The diagnosis of hepatitis can be made from the signs and symptoms that manifests clinically combined with the laboratory investigations.

Clinical Features
  -Jaundice
  -Dark Urine
  -Light-colored stools
  -Pruritus

Laboratory Features
  -Increased serum bilirubin
  -Increased serum bile acids
  -Increased serum cholesterol
  -Increased serum alkaline phosphatase
  -Slight increase in serum alanine (ALT) and aspartate (AST) transaminases
  -Prolonged prothrombin time (PT)
  -Normal serum albumin

The most common causes of acute hepatitis in the US is viral hepatitis. More than 250,000 new infections occurs annually. The diagnosis of each type of viral hepatitis can be made from specific serologic studies as follow.

Alcohol has been implicated in 15 million of people in the US, alcoholic physicians in the US is as high as 22,000. Alcohol is the 3rd leading cause of death and disability. The effects of alcohol on various organ systems are shown below :

Cardiovascular
   T arrhythmia
   T cardiomyopathy
   T hypertension
   T hyperdynamic status : increased CO, AV shunting, increased intravascular volume
   T congestive heart failure
Pulmonary
   T Hypoxia : secondary to extrinsic restrictive lung disease (from ascites)
   T Rt to Lt shunting : from portal vein hypertension
   T Intrapulmonary AV shunting
   T Frequent pneumonia : secondary to decreased pulmonary phagocytic activity/aspiration.
Renal system
   T Decreased renal blood flow, decreased GFR
   T Increased renin, angiotensin and aldosterone
   T Hepatorenal syndrome (abrupt oliguria with concomitant cirrhosis)
Central nervous system
   T Wernicke's syndrome
   T Korsakoff's syndrome
   T Peripheral polyneuropathy
   T Cerebellar degeneration
Gastrointestinal system
   T Erosive gastritis, Hepatic cirrhosis, Acute hepatitis, Pancreatitis, Fatty liver, portal vein hypertension, esophageal varices, decreased gastroesophageal sphincter tone, splenomegaly
Nutritional system
    T Hypoalbuminemia, megaloblastic anemia (require B12 and Folate), Decreased Vit K absorption, hypoglycemia
Endocrine system
    T Gynecomastia, testicular atrophy, irregular menses (female)
Hematological system
    T Coagulopathy from liver dysfunction, Leukopenia, anemia, thrombocytopenia
Immunologic system
    T Decreased immune defense mechanism.

The anesthetic consideration for the alcoholic patients can be discussed as

1. Preoperative preparation : gastric prophylaxis, the patient should be considered full stomach in acute intoxication. The chronic alcoholic may need aspiration prevention due to the alcohol effect on the EG sphincter. Patients may need a blood ETOH and toxicology panel as a screening.
2. Intraoperative period.
   -Monitoring : routine monitoring, the invasive CVS monitoring may be indicated for severe cardiomyopathy or severe derangement in CVS. The blood glucose and electrolytes monitoring may be useful.
   -Induction : consider benzodiazepines, rapid sequence induction with Sellick's maneuver, the plasma cholinesterase may be decreased (usually clinically insignificant). The induction agent dose is decreased in acute intoxication and increased in chronic alcoholics.
   -Maintenance : MAC of inhalation gas is decreased in acute intoxication and increased in chronic alcoholics. Patients with cardiomyopathy may not tolerate the myocardial depressant agents. Opioids and benzodiazepines may have prolonged half-lives because of impaired hepatic biotransformation. Resistant to non-depo MR is noted, the albumin is decreased but the gamma-globulin is markedly increased and results in low free fraction of drug. The increase in volume of distribution also plays a role. The elimination of vecuronium may be affected while the metabolism of atracurium and cis-atracurium is unaffected.
3. Postoperative period.
   -provide adequate analgesia, anxiolytic may be needed.
   -withdrawal syndrome may developed within 6-8 hr, which may progress to delirium tremens (DTs). DTs develops in 5% of patients with withdrawal with 10% mortality rate. The signs and symptoms include tremulousness, disorientation, hallucinations, autonomic hyperactivity (diaphoresis, hyperpyrexia, tachycardia and hypertension), Grandmal seizure. The treatment with benzodiazepines should be started promptly.
4. Other considerations
   -Regional anesthesia : may be used in chronic alcoholism. The relative contraindications includes presence of polyneuropathy, coagulopathy, decreased intravascular status (central neuraxial blockade), etc.
   -Disulfiram (Antabuse) which is used in chronic alcoholism has a long half-life (1-2 weeks). This drug inhibit dopamine-ß-hydroxylase which converts dopamine to NE, resulting in peroperative hypotension, potentiation of benzodiazepines and drowsiness.
   

