Essential Notes in General Surgery

ESSENTIAL NOTES IN

GENERAL

SURGERY

Mohammed Othman Almaimani

©

Copyright 2021 Mohammed Othman Almaimani.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the written prior permission of the author.

ISBN: 978-1-6987-0355-8 (sc)

ISBN: 978-1-6987-0356-5 (hc)

ISBN: 978-1-6987-0354-1 (e)

Library of Congress Control Number: 2020924671

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Contents

Preface

Acknowledgments

Section I

Basic Surgical Principles

■  

Fluid and Electrolyte

Fluid physiology, electrolytes imbalance, acid-base balance

■  

Hemostasis

Biology of hemostasis, coagulation factor deficiency, platelet function defect, blood transfusion and its complications

■  

Systemic Response to Injury

Detection of cellular injury, neuroendocrine response to injury, cellular stress responses, mediators of inflammation, metabolism after injury

■  

Nutrition in Surgical Patients

Nutritional assessment, enteral feeding, TPN

■  

Wound Healing

Phases of wound healing, heritable disease of connective tissue disorders, healing in specific tissues

■  

Burn

Classification, assessment, treatment, types of graft

■  

Surgical Infections

Pathogenesis of infection, SIRS, treatment of surgical infection, types of antibiotics, surgical site infection

■  

Shock

Pathophysiology, neuroendocrine response in shock, types of shock

■  

Trauma

Primary survey, secondary survey, operative approach and exposure, damage control surgery, definitive management of specific injury

Section II

General Surgery

■  

General

o   Abdominal Wall, Omentum, Mesentery, and Retroperitoneum

o   Anatomy, omental cyst, omental neoplasm, mesenteric cyst, retroperitoneal infection, retroperitoneal fibrosis

o   Skin and Subcutaneous Tissue

o   Anatomy and histology, inflammatory condition, benign tumors, malignant tumors

o   Hernias

o   Inguinal hernia, femoral hernia, ventral hernias

o   The Appendix

o   Anatomy, acute appendicitis, neoplasm of the appendix

o   Soft Tissue Sarcoma

o   Approach, extremities sarcomas, GIT sarcomas, desmoid tumor, pediatric sarcomas.

■  

Upper GI Tract

o   Esophagus

o   Anatomy, physiology, GERD, Barrett’s esophagus, hiatal hernia, motility disorder of the esophagus, esophageal perforation, carcinoma of the esophagus.

o   Stomach

o   Anatomy, physiology, GI hormones, peptic ulcer disease, benign gastric neoplasms, , GIST, UGIB, malignant neoplasm of the stomach, post gastrectomy problems.

o   Small Bowel

o   Anatomy, physiology, small bowel obstruction, Crohn’s disease, mesenteric artery disease, miscellaneous, small bowel neoplasm.

■  

Colorectal

o   Colon

o   Anatomy, physiology, diagnostic tools, surgical consideration, inflammatory bowel disease, diverticular disease, ischemic colitis, infectious colitis, colonic obstruction, colon cancer and polyps

o   Rectum

o   Benign rectal condition, Rectal cancer

o   Anal Canal

o   Benign anorectal conditions, anal cancer

■  

Hepatobiliary

o   Liver

o   Anatomy, physiology, acute liver failure, portal hypertension, ascites, differential diagnosis of liver masses, infections of the liver, benign liver lesions, malignant liver tumors

o   Gallbladder and Biliary System

o   Anatomy, physiology, gallstone disease, CBD stones, acute cholangitis, Mirizzi syndrome, biliary injury, cystic disorders of the bile duct, carcinoma of the gallbladder, cholangiocarcinoma

o   Pancreas

o   Anatomy, physiology, acute pancreatitis, pancreatic necrosis and pancreatic pseudocyst, gallstone pancreatitis, pancreatic divisum, chronic pancreatitis, neoplasm of endocrine pancreas, neoplasm of exocrine pancreas, cystic neoplasm of the pancreas

o   Spleen

o   Anatomy, physiology, hematological disease, splenic artery aneurysm, OPSI

■  

Endocrine Surgery

o   Breast

o   Anatomy, physiology, benign disease of the breast, breast cancer

o   Thyroid Gland

o   Anatomy, physiology, benign thyroid disorders, malignant neoplasms

o   Parathyroid Gland

o   Anatomy, physiology, hyperparathyroidism

o   Adrenal Gland

o   Anatomy, physiology, disorders of adrenal cortex, adrenal cancer, disorders of the adrenal medulla, malignant pheochromocytoma, Addison disease, pituitary gland.

o   Pituitary Gland

Section III

Subspecialty

■  

Pediatric Surgery

Umbilical hernia, congenital defects of abdominal wall, inguinal hernia, undescended testis, pyloric stenosis, small bowel atresia, meconium ileus, Meckel’s diverticulum, intussusception, intestinal malrotation, necrotizing enterocolitis, Hirschsprung disease, anorectal malformation, biliary atresia, tracheoesophageal fistula, diaphragmatic hernia, cystic lung lesions, Wilms’ tumor, neuroblastoma, neck Cyst and Sinuses

■  

Thoracic Surgery

Trachea and its disorders, lung anatomy and histology, benign and malignant lung lesions, pulmonary infections, the mediastinum

■  

Vascular Surgery

Peripheral vascular disease, abdominal aortic aneurysm, acute limb ischemia, chronic limb ischemia, diabetic foot, thoracic aortic aneurysm, aortic dissection, venous thromboembolism, lymphedema

■  

Surgical management of Obesity

The disease of obesity, types of surgery and outcomes

■  

Critical Care

Lung physiology, receptors and inotropes, ventilation

■  

Anesthesia

ASA classification, pain management, types of anesthesia, types of inductions

Abbreviation

Preface

Essential Notes in General Surgery is a summary of years of work, after reading several text books, articles, attending the conferences, hospital daily rounds, and many review courses.

It is précis, digested, updated and provides essential knowledge that will help you pass the board exams, especially the American, Canadian, and Saudi board exams.

This book was designed to be sufficiently used by medical students, general surgery residents and senior general surgeon.

The book contains basic knowledge of the anatomy, physiology, pathology as well as history, physical examination, investigation, detailed management, operative intervention, and follow-up of each disease.

The material is divided into three main sections:

▪ Basic surgical principles

Fluids, hemostasis, shock, surgical infection, trauma, wound healing, and critical care

▪ General surgery

Upper GIT, Colorectal, Hepatobiliary, and Endocrine surgery

▪ Subspecialty

Pediatric, Vascular, Bariatric and Thoracic surgery.

Acknowledgments

In the name of the Almighty Allah, the beneficent and most merciful. We are immeasurably thankful to Allah, whose blessings flourished our thoughts and thrived our ambitions.

To my parents, thank you for everything you have done in my entire life, for your love and support throughout my academic career. There is no way for me to express my utmost gratitude and thanks to you two.

I thank my wife, sweetheart, and best friend, Shaimaa Althubaity. Through the good and bad times, you have always been there for me.

I thank my sons, Othman and Abdulrahman, who endured my absence and motivates me to be the best.

I thank my brother and sisters.

Special thanks to Mansul H. Amsud for typing the book.

Special thanks to Khalaf Shehab for algorithms and figures design.

I thank the general surgery departments in Makkah City: Al Noor Specialist Hospital, KFH, KAAH and KAMC for their support.

