15. External-surgery or trauma

16. Internal-GI bleeding

17. Cardiogenic Shock

18. Hearts inability to pump appropriate amount of blood

19. Decreased Cardiac Output

20. Septic Shock- Discussed in detail

21. Obstructive Shock

22. Subtype of Hypovolemic Shock

23. Increase pressure of the jugular vein distended jugular vein

24. Neurogenic Shock

25. Injury of the spine

26. Loss of cardiac nerve fibers from the sympathetic nerve fibers at T1-T4 resulting in profound bradycardia

27. Diaphoretic Skin

28. Anaphylactic Shock

29. Angioedema like reaction

30. Large Eruptions or bumpy skin

31. Edema, Massive Swelling

32. Constricted Airways; Swollen throat; Breathlessness and cough

34. It is a systemic inflammatory Response syndrome

35. Criteria must include the following (2 out of 4)

36. WBC >12K or <4K or >10% bands

37. Temperature > 38C or < 36C

38. Heart rate > 90bpm

39. Respiratory Rate > 22 breaths/min

40. PaCO2 < 32mmHg

41. Systemic Infection- Any etiology

42. Bacterial- Presence of Bacteria in the bloodstream

44. 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

46. Most Common pathogens

47. Candida Albicans ( Most Dominant)

48. Candida Glabrata

49. Candida Tarapsilosis

50. Candida Tropicalis

51. Candida Krusei

52. Risk factors of fungal-sepsis

53. Abdominal Surgery

54. Poorly controlled Diabetes Mellitus

55. Broad-spectrum Antimicrobials

56. Corticosteroids

57. Foley

59. Clinical Presentation

61. SIRSSepsisSevere Sepsis Septic Shock

62. Higher mortality rates with co-morbidities

63. Advanced age

64. COPD

65. HIV

66. Pseudomonas Infection

67. Failing Organs

68. Ex. From 2 to 4 organs Increase mortality from 54% to 100%.

70. 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%

72. Systemic Complication

73. Recent Travel history

74. Animal Exposure

75. Use of antimicrobials

76. Two sets of Blood samples

77. Peripheral Vein- Culture in an aerobic and an-aerobic environment

78. Cather-related suspecting

79. Two sets of blood culture

80. Catheter Hub

81. Peripheral Vein

82. Abdominal infections- Fluid Collections by imaging studies

84. MAP greater than 50mmHG-Goal

85. MAP less than 50 decrease coronary and cerebral blood flow

86. Monitor Continuously- Arterial Catheter in the Radial Artery

87. Central Venous Catheter

88. Placed in 3 veins-Triple Lumen

89. Internal Jugular Vein-Neck

90. Subclavian Vein- Chest

91. Femoral Vein- Groin

92. Measures the central venous oxygen saturation- ScvO2, Central Venous Pressure (CVP)

93. Goal CVP = 8-12 mmHg during fluid resuscitation

95. Depends on CO, Oxygen demand, SaO2 and Hemoglobin

96. Goal SaO2 = >70% in shock

97. Lower Value Inadequate O2 oxygen delivery to tissue and high extraction by tissue

98. Lactate

99. Metabolic product of Pyruvate increase production in anaerobic conditions

100. Goal= 0.5 – 2.2 mmol/L

103. Selection of the antimicrobial depends on

104. Suspected site of infection

105. The most likely pathogens

106. Community acquired or Hospital Acquired

107. Immune status of the patient

108. Institution susceptibility profile of the ABX

109. Re-asses the regimen 48-72 hours laterSwitch to narrow spectrum based on culture and susceptibility

111. Empiric Antimicrobial Therapy

113. Fungal Species

114. Presence of Liver and Kidney dysfunction-Elimination

115. Prior Exposure to anti-fungal agents

116. Treatment of Choice-

117. Amphotericin B based preparations

118. Fluconazole, Itraconazole

119. Fluconazole plus Amphotericin B

120. Voriconazole- Fluconazole resistant isolates

121. Caspofungin- Potent against all Candida Species

122. Initial Empiric Therapy-

123. parenteral amphotericin B or caspofungin

125. 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

126. 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)

127. Crystalloids vs. Colloids

128. Crystalloids vs. Colloids Cont…

129. 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

130. 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

131. 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

132. Vasopressors cont… Norepinephrine(Levophed) First line agent for septic shock Stimulates a1,2 > b1 Increases MAP by vasoconstriction on peripheral vascular beds

133. 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

135. nonspecific a and b-adrenergic agonist

136. significant peripheral vasoconstriction- Last line therapy for refractory shock