Fluid resuscitation can be achieved by using crystalloid or colloid solutions. The distribution of these is going to be affected firstly by the inherent nature of the fluids, and secondly by the state of the patient's vascular system (affected by disease states, sepsis, vascular injury). Dynamics of fluid shifts from the intravascular space is also affected by the degree of tissue manipulation that occurs during the surgical procedure. We can account for replacement values varying from 2 ml/k/hr up to 6 ml/k/hr for small incisions to major surgical procedures, respectively. Another way of considering this with abdominal surgery is by adding 500 mls of replacement fluid per quadrant of the abdomen undergoing operative intervention in addition to the volume of maintenance and replacement fluids. This "additional" replacement is necessary due to the tissue edema and transcellular fluid displacement that occurs secondary to manipulation, as this volume becomes unavailable to the vascular space. As would be expected, with vascular damage or tissue manipulation colloid solutions would enter the injured tissue at a more rapid rate than they would normal tissues but still at a slower rate than do the crystalloid solutions.
Controversy exists with the use of colloids in ill patients and the leakage of colloid molecules from the vascular spaces leading to increased oncotic pressures in the tissues. Use of colloids would have to be weighed with the patients' health state and potential risks of increased interstitial edema, which could increase post surgical morbidity. The following is a review of crystalloid and colloid fluids and their characteristics.

Crystalloids:
Provide maintenance water and electrolytes
Expand intravascular fluid volume
Replacement requires 3-4 times the volume of blood loss
Rapidly filter from the intravascular space to the interstitial space
Distribution is 1:4 to equilibrate with the extracellular fluid
Isotonic solutions are effective plasma volume expanders
Dextrose solutions provide free water, which equilibrates throughout the total body fluid
Balanced electrolyte containing fluids good for replacing GI and third space losses, and provide buffers

Choices of Crystalloids:
a. Normal Saline
b. Hypertonic saline solutions: "small volume resuscitation" draws fluid in from interstitial space
c. Balanced salt solutions (Lactated Ringer's, Plasmalyte, Normosol): provide buffering

Colloids:
Provide large molecules to assist in maintenance of Colloid Oncotic Pressure
Administered in a 1:1 ratio relative to blood loss
Initial volume of distribution is equivalent to blood volume
Circulation half life varies per solution choice (below)
Added risk of infection with albumin
Minimal risk of infection with other colloids
Blood substitutes provide repletion of intravascular fluid volume, increased shelf life, lower cost and no risk of viral transmission.

Choices of Colloids:
a. Albumin (5%) and plasma protein fractions: COP ~20 mmHg, human product, expensive, possibility of infection

b. Albumin (25%) "salt poor": potential to expand plasma volume up to 5 times of the volume infused by drawing fluid from the interstitial fluid space, plasma half life is about 16 hours

c. Dextrans: molecular weights of 40, 60 or 70 kDa in solution, Dextran 70 used for same indications as 5% albumin, Dextran 40 used in vascular surgery to prevent thrombosis, Dextrans are not metabolized but small molecular fractions are excreted by the kidneys, larger fractions are hydrolyzed when they pass into tissues, associated with hypersensitivity reactions although less than previously when hapten prophylaxis is used, cause decreased platelet adhesion

d. Hydroxyethyl Starch (Hetastarch): synthetic colloid with molecular weights from 40K to 450K, produce a dilution effect on clotting factors (decrease factor VIII: C), adverse effect on coagulation, platelet and reticulo-endothelial function with volumes >20 mls/k/24 hrs, plasma half life is about 24 hours

e. Gelatins: plasma half life about 1-2 hours, produce dilution of clotting factors, anaphylactoid reaction with solutions containing high levels of urea cross linkage