Mohammed Othman Almaimani

General Surgery Senior Registrar

Pediatric Surgery Fellow

Section I

Basic Surgical Principles

Fluid and Electrolyte

Body Fluids

Total Body Water

- The total body weight contains 50%–60% water. It differs from male to female.

- Lean tissue (i.e., muscles and solid organs) has more fluid than fat and bones.

- Obese people has 10%–20% less body water than the normal population.

- An infant’s total body weight is 80% water. At the end of its first year, it decreases to 65%.

Fluid Compartments

- The total body weight is 60% water, which is distributed as follows:

Spaces

Composition of Fluid Compartment

Osmotic Pressure

Molal = 83890.png

Molar = 83903.png

- Number of particles per unit volume (mmol/L)

- Number of electric charges per unit volume (mEq/L)

- Number of osmotically active per unit volume (mOsmol/L)

Equivalent = atomic weight (g)/valance

- For Na+ (univalent) 1 mEq = 1 mmol

- For Mg++ 2 mEq = 1 mmol

- Serum osmolarity = 2 Na+ + 83911.png

≈ 290–310 mOsmol in each compartment.

Body Fluid Changes

- A healthy person consumes 2 L/day.

- 75% of oral intake is fluid, and 25% is extracted from solid food.

- Daily fluid losses are 800–1,200 mL in urine (sensible), 200–600 mL in sweating, and 250 mL in stool (sensible).

- Insensible loss is 600 mL, 75% by skin (evaporation) and 25% by lungs.

- Kidney excretes a minimum of 500–800 mL/day to clear metabolites, regardless of intake.

- Normally, the daily intake of salt is 3–5 g.

→ Balanced by kidney, it can excrete 1–500 mEq/day.

Classification

A. Volume

By osmoreceptor and baroreceptor

o Osmoreceptor: the kidney either excretes or reabsorbs through the thalamus & vasopressin.

o Baroreceptor: a specialized pressure sensor in the aortic arch and carotid sinus, responds to neural stimulus (sympathomimetic and parasympathomimetic) or hormonal renin-angiotensin-aldosterone, ANP.

B. Concentration

▪ Total body water reflects serum Na+ level.

▪ Normal range of Na+ 135–145 mEq/L.

▪ Hyponatremia, classified as follows:

o Hypervolemic hyponatremia

• The most common type

→ Excess water intake or administration of IV hypotonic fluid

• Postoperative patient → ↑ ADH →

↑ reabsorption of water by the kidneys

o Normovolemic hyponatremia

• Drugs such as ACE inhibitor, antipsychotic, antidepressant

o Hypovolemic hyponatremia

• ↓ intake, vomiting, NGT, or diarrhea

Symptoms

- Nausea, vomiting, headache, confusion, fatigue, irritability, weakness, spasm or cramps, seizures, and coma

NB:

- Pseudohyponatremia: (hyperglycemia, hyperlipidemia, hyperproteinemia) → shift of water from ICF to ECF.

→ For every increase of 100 mg/dL in plasma glucose

→ ↓ Na+ by 1.6 mEq/L

➢ Hypernatremia

- Loss of water or gain in Na+

- Serum osmolarity > 300 and urine Na+ > 20 mEq/L

▪ Hypervolemic hypernatremia

• Administration of IVF with Na+ such as normal saline, NaHCO3, mineralocorticoids, congenital adrenal hyperplasia

• Cushing syndrome

▪ Normovolemic hypernatremia

• Diabetes insipidus, diuretic use, renal disease, or from nonrenal water loss from the GI tract or skin

▪ Hypovolemic hypernatremia

• Isotonic GI fluid losses such as that caused by diarrhea

• Hypotonic skin fluid losses such as loss due to fever or losses via tracheostomies during hyperventilation

• Water loss caused by thyrotoxicosis

• Use of hypertonic glucose solutions for peritoneal dialysis.

• Urine sodium concentration is < 15 mEq/L

• Urine osmolarity is > 400 mOsm/L

Symptoms are rare unless > 160 mEq/L.

- Confusion, muscle twitching, seizures and coma

Sodium Deficit = 0.6 × weight × (desired Na+ − actual Na+)

C. Composition Changes

Potassium (K+)

- Intake is 50–100 mEq/day.

- Normal range is 3.5–5 mEq/L.

- Excretion by kidneys is 10–700 mEq/day.

- Only 2% of total K+ is located in ECF.

- K+ in ECF: 4.5 mEq/L × 14 L = 63 mEq.

- Minor change can have major effect on heart.

➢ Hyperkalemia

- ↑ intake

- Hemolysis, rhabdomyolysis, crush injury

- Acidosis → ↑ ECF osmolality → shift K+ to ECF

- Spironolactone, ACE inhibitor, NSAIDs

- ARF, CRF

Symptoms

CNS: weakness to paralysis

CVS: arrhythmia, cardiac arrest

ECG: peaked T wave, wide QRS complex, flattened P wave, and prolonged PR interval (first-degree block)

➢ Hypokalemia

- Much common than hyperkalemia

- ↓ intake, ↑ excretion, e.g., loss of GI section, diarrhea, enterocutaneous fistula, NGT, alkalosis

- Potassium decreases by 0.3 mEq/L for every 0.1 increase in pH

- ↓ Mg++ → decrease Mg++ intracellular → release of Mg++-mediated inhibition of ROMK channel → ↓ K++ secretion from intracellular

- Symptoms related to failure of normal contraction, ileus, constipation, ↓ tendon reflex, paralysis.

- ECG: U wave, flattening T wave

K+ deficit = (normal K+ − measured K+) × body weight × 0.4

Calcium (Ca++)

- Vast majority is in the bone.

- Extracellualr Ca++ represents 1% of total calcium in the body.

- Normal range is 8.6–10.5 mg/dL.

- Three forms are as follows:

- Protein bound, 40%

- Complex to phosphate or another ions, 10%

- Ionized, 50%

- Ionized is responsible for neuromuscular stability.

- decrease in Ca++ 0.8 mg/dL for every decrease of 1 g/dL in albumin.

- Acidosis ↓ Ca++ binding to protein → ↑ ionized Ca++.

- Daily intake is 1–3 g.

➢ Hypercalcemia

- Above 8.5–10.5 mg/dl

- Or above ionized Ca++ 4.2–4.8 mg/dL

Causes: hyperparathyroidism in outpatients and malignancy in hospitalized patients

- Symptoms: nausea, vomiting, constipation, abdominal pain, confusions, headache, and depression

- ECG: prolonged PR–QRS, high-voltage QRS, flattening of T wave

➢ Hypocalcemia

- Causes: pancreatitis, necrotizing fasciitis, renal failure, small bowel fistula, hypothyroidism, toxic shock syndrome, low Mg++, and tumor lysis syndrome from hyperphosphatemia

- Transient after parathyroid adenoma excision → bone hunger

- Malignant with osteoblastic activity: lung, breast and prostatic CA.

- Symptoms: paresthesia in face, extremities, muscle cramps, carpopedal spasm, stridor, tetany.

- Chvostek sign (spasm when tapping over facial nerve)

- Trousseau sign (spasm when pressure over nerve and vein of upper limb)

- ECG: prolonged QT, inverted T wave

Phosphate

- Primary intracellular, energy production.

- Controlled tightly by renal excretion.