137. 1-10 mcg/min

138. Phenylephrine (Neosynephrine)

139. selective a1-agonist

140. Rapid onset, short duration, and primary vascular effects, and it is least likely to produce tachycardia

142. 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

144. Inhibits Coagulation, reduces inflammation

145. Clinical Trial- Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)

146. Reduced Mortality by 24.7% in those who received rhAPC

147. Current recommendations

148. APACHE II score ≥25, sepsis-induced multiple organ failure, septic shock, or

149. Sepsis-induced ARDS and with no absolute contraindication related to bleeding risk

151. 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

153. Proton Pump Inhibitors (PPIs)

154. Greater acid-suppression (less evidence)

155. First line for patients with upper GI bleed

156. Histamine-2 receptor antagonists (H2RAs)

157. Most Evidence

158. Sucralfate-Sucrose octasulfate, Aluminum Hydroxide

159. Patient Considerations

160. Thrombocytopenia- Consider PPI

161. More gastric acid suppression may lead to Clostridium Difficile- associated diarrhea, pneumonia

162. PPIs are the most common cause of interstitial nephritis

164. Reach the following endpoints w/in 6 hours of onset

165. CVP=8-12mmHg, (or 12-15 if mechanically ventilated)

166. MAP ≥65mmHg, UOP ≥0.5mL/kg/hr

167. ScvO2 >70%

168. Fluid challenges with crystalloids 1000mL or colloids 300-500mL over 30 min

169. Target CVP= 8-12mmHg or (12-15 if mechanically ventilated)

170. Begin Broad-Spectrum ABX w/in 1 hour

171. Consider most likely pathogens and fungal infections based on suspected source of infection

172. Skin and Soft tissue

173. Intra-Abdominal

174. Respiratory

176. Administer centrally

177. NE or DA are first line

178. NE-1st line

179. Phenylephrine, Epinephrine, Vasopressin- Last line

180. Use epinephrine if blood pressure unresponsive to first line

181. Do not use low dose DA for renal protection

182. If ScvO2 target not reached with fluids, transfuse packed RBCs to hematocrit ≥ 30% and/or dobutamine infusion

183. Corticosteroids

184. Refractory Septic Shock

187. Must Achieve the following parameters within the first 6 hours

188. Measured Serum Lactate

189. CVP= 8-12mmHg

190. MAP > 65mmHg

191. urine output ≥0.5 mL/kg/hr

192. ScvO2 ≥70%

193. Provide Supportive therapy

194. Treat the systemic infection

197. Objective

198. Heart Rate >90bmp

199. RR >22bpm

200. WBC >12,000

201. Severe HOTN

202. Elevated Lactate

203. Gram (-) rods on blood culture

204. Pyelonephritis

205. Subjective

206. Flank abdominal pain

207. Vomiting/headache/anxiety

208. Objective

209. Urinary Stent

210. Moderate Esterase

211. Pyuria

212. WBC 10-50K

213. Urine Culture: Pseudomonas and other organism

214. Metabolic Acidosis

215. Objective

216. pH less than 7.35

218. Gentamicin- Good Choice

219. Primaxin and Merrem- Not the DOC; therapy duplication

220. Metabolic Acidosis

221. Sodium Bicarbonate 7.5%- Good Choice

222. Septic Shock

223. The patient is receiving the appropriate fluid therapy

224. Antibiotics

225. Gentamicin- Good Choice

226. Primaxin and Merrem- Therapy Duplication

227. Flagyl- No indication

228. Vasopressors

229. Norepinephrine-DOC

230. Supportive Care

231. Glucose Control

232. Regular Insulin- Good Choice

233. Stress Ulcer Prophylaxis

235. Continue IV Normal Saline

236. Antibiotics

237. Tobramycin IV 500mg Q36H

238. Pseudomonal Coverage

239. Maximizes concentration-dependent killing activity

240. Ceftazadime 1 gram IV q12h

241. Excellent Gram (-) infection plus Pseudomonal Coverage

242. Vasopressors

243. Norepinephrine 1-4mcg/kg/min IV

244. Increase by 1-4 mcg/kg/min titration to the desired effect

245. Supportive Care

246. Head of the bed elevation 30-45 degree angle

247. Analgesia

248. Fentanyl 200 mcg/hr IV

249. Glucose Control

250. Regular Insulin- Good Choice

251. Stress Ulcer Prophylaxis

252. Protonix 40 mg IVPB q6h- Good Choice

253. Agitation

254. Precedex- 0.4mcg/kg/hr via IV

255. DVT Prophylaxis

256. Lovenox 40 mg SQ QD plus Compression Stockings

258. 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

260. Aminoglycoside

261. Nephrotoxicty

262. Ototoxicity

263. Neuromuscular Blockade

264. HOTN

265. Ceftazadime

266. Anaphylaxis Reaction

267. Norepinephrine

268. Chest Pain

269. Palpitations

270. Extravasations

271. Toxicity

272. Fentanyl

273. Respiratory Depression

274. Precedex

275. Hypotension

276. Bradycardia

277. Regular Insulin

278. Hypoglycemia

279. Lovenox

280. Bleeding

281. Decrease Hemoglobin level

282. Protonix

283. Diarrhea

285. 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