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Anesthesia or anesthetic techniques has little impact on wound healing or wound infection when compare to surgical considerations and patient-related factors.. The surgical techniques play a direct role on wound infection e.g. presence of suture/foreign body, site, duration, complexity of surgery, suturing quality, pre-existing local or systemic infection, prophylactic antibiotics, haematoma, mechanical stress on wound, etc. The patient related factors includes DM, smoking, poor nutrition, alcoholism, chronic renal failure, obesity, advanced age, poor physical condition, etc.

For anesthetic considerations, the factors that may influence the surgical wound healing includes.

• Tissue Oxygen Partial Pressure (PTO2) : influences both the bactericidal ability of neutrophils and the amount of scar formation, which reflects wound tensile strength. The critical period of wound infection is during the surgery and the first 2-3 postoperative hours. Studies in 500 patients undergoing colorectal surgery has shown that the patients who receives 80% FiO2 has significant reduced number of postop-wound infection compare to patients who receives 30% FiO2.
• Tissue perfusion : related to tissue vascular resistance and blood viscosity.
• Normovolaemia/hypovolaemia : it's important for the anesthesiologist to maintain hemodynamic stability, minimize hypovolemia to prevent compensatory vasoconstriction.
• Perioperative body temperature : Studies have shown that inadvertent core hypothermia (<2 °c) yield more incidence of postoperative wound infection. The hypothermia inhibits neutrophil function and also induces thermoregulatory vasoconstriction which decreases PTO2.
• Quality of analgesia : pain can evoke a profound neuroendocrine and cytokine activity as known as "stress response". The sympathetic stimulation also causes vasoconstriction which reduces PTO2.
• Autologous blood transfusion : as we all know that giving allogeneic blood transfusion can reduce the patient's immunity. But the 2 RCT studies comparing allogeneic and autologous transfusion yielded conflicting results.
• General or Regional anesthesia : most GA cause transient immunosuppression and does not suppress stress response while the regional anesthesia does. Epidural anesthesia and postop. epidural analgesia preserves immune function. Combined GA and epidural anesthesia/analgesia also reduces postop. loss of body protein, by attenuating decrease in muscle synthesis, which is associated with the surgical stress response.

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• Viral : - Hepatitis ; mainly HCV (1%). 75% of cases are anicteric, 50% evolve in chronic liver disease, 10% in cirrhosis
            - AIDS
            - HIV2
            - CMV, EBV: especially in immunocompromised patient
            - HTLV1 /HTLV2 : leukemia/lymphoma
• Parasitic : - malaria, toxoplasma, Chagas disease
• Bacterial : Gram +ve - Staphylococcus, Gram-ve -Yersinia, Atrobactor (rare)

IMMUNE PROCESS
     immune reactions can be divided into hemolytic and non-hemolytic

Hemolytic : usually caused by destruction of transfused RBC by recipient antibodies (less common is the destruction of recipient RBC by transfused antibodies)

1. Acute : usually happens during transfusion. Most common cause is ABO incompatibility (most commonly related to clerical error) . If the patient is awake, classic symptoms/sings includes : fever, chills, nausea/vomiting, flank pain. Under anesthesia, signs are : increase temperature, tachycardia, hypotension, hemoglobinuria, renal failure
   
   If an acute transfusion reaction is suspected
     1. Stop transfusion
     2. check the name and the unit of blood again.
     3. draw blood sample
     4. check urine for Hb
     5. Increase IV fluids ± mannitol (to maintain diuresis)
     6. considers diuretics e.g. lasix or dopamine renal dose
   If rapid blood loss, considers using FFP ± Plt
   
   
2. Delayed : usually manifest after 20 days from transfusion as extravascular hemolysis, being caused by re-exposure to Ag. They are caused by Ab, anti-nonD antigen of Rh system, anti Kelly-Duffy-Kidd (1.6%). Classic signs and symptoms : malaise, jaundice ( with increase indirect bilirubin) and fever. Diagnosis is made by direct Coomb's test.
   Treatment : supportive treatment.