➢ Hyperphosphatemia

- ↓ urine excretion, ↑ intake

- Mostly in renal failure

- Hypoparathyroidism, hyperthyroidism

- Rhabdomyolysis, tumor lysis syndrome, hemolysis, sepsis, hyperthermia, malignant hyperthermia

- Laxative: sodium phosphate

- If hyperphosphatemia prolonged → metastatic deposition of calcium-phosphorus complexes in the soft tissue.

➢ Hypophosphatemia

- Most cases due to shift of phosphate to ICF in response to respiratory alkalosis, insulin therapy and hungry bone syndrome.

- Symptoms related to adverse effect on O2 availability and ↓ energy.

Magnesium (Mg++)

- Fourth most common mineral in the body.

- Normal range 1.3 – 2.1 mEq/L

- Half in the bone and ⅓ is complex to albumin,.

- Normal daily intake is 400 mg/day.

➢ Hypermagnesemia

- Antacids, laxative, TPN, massive trauma, thermal injury, severe acidosis

- Symptom: neuromuscular dysfunction similar to hypercalcemia

- ECG similar to hyperkalemia

➢ Hypomagnesemia

- Mg++ depleted in critically ill

- Kidney is responsible for Mg++ and Ca++ homeostasis

- Prolonged IVF, TPN, not sufficient Mg++

- Alcohol abuse, amphotericin B

- Diarrhea, primary aldosterone, acute pancreatitis

- ECG: inversion of P wave or flattened, torsades de pointes.

Acid-Base Balance

- The important buffer intracellularly is protein, phosphate and extracellularly is bicarbonate and carbonic system.

- Compensation of acid-base derangement by respiratory system for metabolic cause and metabolic mechanism if respiratory cause (Kussmaul breathing).

- Change in ventilation in response to metabolic derangement mediated by H+ sensitive receptor.

- Acidosis stimulates chemoreceptor to increase ventilation, and alkalosis decreases it.

- Kidney compensates respiratory abnormalities by ↑ or ↓ bicarbonate, and it is delayed compensation for 6 hrs to days.

Metabolic Acidosis

➢ Increase acid intake, increase generation of acid, or significant loss of HCO3 → Kussmaul respiration, increase HCO3 reabsorption and H+ execration.

Anion gap (AG) = Na+ − (CT + HCO3)

Normally is < 12.

Correct AG = actual AG – (2.5 [4.5 − albumin])

• Metabolic acidosis with high AG

- Ingestion of exogenous acid, salicylate, methanol.

- ↑ production of acid, ketoacidosis, ↑ lactate, renal failure.

- Common cause in surgery is lactic acidosis. Lactate is produced by hypoxic tissue.

→ Treatment: resuscitation for adequate perfusion

- The liver metabolizes lactate.

- Administration of bicarbonate does not improve mortality and cellular function.

→ Overzealous → alkalosis, curve shifts to the left

- Interfere with O2 → arrhythmia and increase intracellular acidosis to form carbonic acid

- HCO3 + H+ = H2CO3 → CO2 + H2O → higher PCO2 → ventilation problem in patient already with respiratory distress.

• Metabolic acidosis with normal AG

- Result of acid administration (HCl-, NH4) or from bicarbonate loss (e.g., diarrhea, fistula, ureterosigmoidostomy, or from renal losses).

→ Carbonate loss and gain of Cl-

→ Proximal renal tubular acidosis from ↓ tubular reabsorption of HCO3, while distal renal tubular acidosis from ↓ acid excretion

Metabolic Alkalosis

➢ Loss of acid or gain of bicarbonate.

➢ Associated with low K+ because alkalosis enhances K+ to enter the cell.

➢ Excess HCO3, milk alkali syndrome, citrate in blood transfusion.

➢ Hyperchloremic metabolic alkalosis occurs in infant with pyloric stenosis or adult with duodenal ulcer.

➢ The loss in patent pylorus will be gastric, pancreatic, and biliary content.

→ Urine HCO3 is high, H+ reabsorption + K+ excretion.

→ If hypokalemia persists → H+ excretion → paradoxical aciduria.

➢ Treatment is volume repletion with isotonic saline

Respiratory Acidosis

➢ Retention of CO2, hypoventilation.

➢ Delayed response from kidney, so correct by treating underlying cause.

➢ CNS: narcotic.

Pulmonary: PE, atelectasis.

Abdomen: abdominal compartment syndrome, distention.

➢ Treatment may require intubation after trial of noninvasive methods.

Respiratory Alkalosis

➢ Common in surgical patients because of alveolar hyperventilation caused by pain, anxiety, CNS injury.

➢ Drugs: salicylate, fever, gram-negative bacteria, thyrotoxicosis, hypoxemia.

➢ Treat the underlying cause of hyperventilation.

Fluid and Electrolyte Therapy

- Ringer’s lactate is slightly hypotonic and contains 130 mEq/L of lactate, which is converted in the liver to bicarbonate after infusion (lactate more stable in storage than bicarbonate).

- Used in resuscitation in trauma.

- Normal saline: NaCl mildly hypertonic, contains 154 mEq/L of Na+ and 154 mEq/L of Cl-.

Disadvantage → chloride load in kidney → hyperchloremic metabolic acidosis.

- Used to correct hyponatremia and replace GI losses.

- 5% dextrose (hypotonic) contains dextrose 50 g/L.

→ 170 kcal/L to prvent catabolism + ½ NS to maintain osmolarity and prevent lysis of RBCs and.

Alternative Resuscitation Fluid

- Hypertonic saline is 3%, 5% to correct severe hyponatremia.

- 7.5% used in closed-head injury → ↑ perfusion, ↓ ICP, ↓ edema.

- Colloid (volume expander): high molecular weight, not used in severe hemorrhagic shock → enters the interstitial space and worsens the edema.

- Types: (1) albumin, (2) dextran, (3) hetastarch, (4) gelatin

1. Albumin

- 5%, 25%

- Induce allergic reaction and renal impairment

2. Dextran

- Glucose produced by bacteria in sucrose media

- 40,000–70,000 medium weights

- Used to lower blood viscosity + normal saline → maintain IV volume

3. Starch (hetastarch)

- Molecular weight is 1000 - 3000,000

- 6% solution

- Cause hemostatic derangement, ¯ vWF and factor VIII → renal dysfunction

- Hextend, a modified form

4. Gelatin: Bovine collagen

Correction of Electrolyte Abnormality

Hypernatremia

- Treatment of water deficit.

- D5% or D5 in ¼ NS or enteral water.

Water deficit = % body water × weight (kg) × 83947.png

- No more than 1 mEq/hr or 12 mEq /day → rapid correction → cerebellar edema, demyelination and herniation.

Hyponatremia

- Treatment with free water restriction.

- If severe, administer Na+Cl-.

- In normal patients, they usually become symptomatic if Na+ is less than 120 mEq/L.

- Sodium deficit = 0.6 × weight (kg) × (desired Na+- actual Na+)

- Use 3% NS but no more than 1 mEq/hr until it reaches 130 mEq/L and maximum 12 mEq/L/day.

Hyperkalemia

- Stop exogenous K+.

- Kayexalate 15–30 g in 20–100 mL of 20% sorbitol.

- Shift K+ to intracellular with glucose + insulin and bicarbonate infusion.

→ Nebulizer albuterol (10–20 mg)

- When ECG changes, Ca++ gluconate or Ca++ chloride (5–10 mL 10% solution) over 10 min.

- If high K+ persists → dialysis.

Hypokalemia

- Potassium deficit = (K+ lower normal − K+ measured) × body weight (kg) × 0.4.

- Oral KCl syrup if mild or asymptomatic.

- If symptomatic, correct K+ deficit first then administer maintenance therapy.

- KCl 10 mEq diluted in 100 mL normal saline with no monitoring

→ can be up to 40 mEq/hr but through large veins, diluted in 200–400 mL normal saline, slowly over 2–4 hrs.

Hypercalcemia

- Treatment indicated if Ca++ is > 12 mg/dL.

- NS infusion to treat volume deficit + diuretic if severe hypercalcemia.

Hypocalcemia

- Asymptomatic → oral Ca++ carbonate 600–1,200 mg PO.

- Symptomatic → IV 10 mg Ca++ gluconate with concentration 10% over 10 min to achieve 7–9 mg/dL.

- If associated Mg, K+ deficiency should be corrected.

Hyperphosphatemia

- Phosphate binder such as sucralfate or aluminum-containing antacid.

- Ca++ acetate tablet can be used.

- Dialysis if failed.

Hypophosphatemia

- If phosphate is 1–2.5 mg/dL,

→ tolerating enteral nutrition → Neutra-Phos 2 packets Q6H.

→ parenteral KPHO4 (0.15 mmol/kg) IV over 6 hrs for 1 dose.

- If phosphate is < 1 mg/dL, IV KPHO4 or NapHO4 0.25 mmol/kg over 6 hrs for 1 dose.

Hypermagnesemia

- Eliminate exogenous cause and correct acidosis.

- If acute symptom, Ca++ chloride 5–10 mL IV STAT.

Hypomagnesemia

- If asymptomatic, oral administration.

- If level 1–1.8 mEq/L, magnesium sulfate 0.5 mEq/kg in 250 cc NS IV over 24 hrs × 3 days.

- If < 1 mEq/L, magnesium sulfate 1 mEq/kg in 250 cc NS over 24 hrs × 1 day, then 0.5 mEq/kg in 250 cc NS IV over 24 hrs × 2 days.

- If severe, 1–2 g of magnesium sulfate IV over 15 min with monitoring.

Fluid Therapy

Preoperative

- IV fluid calculation:

- Other formulas:

4 mL/kg/hr for first 10 kg

2 mL/kg/hr for second 10 kg

1 mL/kg/hr for every kilogram

- Mostly D5 ½ NS 125 cc/hr + KCl- 20 mEq/L.

- Consider volume deficit (GI and third space losses).

- Maintain UOP at 0.5–1 mL/kg/h.

- If hypernatremia, unsafe to give D5 alone; it should be accompanied with ¼ NS or RL.

Intraoperative

- During induction → compensatory mechanism lost → ↓ BP.

- Consider blood loss in major abdominal surgery.

- During major abdominal surgery, the water loss is 500–1,000 mL/hr.

- No colloid administration.

- Best is RL; in the past, it was NS (salt intolerance).

Postoperative

- Any deficit during preoperative or intraoperative therapy should be corrected with isotonic saline.

- Usually RL or NS for the first 24 hrs then change to D5% ½ NS + K+.

- Should Replace deficit and all losses: NGT, drain, UOP + insensible losses.

Special Consideration Postoperative

- Don’t exceed actual need.

- Early sign of volume overload is weight gain.

- Postoperative weight loss should be 0.23 kg.

- Symptoms of volume deficit: tachycardia, orthostasis, oliguria, and hemoconcentration.

Electrolyte Abnormalities in Specific Patients

Secretion on Inappropriate Antidiuretic Hormone (SIADH)

- After head injury or CNS surgery.

- Also associated with administered morphine, NSAIDs, oxytocin.

- Pulmonary and endocrine disease: hypothyroidism, glucocorticoid deficiency.

- Malignant: small cell CA (lung), pancreatic CA.

- Patient has euvolemic hyponatremia with elevation of urine Na+.

- Furosemide to induced free water loss along with fluid restriction.

Diabetes Insipidus (DI)

- Disorder of ADH stimulation.

- Diluted urine with hypernatremia.

- Seen in closed-head injury, pituitary surgery.

- There is nephrogenic DI + low K+ associated with contrast dye and use of aminoglycosides and amphotericin B.

- Diagnosis by high urine osmolarity in response to water deprivation.

- In mild cases free water replacement is adequate therapy.

- If severe → vasopressin 5 units SC Q6–8H.

Cerebral Salt Wasting

- Diagnosis of exclusion.

- Hyponatremia occurs with secondary events, which can be differentiated from SIADH.

Refeeding Syndrome

- Rapid excessive feeding in malnourished patient.

- Shifting metabolism from fat to carbohydrate → ↑ insulin release → ↑ cellular uptake of electrolyte Mg, K, Ca, phosphate, as well as glucose (hypoglycemia).

- Symptoms: arrhythmia, confusion, respiratory failure, death.

- Correct electrolyte and volume deficit.

- Add thiamine before feeding.

- To prevent: ↑ fat administration and ↓ carbohydrate with slowely progression.

Acute Renal Failure

- Azotemia → correct volume deficit.

- Acute renal tubular necrosis → fluid restriction.

- Correct high K+.

- Hyponatremia is a result of breakdown of protein, fat, carb.

- Low Ca++, high Mg++, high phosphate.

- Measure ionized Ca++ as patient usually experiences hypoalbuminemia.

- Bicarbonate can benefit, but dialysis is a must.

Cancer Patients

- Hyponatremia by caused by diuretics, salt-wasting nephropathy, cisplatin.

- Cerebral salt wasting, SIADH.

- Hyponatremia also occurs with poor oral intake.

- Hypokalemia from diarrhea, chemotherapy and atrophy of villi

- Hypocalcemia: thyroid surgery, bone hunger, high phosphate.

- Hypomagnesemia: cisplatin, hypophosphatemia, hyperparathyroidism

→ Low phosphate reabsorption, oncogenic osteomalacia, multiple myeloma

- The tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.

Hemostasis

Biology of Hemostasis

1. Vasoconstriction

2. Platelet plug formation

3. Fibrous formation

4. Fibrinolysis

Vasoconstriction (VC)

- VC is an initial response, more evident in medium and large vessels, depending on smooth muscle.

- Subsequent link to platelet formation.

- TXA2 is produced at the site of injury via release of arachidonic acid from the platelet membrane, a potent VC of smooth muscle + endothelin and serotonin (from injured vessel) released during platelet aggregation.

- Bradykinin and fibrinopeptide is involved in coagulation + VC.

- The extent of VC correlates with the degree of vessel injury.

Platelet Function

- Anucleate fragment from megakaryocyte.

- Count: 150,000–450,000.

- Up to 30% sequestrated in spleen, and average life span is 7–10 days.

- Platelet aggregation → thrombus formation.

- Injury to intimal layer (vWF) → exposes subendothelial collagen that allows platelet adhesion.

- vWF binds to glycoprotein (GP) I/IX/V on platelet membrane.

- Up to this point → primary hemostasis.

- Platelet aggregation is reversible.

- Arachidonic acid, which is released from the platelet membrane, is converted by cyclooxygenase to prostaglandins PGG2; PGH2 converted to TXA2 which is a potent VC, ↑ platelet aggregation.

- Arachidonic acid may shutter and convert.