Non hemolytic : they can manifest as :

1. Fever : usually caused by Ab, anti WBC or Plt (1-3%). It's prevented by using poor leukocyte PRBC (washed PRBC), use of leukocyte filter).
2. Urticaria : it's caused by a sensitivity to plasma proteins. It manifests as erythema, hives, pruritus, fever. Antihistamines are efficacious.
3. Anaphylactic : usually caused by an allergen (protein in the transfused blood component to which the patient was previously sensitized) and IgE Ab present on mast cells/basophils of the recipient.
   The severity of symptoms range from mild urticaria to bronchospasm, laryngeal edema, severe hypotension or death. (the shorter the interval between xxxxx of transfusion and onset of symptoms, the more severe the reaction). Fever usually is not associated with anaphylaxis. A small percentage is associated to IgA deficiency in recipient. In case of anaphylactic reaction
      1. discontinue transfusion
      2. airway management
      3. epinephrine to support hemodynamic
      4. corticosteroid
      5. diphenhydramine
      6. IV fluid management
   The patient should be tested for IgA deficiency and the IgA deficient blood used for future transfusions.
4. ARDS : characterized by severe bilateral pulmonary edema, hypoxemia, tachycardia, fever, hypotension. It manifests within 1-6 hrs after transfusion of plasma-containing blood product. It seems to be related to a passive transfer of Ab from donor plasma (anti HLA, anti granulocyte Ab). The reaction between these Ab and patient's Ag on granulocytes triggers complement activation and pulmonary injury. With adequate ventilatory and hemodynamic support. Most patients recover within 48 hrs.
5. GVHD : occurs when immunocompetent donor lymphocytes are transfused into an HLA incompatible recipient, immunologically unable to eliminate the donor cells e.g. in patients with Hodgkin's disease, BMT, congenital cell-mediated immunodeficiencies). Sign and symptoms includes fever, rash, severe diarrhea, hepatitis, pancytopenia. They manifest within 10 days from transfusion. Death can occur within 2-4 wks. Irradiating the blood reduces the risk of GVHD.
6. Purpura : it's characterized by severe thrombocytopenia 5-10 days after transfusion of a patient who is already sensitized by prior transfusion or pregnancy. It seems to be related to Plt-specific Ab following transfusion. It usually recovers spontaneously, although steroids and IVIG may be needed. Plasmapheresis is also efficacious.
7. Immunomodulation : controversial. It appears that perioperative transfusion increase the incidence of postop. infections and recurrence of resected malignancy in transfused patients.
          

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The initial stages of severe sepsis and septic shock are often characterized by hypovolemia (from venous pooling or transudation of fluid). This tends to produce a hypodynamic state (i.e. low cardiac output). When the intravascular volume is adequate, the CO is usually elevated. However, intrinsic cardiac function (systolic and diastolic) is impaired in sepsis and the increase in CO is the result of tachycardia rather than an increase in stroke volume. Despite the increase in CO, peripheral blood can be diminished, as demonstrated below. In fact, contrary to the popular notion that sepsis is a hyperdynamic changes in advanced stages of sepsis more closely resemble a hypodynamic state (i.e., reduced blood flow and vasoconstriction).

Hypodynamic circulatory changes in sepsis and septic shock. (Data from Astiz ME et al. Peripheral vascular tone in sepsis. chest 1991;99:1072-1075)

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The liver transplantation is performed at over 2,000 cases annually in the United States, 25% are pediatrics. These patients are suffering an end stage liver disease and many life-threatening complications e.g. GI/variceal bleeding, encephalopathy, etc. The pathophysiology of each organ system involvement has been discussed in the topic no. 2 (alcoholism).
    Mostly, the allograft (transplanted liver) will be placed into the original site after the native hepatectomy performed. This is called "Orthotopic Liver transplantation"which is indicated in nonmalignant end-stage liver disease e.g. Budd-Chiari syndrome, congenital hepatic/cystic fibrosis, acute liver failure (viral or drug or toxin induced), Wilson disease, etc. Sometimes, the neo-liver will be placed without taking the diseased-liver out. This is called "Auxilliary or heterotopic liver transplantation" which is uncommonly performed, used to treat a reversible hepatic failure in the patients too unstable for orthotopic operation.

Preanesthetic Consideration
    Most of these patients are sick, complicated with many derangements associated with end-stage hepatic disease and uncorrectable at the time of surgery. The bleeding and metabolic derangements, the CNS abnormalities are not uncommon. The full labs investigation should be obtained, any correctable abnormalities should be made. The causes of liver failure should be identified, in some uncommon disease e.g. Crigler-Najjar syndrome - should avoid barbiturates, Budd-Chiari syndrome - may require perioperative anticoagulation. The blood bank should be informed to supply a large quantity of blood and blood products. The special instrument to salvage the blood intraoperatively including the rapid infusion system should be prompt. All kinds of invasive monitoring should be prepared. Some authors even placed 2 arterial line in the upper and lower extremities. The large bore (preferred 8 French) IV access in the upper extremities or centrally to the SVC is mandatory. The IV access in the groin may be useless when the dissection involves the clamping of IVC. The PA catheter is almost always employed in adult. Other special monitorings may be needed e.g. Blood gases/pH, electrolytes, glucose monitoring, cerebral oximeter, TEG, etc.

Intraoperative Consideration
   -Induction : considered rapid sequence induction or even awake intubation in a very sick patient. Although the plasma cholinesterase level is decreased in these patient but it has been used successfully. Variety of induction agents e.g. thiopental, etomidate, propofol, ketamine has been used. Avoid barbiturate in certain disease like stated above.
   -Maintenance : isoflurane, desflurane has been used safely. Avoid drugs that may compromise the splanchnic blood flow. The N2O may be avoided due to the bowel distention. Cis-atracurium or atracurium is preferred for muscle relaxation. The pharmacokinetic of fentanyl and sufentanil are largely unchanged. The surgical technique which will implicate the anesthetic management can be summarized as follow.

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PEEP exists whenever the airway pressure is greater than ambient pressure prior to next inspiratory cycle. PEEP in conjunction with spontaneous breathing is termed CPAP. To avoid confusion, the acronym PEEP/CPAP is used together dependent on which respiratory dynamic is referred.

The PEEP/CPAP effects are very well known for

1. Increase FRC
2. Redistribution of extravascular water

The beneficiary effect of PEEP/CPAP on pulmonary edema either cardiogenic or non-cardiogenic is the effect no.2. Please note that PEEP/CPAP does not decrease total lung water, but it improves oxygenation and pulmonary mechanics largely because of the effects on the distribution of lung water (please see picture). PEEP/CPAP decrease intra-alveolar fluid volume and facilitates the movement of water from the stiff (less compliant) interstitial spaces (between the alveolar epithelium and pulm capillary endothelium) where gas exchange occurs to the more compliant interstitial spaces (peribronchial and hilar regions).

Redistribution of lung water with PEEP. Picture from reference no. 1

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1. Acute IgE-mediated hypersensitivity reaction
2. Acute pulmonary venous vasculitis with resultant pulmonary hypertension
3. Chronic pneumonitis with or without progressive fibrosis.

Picture from reference no. 1	Risk of pulmonary toxicity and cumulative bleomycin dosage. The risk of pulmonary toxicity increases significantly once a total dose of 400 units is received by the patient.

picture from reference no. 1

picture from reference no. 2

picture from reference no. 2

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