- Platelet cyclooxygenase inhibited by aspirin (irreversible) and NSAIDs (reversible), but not affected by COX-2 inhibitor.

- Second wave of platelet aggregation → fibrinogen required.

- Cofactor acting as bridge for GP IIb, IIIa in activated platelet.

- If platelet plug formed (irreversible).

- Thrombospondin: stabilized fibrinogen binding to activated platelet.

- Platelet factor 4 and α-thrombomodulin are secluded during this reaction.

- PF4 is a potent heparin antagonist.

- Second wave of platelet aggregation is inhibited by aspirin and NSAIDs and nitric oxide (NO).

- Alteration of phospholipid in platelet membrane (PF3) allows Ca++ and clotting factor bind platelet membrane.

Coagulation

- Hemostasis is a combination of interaction between platelet + endothelin + coagulation factor.

- Coagulation 2 pathways converting to common pathway.

- Intrinsic factors are XII → XI → IX → (VIII), then common pathway X → (V) → II → I.

- Extrinsic factors are tissue factors (III) → VII, then common pathway X → (V) → II → I.

- PTT measures: I, II, V, VIII, IX, X, XI, XII.

- PT (INR)measures: I, II, VII, X.

- Vitamin K and warfarin affect factor II, VII IX, X.

- Factor X + Va + Ca++ + phospholipid (prothrombin complex) convert prothrombin → thrombin → fibrinogen → fibrin.

- Last step, thrombin activates fibrinolysis inhibitor (TAFI), which stabilizes the colt.

- Balanced mechanism to prevent propagation of clot beyond site of injury.

1. Feedback inhibition to deactivate cascade → activated protein C → inhibit factors V and VIII.

2. Tissue plasminogen activator (tPA) is released from endothelin following injury → fibrinolysis.

- Tissue factor pathway inhibitor (TFPI) → block tissue factor and VIIa (7) complex.

- Antithrombin III inhibits tissue factor, VIIa.

- Activated protein C system with cofactor protein S inhibit factors V and VIII to form TF-7a.

- Factor V Leiden, resistant to cleavage by activated protein C.

- Plasmin degrades clot.

- Other major plasminogen activator is uPA (urokinase plasminogen activator).

Fibrinolysis

- Plasminogen → plasmin → degrade fibrous mesh → production of circulating fragment (fibrous degradation product or FDP) cleaned by liver, kidney.

- Clot lysis FDP → E-nodules, D-dimer.

- D-dimer is a marker for thrombolysis (fibrinolysis).

Coagulation Factor Deficiency

Four most common are the following:

1. Hemophilia A factor VIII

2. Hemophilia B (Christmas disease) factor IX

3. vWF disease

4. Factor XI deficiency

▪ Hemophilia A (VIII), Hemophilia B (IX)

- Inherited sex-linked recessive disorder.

- Severity depends on factor level in the blood:

- Symptoms: hemarthrosis, ICH, GI hemorrhage.

- Patient with moderate disease is less likely to bleed spontaneously but ↑ the risk with trauma or surgery.

- Mild, no spontaneous bleeding, only minor bleeding after trauma or surgery.

- Platelet function is normal, i.e., plug formation and aggregation.

- For hemophilia A and B, give factors VIII and IX.

- Consider factor VII if not received previously.

- Activity level should be:

▪ von Willebrand’s Disease (vWD)

- Most common congenital bleeding disorder.

- is characterized by a quantitative or qualitative defect in vWF

- vWF is a glycoprotein responsible carrying factor VIII and platelet adhesion.

- Symptoms: easy bruising, mucosal bleeding, menorrhagia in female.

➢ Types:

➢ Therapy:

▪ Factor XI Deficiency

➢ Referred as hemophiliac.

➢ Spontaneous bleeding is rare, but trauma or surgery can produce bleeding.

➢ Treatment: FFP.

➢ Each 1 mL of FFP contains 1 unit of factor XI.

➢ Antifibrinolytic may be useful in menorrhagia.

➢ Factor VII recommended in patient with factor XI antibody.

▪ Deficiency in Factors II, V, X

➢ Bleeding is treated with FFP.

➢ Half-life of factor II is 72 hrs, 25% needed to achieve hemostasis.

▪ Factor VII

➢ Bleeding varies and does not always correlate with factor VII level.

➢ Bleeding is uncommon unless < 3%.

➢ Treatment: FFP or recombinant factor VII, half-life of 2 hrs.

▪ Factor XIII

➢ Associated with liver failure, IBD, myeloid, leukemia.

➢ Clot and coagulation is normal but with early fibrinolysis.

➢ Treatment: FFP, cryoprecipitate, factor XIII.

Platelet Function Defect

- Either abnormal surface protein or platelet granules or enzyme defect.

- The major surface of protein abnormality is thrombasthenia (Glanzmann’s disease) or Bernard-Soulier syndrome.

- Glanzmann’s disease → lack or dysfunctional IIb/ IIIa → Tx is platelet transfusion.

- Bernard-Soulier syndrome defect in GP Ib/IX/V receptor, vWF necessary for platelet adhesion.

- Most common intrinsic platelet defect is storage pool disease, i.e., loss of dense granule.

- Treatment: DDAVP, if severe platelet transfusion.

Acquired Hemostatic Defect

Platelet Abnormalities

- Failure of production: bone marrow disorder; leukemia, vitamin B12 deficiency, folate deficiency, chemotherapy, radiotherapy

- Decrease survival with ITP, HITT, DIC, TTP

- Sequestration, portal HTN, lymphoma, Gaucher disease

- Massive transfusion, antiplatelet, liver disease

▪ Quantitative

➢ Idiopathic thrombocytopenic purpura (ITP): impaired platelet production and T cell destructs the platelets.

➢ Heparin-induced thrombocytopenia and thrombosis (HITT):

• drug induces immunity against PF4 after exposure to heparin → thrombocytopenia + IV thrombosis.

• Platelet ↓ 5–7 days after heparin administration.

• Increase suspicions if platelet is < 100,000 or drops 50% of initial platelet count.

• Can occur with LMWH as well.

• Occurs in 17% with unfractionated 8% with LMWH.

• Diagnosis: serology or ELISA.

• Treatment: stop heparin or LMWH and start thrombin inhibitor (argatroban) for renal insufficiency and lepirudin, danaparoid with normal renal function.

➢ Hemolytic uremic syndrome (HUS) → secondary to infectious E. coli or shigella associated with renal failure, HIV, SLE → plasmapheresis.

➢ One unit platelet 5.5 × 10¹⁰ = increase 10,000.

▪ Qualitative

➢ Aspirin, clopidogrel (Plavix), irreversible antiplatelet.

➢ General recommendation to stop 5–7 days before elective procedure. If emergent operation → platelet transfusion.

➢ Uremia → dialysis or DDAVP (desmopressin)

Acquired Hypofibrinogenemia

Disseminated Intravascular Coagulopathy (DIC)

- Systemic activation of coagulation pathway → excessive thrombin generation and formation of microthrombi → depletion of platelet and coagulation factor → resultant classic picture of diffuse bleeding.

- Fibrin thrombi developing in the microcirculation may cause microvascular ischemia and subsequent end-organ failure if severe.

- Predisposing factor: severe hemorrhage, embolization of material from brain, bone marrow, amniotic fluid, severe pancreatitis, liver dysfunction, malignancy, snakebite, large aneurysm.

- Diagnosis: low platelet, low fibrinogen level.

- Treatment: FFP, cryoprecipitate, platelet, fibrinogen.

- Heparin is not helpful.

Primary Fibrinolysis

- Acquired hypofibrinogen.

- Risk factor, prostate surgery when urokinase release during surgery.

- Treatment: antifibrinolytic, Ɛ-aminocaproic acid, or tranexamic acid that inhibits activation.

Myeloproliferative Diseases

- Polycythemia → spontaneous thrombosis, polycythemia vera, neoplasm.

- Treatment: low dose of aspirin, phlebotomy.

Coagulopathy with Liver Disease

- Liver synthesized many coagulation factors.

- Factors I, II, III, V, VII, VIII, IX, X, XI, XII, XIII, protein C, S, plasminogen are synthesized in the liver except factors VIII and vWF, which are synthesized in liver sinusoidal endothelial cells.

- IL-11: cytokines stimulate proliferation of hematopoietic stem cells and megakaryocytes → good for cancer patients as well as cirrhotic patients.

- Treatment of coagulation caused by liver disease is usually with FFP.

- If fibrinogen is < 200 mg/dL → cryoprecipitate, rich in factor VIII.

Coagulopathy in Trauma

- Acidosis, hypothermia, and dilution of coagulation factor are the components of the triad of death.

- Patient arrived with coagulopathy → ↑ mortality in the first 24 hrs.

- Tranexamic acid ↓ mortality.

Acquired Coagulation Inhibitor

- Most common antiphospholipid syndrome → lupus anticoagulant and anticardiolipin antibody.

- Arterial or venous thrombosis.

- Antiphospholipid antibody common with rheumatoid arthritis, Sjogren’s syndrome.

Anticoagulation and Bleeding

- Spontaneous bleeding can happen with any anticoagulant.

- Heparin, LMWH, warfarin, factor Xa inhibitor, direct thrombin inhibitor.

- The most reliable is LMWH.

- Warfarin for long term treatment: DVT, PE, heart disease, MI.

→ ↓ effect of warfarin: OCP, barbiturate, estrogen, steroid

→ ↑ effect of warfarin: anabolic steroid, L-thyroxine, glucagon, cephalosporin

- Reversal, in emergency situation: FFP, vitamin K (it takes at least 6 hrs)

Life-threatening: prothrombin complex, FFP, factor VII, cryoprecipitate with vitamin K.

→ New generation: dabigatran, rivaroxaban, but no detectable level, no reversal → only dialysis, may be reversed by prothrombin complex.

→ If not urgent, stop 36–48 hrs when aPTT less than 1.3 times or INR 1.5, reversal not necessary.

- Patient on anticoagulant → stop heparin. If emergent surgery → protamine sulfate (can produce allergy).

- Vitamin K for biliary obstruction, malabsorption.

- Vitamin K is ineffective in hepatic failure.

- If patient for surgery and he is on warfarin → need (bridging) therapy, i.e., stop warfarin and start IV heparin.

→ Heparin should be held 4–6 hrs preoperative and restart 12–24 hrs postoperative along with warfarin.

Cardiopulmonary Bypass (CPB)

- Patient underwent CPB.

- contact with circuit tubing and membranes results in abnormal platelet and clotting factor activation, as well as activation of inflammatory cascades, that ultimately result in excessive fibri-nolysis and a combination of both quantitative and qualitative platelet defect.

- Empiric FFP, cryoprecipitate used for bleeding.

- TEG gives better assay for coagulation.

- Platelet given when patient bleeds postoperative.

- Desmopressin stimulates factor VIII.

Local Hemostasis

- Mechanical Procedure

➢ Oldest method: direct digital pressure.

➢ Tourniquet if limb is bleeding.

➢ Liver packing, Pringle maneuver if liver is bleeding.

➢ Small vein → ligation.

➢ Large vein → transfixation.

- Thermal Agent

➢ Denaturation of protein that results in coagulation.

➢ 20–100 mA.

- Topical

➢ Absorbable, biologic, synthetic agent.

- Absorbable: gelatin foam (Gelfoam), oxidized cellulose (surgicel), microfibrillar collagen (Avitene).

→ Gelfoam: physical matrix for clotting initiation.

→ Avitene: platelet adherence.

- Biologic: Floseal, Vitagel.

- Caution should be undertaken: thrombotic enter circulation → thrombosis.

Transfusion

Replacement Therapy

- 15% is −ve Rh.

- Administer Rh +ve for Rh −ve if not available, accepted unless female is in childbearing age.

- In emergent situation, −ve to all people but not more than 4 units → hemolysis.

- Crossmatch RBCs of donor and recipient.

- If antibody is present → avoid use.

- Crossmatch if administering dextran.

- Autologous transfusion (patient’s own blood), 40 days before OR, but Hb > 11 and hematocrit > 34%; last donation should be 3 days before surgery.

- Another modality cell saver machine (in trauma or long surgery).

Banked Whole Blood

- Rarely done.

- Shelf life is 42 days.

- During storage, ↓ ADP, 2, 3 DPG, alter oxygen dissociation curve

→ acidic, ↑ lactate, ↑ K+, ↑ ammonia.

- Recent evidence has demonstrated that the age of red cells may play a significant role in the incidence of inflammatory response and MOF.

Platelet

- Transfusion for thrombocytopenia.

- Shelf life is 120 hrs.

- One unit contains 50 mL.

- Therapeutic platelet level is 50,000–100,000.

- If the patient previously received platelet transfusion → HLA matching.

Fresh Frozen Plasma (FFP)

- Usual source of vitamin K dependent factor and is only source of factor V.

- Stored up to 5 days.

Tranexamic Acid (TXA)

- Antifibrinolytic agent.

- ↓ bleeding especially in CABG.

- ↓ risk of death due to ↓ hemorrhage by 21%.

- S/E: nausea, vomiting, blurred vision, DVT, PE, PV thrombosis.

- In urinary bleeding → TXA → ureter obstruction from thrombosis.

- Contraindicated in aneurysm, SAH.

- TXA: inhibit plasmin and plasminogen.

- TXA is ten times potent than aminocaproic acid.

- Not effective on platelet.

- Half-life is 2 hrs.

- No adjustment needed.

Indication for Replacement of Blood Products

- ↑ O2-carrying capacity.

- Treatment of anemia → if Hb 10 and hematocrit is < 30%

→ RCT study compares Hb > 10 vs. Hb 7–9 → no difference in mortality.

- Volume replacement → blood loss up to 20% → crystalloid. If more, give blood (RBCs, platelet, FFP).

New Concept in Resuscitation

- New concept damage control resuscitation.

→ ½ death before reaching hospital and all nonpreventable.

→ Truncal trauma → shock → ↑ death.

- Defined as administer ≥ 4–6 units within 4–6 hrs.

Damage Control Resuscitation (DCR)

- Composed of permissive hypotension, decreased crystalloid administration, and immediate release and administer PRBCs, platelet, FFP.

- Rate is 1:1:1.

Complication of Transfusion

- Related to blood-induced pro-inflammatory response.

- 10%, less than 0.5% is serious.

- Transfusion-related acute lung injury (TRALI), 16%–20%.

- ABO hemolytic transfusion reaction, 12%–15%.

- Bacterial contamination, 11%–18%.

Nonhemolytic Reaction

- Febrile nonhemolytic reaction, ↑ temperature > 1°C, associated with transfusion (1% of transfusion).

- Cytokines of donated blood to recipient antibody.

- Decreased due to ↓ leukocyte in blood product.

- Treatment: paracetamol.

- Bacterial contamination is rare, −ve gram stain capable of growing at 4°C.

→ Mostly from platelet stored at 20°C.

→ FFP in container with water both repeated.

→ Death and sepsis, 25%.

→ Symptoms: chills, tachycardia, hypotension, abdominal pain, diarrhea.

→ Treatment: stop transfusion, blood culture.

→ Adrenergic blocking agent and use leukocyte filter.

Allergic Reactions

- 1% with all transfusions.

- Usually mild rash, urticaria, and flushing, rarely anaphylactic shock.

- Caused by antibody of donor to recipient antigen.

- Affects all blood product, but platelet and FFP are common.

- Treatment: antihistamine; if shock → epinephrine and steroid.

Respiratory Complication

• Transfusion associated with circulatory overload (TACO).

→ Rapid infusion of blood, plasma expander, crystalloid.

→ Increase heart disease.

- CVP should be monitored.

- Overload, high CVP, dyspnea, cough, basal lung rales.

- Treatment: diuresis, ↓ blood administer rate.

- Transfusion-related acute lung injury (TRALI)

- Noncardiogenic pulmonary edema.

- Occurs with transfusion of any blood product.

- Symptoms: as TACO and hypoxemia + fever, rigor, bilateral lung infiltrate on CXR.

- Within 1–2 hrs after transfusion and before 6 hrs.

- ↓ TRALI with ↓ transfusion of plasma due to ↓ HLA class II antibody + HNA antibody.

- Treatment: D/C transfusion, ventilation support.

Hemolytic Reaction

- Acute and delayed

- Acute ABO incompatibility = 6% fatal, caused by laboratory technical error

→ IV destruction of RBCs → anemia, hemoglobinuria

→ Activation of coagulation cascade → acute renal failure from tubular necrosis

- Delayed 2–10 days

- Extravascular hemolysis, mild anemia, and high bilirubin (indirect)

→ Occurs in population with low antibody titer at time of transfusion

→ Reaction to non-ABO antigen → IgG by RES

→ Facial flushing, back and chest pain, fever, respiratory distress, hypotension, pulse in awake patient

→ In anesthetized patient → diffuse bleeding + hypotension

- Diagnosis: laboratory—hemoglobinuria and serology for incompatibility of donor and recipient of blood

- +ve Coombs test

- Delayed hemolytic transfusion fever, recurrent anemia, jaundice, low haptoglobin

- Treatment: hydrate and stop transfusion, send blood for retest from both samples

- Delayed reaction has no special treatment

Transmission of the Disease

- Malaria, Chagas disease, brucellosis disease, syphilis (rare).

→ Malaria’s incubation period is 8–100 days.

- Symptoms: shaking chills and spiking fever.

- CMV: infectious mononucleosis.

- HIV, HCV decreased by screening.

→ Risk is 1:1,000,000.

- HBV residual risk is 1:100,000.

- HAV is rare.

- West Nile virus.

- Creutzfeldt-Jakob disease (CJD) can also be transmitted.

Tests for Hemostasis and Blood Coagulation

- Bleeding time, clotting time, PTT, PT and INR, TEG.

- Platelet > 1,000,000, ↑ thrombotic complications.

- If major surgery, need to be > 50,000.

→ With minor intervention, > 30,000.

Spontaneous hemorrhage occurs when < 20,000.

- Platelet transfusion if < 100,000 in ophthalmology and neurosurgery procedures.

- The PT test measures the function of factors I, II, V, VII, and X.

- Factor VII is part of the extrinsic pathway, and the remaining are part of the common pathway.

- PT is to detect vitamin K deficiency and warfarin therapy.

- INR = 84014.png

- PTT measures factors I, II, V, and (VIII, IX, X, XII [intrinsic pathway]).

- Heparin action is measured by PTT.

- Bleeding time for platelet action, Ivy test, if prolonged, either platelet or vWF dysfunction.

- TEG is the only test measuring all dynamic steps of clot formation till clot lysis.

→ Also can identify thromboembolic complication after injury and postoperative

→ Can predict the need for lifesaving intervention and 24-hr mortality

→ Useful to guide administration of TXA to injured patients with hyperfibrinolysis.

Systemic Response to Injury

Overview: Injury Associated with Systemic Inflammatory Response

- Minor host insults: localized inflammatory response that is transient and most often beneficial.

- Major host insults: leads to amplified reaction, resulting in systemic inflammation, remote organ damage, and multiple organ failures.

- SIRS should meet two of the following:

o Temperature > 38°C or < 36°C

o Heart rate 90 beats/min

o Respiratory rate > 30 breaths/min or arterial CO2 < 32 mmHg

o WBCS > 12,000 or < 4,000

- Sepsis: SIRS + documented or suspected source of infection; in addition, other possible manifestations include elevations of procalcitonin, c-reactive protein, hyperglycemia in those without diabetes, altered mental status.

- Severe sepsis: sepsis + evidence of organ dysfunction.

o Arterial hypoxemia (PaO2/FiO2 < 300)

o Acute oliguria (urine output < 0.5 mg/dL)

o Increase in creatinine > 0.5 (INR > 1.5, PTT > 60 s, platelets < 100,000)

o Hepatic dysfunction (elevated bilirubin)

o Paralytic ileus

o Decreased capillary refill or skin mottling

- Septic shock sepsis with hypotension refractory to fluid resuscitation, needs pressor.

Detection of Cellular Injury

- Mediated by members of damage-associated molecular pattern family. Systemic inflammatory responses that limit damage and restore homeostasis:

1. Acute pro-inflammatory response: innate immune system recognizes ligands.

2. Anti-inflammatory response: modulate pro-inflammatory phase and return homeostasis.

Alarmins or Damage-Associated Molecular Patterns (DAMPs)

- With pathogen-associated molecular patterns (PAMPs), interact with specific cell receptors on cell surface and intracellular.

- It includes HMGB1, formyl peptides (mitochondrial DNA), S100 protein, biglycan.

High-Mobility Group Protein B1 (HMGB1 protein)

- It is the best characterized DAMP.

- It was first described as a constitutively expressed nonhistone chromosomal protein that participated in a variety of nuclear events, including DNA repair and transcription.

- It has been shown to signal via the toll-like receptors (TLR2, TLR4, TLR9).

- HMGB1 is actively secreted from immunocompetent cells stimulated by PAMPs (e.g., endotoxin) or by inflammatory cytokines (e.g., tumor necrosis factor and interleukin-1).

- It has the ability of HMGB1 to influence its activity, including cytokine production.

- It is rapidly released into circulation within 30 min following trauma.

Pro-Inflammatory Biologic Responses from HMGB1

Signaling

1. Release cytokines and chemokines from macrophages, monocytes, and dendritic cells

2. Neutrophil activation and chemotaxis

3. Altered epithelial barrier function

4. Increased procoagulant by platelets

5. Mitochondrial DAMPs

DAMPs—Ligands for Pattern Recognition Receptors (PRR)

Four distinct classes of PRR:

1. Toll-like receptors (TLRS)

2. Calcium-dependent (C-type) lectin receptors (CLRS)

3. Retinoic acid-inducible gene (RIG)-I–like receptors (RLRs)

4. Nucleotide-binding domain (NDB), leucine-rich repeat (LRR)–containing receptors

CNS Regulation of Inflammation in Response to Injury

- DAMPs and inflammatory molecules convey stimulatory signals to CNS via multiple routes.

- Inflammatory stimuli interact with receptors on brain to generate pro-inflammatory mediators (cytokines, chemokines, adhesion molecules, proteins of complement system, and immune receptors).

- Inflammation can also signal the brain via afferent fibers (vagus nerve).

Neuroendocrine Response to Injury

- Hypothalamic-Pituitary-Adrenal (HPA) Axis

➢ Results in the release of glucocorticoid hormones and the sympathetic nervous system, which results in release of the catecholamines, epinephrine, and norepinephrine

➢ Corticotropin-releasing hormone (CRH) → acts on anterior pituitary to stimulate ACTH secretion → acts on zona fasciculata to synthesize and secrete glucocorticoids

- Growth Hormone

➢ Promotes protein synthesis and insulin resistance, enhances mobilization of fat stores

➢ Enhances immunocyte phagocytosis by increased lysosomal superoxide production

- Insulin-like Growth Factor (IGF)-1

➢ Anabolic growth factor that improves metabolic rate, gut mucosal function, and protein loss after traumatic injury

- Ghrelin

➢ Natural ligand for GH

➢ Appetite stimulant secreted by stomach

➢ Promotes GI secretion and glucose homeostasis, lipid metabolism, and immune function

- Catecholamines

➢ Fight-or-flight response

➢ Effects: ↑ HR, myocardial contractility, conduction velocity, and BP

➢ Redirects blood flow to skeletal muscle

➢ ↑ cellular metabolism, mobilization of glucose from liver via glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis

- Aldosterone

➢ Mineralocorticoid released by zona glomerulosa

➢ Interferes with insulin-signaling pathways and reduces expression of insulin-sensitizing factors, adiponectin, and peroxisome proliferator–activated receptor

- Insulin

➢ Hormone secreted by pancreas

➢ Mediates overall host anabolic state through hepatic glycogenesis and glycolysis, peripheral glucose uptake, lipogenesis, and protein synthesis

Cellular Stress Responses

1. Reactive oxygen species (ROS) and oxidative stress response

2. Heat shock proteins (HSP)

3. Unfolded protein response

4. Autophagy

5. Apoptosis

6. Necroptosis

Mediators of Inflammation

1. Cytokines

➢ Mediate invading organism and promote wound healing

2. Eicosanoids

Omega-6 polyunsaturated metabolites: arachidonic acid

- Prostaglandins, thromboxane, leukotrienes

- Anti-inflammatory

- Inflammatory mediators

3. Plasma Contact System

A. Complement

- Eliminates immune complexes and damaged cells

- Mobilizes hematopoietic stem cells and lipid metabolism

- Classical pathway, lectin pathway, and alternative pathway

B. Kallikrein-Kinin System

- Group of proteins that contribute to inflammation, blood pressure control, coagulation, and pain responses

4. Serotonin

➢ Monoamine neurotransmitter (5-hydroxytryptamine)

➢ Potent vasoconstrictor and modulates cardiac inotropy

➢ Released by platelets

5. Histamine

➢ Short-acting endogenous amine

➢ Rapidly released or stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets

➢ Increased with hemorrhagic shock, trauma, thermal injury, and sepsis

Tumor Necrosis Factor

- TNF was thought to be produced primarily by macrophages, but it is produced also by a broad variety of cell types, including lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neurons.

➢ Large amounts of TNF are released in response to lipopolysaccharide, other bacterial products, and interleukin-1 (IL-1).

➢ In the skin, mast cells appear to be the predominant source of preformed TNF, which can be released upon inflammatory stimulus.

➢ It has a number of actions on various organ systems, generally together with IL-1 and IL-6.

- On the hypothalamus:

o Stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of CRH

o Suppressing appetite

o Fever

- On the liver: stimulates the acute phase response, leading to an increase in C-reactive protein and a number of other mediators. It also induces insulin resistance by promoting serine phosphorylation of insulin receptor substrate-1 (IRS-1), which impairs insulin signaling.

- It is a potent chemoattractant for neutrophils and promotes the expression of adhesion molecules on endothelial cells, helping neutrophils migrate.

- On macrophages: stimulates phagocytosis and production of IL-1 oxidants and the inflammatory lipid prostaglandin E2 (PGE2)

- On other tissues: increases insulin resistance. TNF phosphorylates insulin receptor serine residues, blocking signal transduction.

- On metabolism and food intake: regulates bitter taste perception.

Lymphocytes and T Cell Immunity

- The expression of genes associated with the adaptive immune response is rapidly altered following severe blunt trauma.

- Significant injury is associated with adaptive immune suppression that is characterized by altered cell-mediated immunity, specifically the balance between the major populations of T cells.

- T lymphocytes are functionally divided into subsets, which principally include Th1 and Th2 cells, as well as Th17 and inducible Treg cells.

Eosinophils

- Immunocytes whose primary functions are antihelminthic.

- Are found mostly in tissues such as the lung and gastrointestinal tract, which may suggest a role in immune surveillance.

- Can be activated by IL-3, IL-5, GM-CSF, and platelet-activating factor. Eosinophil activation can lead to subsequent release of toxic mediators, including ROSS, histamine, and peroxidase.

Mast Cells

- Important in the primary response to injury because they are located in tissues.

- TNF release from mast cells has been found to be crucial for neutrophil recruitment and pathogen clearance.

- It is known to play an important role in the anaphylactic response to allergens.

- On activation from stimuli including allergen binding, infection, and trauma, mast cells produce histamine, cytokines, eicosanoids, proteases, and chemokines, which leads to vasodilatation, capillary leakage, and immunocyte recruitment.

Monocyte/Macrophages

- Monocytes are mononuclear phagocytes that circulate in the bloodstream and can differentiate into macrophages, osteoclasts on migrating into tissues.

- Macrophages are the main effector cells of the immune response to infection and injury, primarily through mechanisms that include phagocytosis of microbial pathogens, release of inflammatory mediators, and clearance of apoptotic cells.

Neutrophils

- Neutrophils are among the first responders to sites of infection and injury and, as such, are potent mediators of acute inflammation.

- Chemotactic mediators from a site of injury induce neutrophil adherence to the vascular endothelium and promote eventual cell migration into the injured tissue.

- Neutrophils are circulating immunocytes with short half-lives (4–10 hrs).

- However, inflammatory signals may promote the longevity of neutrophils in target tissues, which can contribute to their potential detrimental effects and bystander injury.

- Once primed and activated by inflammatory stimuli, including TNF, IL-1, and microbial pathogens, neutrophils are able to enlist a variety of killing mechanisms to manage invading pathogens.

Vascular Endothelium

- Under physiologic conditions, vascular endothelium has overall anticoagulant properties mediated via the production and cell surface expression of heparin sulfate, dermatan sulfate, tissue factor pathway inhibitor, protein S, thrombomodulin, plasminogen, and tissue plasminogen activator.

Nitric Oxide

- Nitric oxide (NO) was initially known as endothelium-derived relaxing factor due to its effect on vascular smooth muscle.

- Normal vascular smooth muscle cell relaxation is maintained by a constant output of NO that is regulated in the endothelium by both flow-