Bongard Frederic , Darryl Sue. Diagnosis and Treatment Critical Care

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HEPATOBILIARY DISEASE

717

Treatment

Initial management is based on restoring blood volume

through intravenous hydration and transfusion. Coagulopathy

should be corrected as appropriate with fresh-frozen plasma.

In patients with significant bleeding or with altered senso-

rium, endotracheal intubation for protection of the airway

may be necessary.

A. Medical Treatment—Vasoactive drugs may be started as

soon as the diagnosis is suspected. These drugs have proven

value in nonesophageal sites of bleeding, such as portal

hypertensive gastropathy and gastric varices. Vasoconstrictors

decrease portal flow and pressure by decreasing splanchnic

arterial flow. Vasodilators decrease hepatic vascular resist-

ance and cause peripheral vasodilation, resulting in reflex

splanchnic vasoconstriction.

Vasopressin’s main role is as a temporizing measure. An

infusion of 0.2–0.4 units/min successfully controls acute

variceal bleeding in half of patients. It is often used for 48–72

hours. However, recurrent episodes of bleeding are common

(approximately 50%). By decreasing the rate of bleeding, it

facilitates initial resuscitation and the performance of

endoscopy for local definitive therapy of the bleeding varices.

Secondary effects are significant vasoconstriction with

hypertension, bradycardia, and risk of myocardial infarction.

Vasopressin generally is used in conjunction with nitroglyc-

erin. The combination, which reduces cardiac ischemia, is

superior to vasopressin alone in controlling acute variceal

bleeding. Nitroglycerin is also delivered via continuous infu-

sion at a dose of 0.2 μg/kg per minute.

Somatostatin is an effective hormone in the control of

acute variceal bleeding. An intravenous infusion of 25–50 μg/h

has been found to be as effective as vasopressin, balloon tam-

ponade, and sclerotherapy in prospective randomized trials.

Octreotide, the longer-acting form of somatostatin, is the

agent of choice in the initial management of acute variceal

bleeding because it is at least as effective as vasopressin but

has fewer side effects. Octreotide has been found to be as

effective as balloon tamponade of the esophagus in a clinical

trial.

B. Endoscopic Management—Sclerotherapy is the treat-

ment of choice in the management of acute variceal bleeding.

Sclerotherapy is successful in 60–90% of patients during ini-

tial management and is superior to vasopressin and balloon

tamponade. Complications of sclerotherapy are esophageal

ulceration, bleeding, perforation, bacteremia, and mediastini-

tis. Complications can occur in 10–30% of patients.

Variceal ligation is an alternative to sclerotherapy. The

efficacy is high and comparable with that of sclerotherapy.

There seems to be a trend toward fewer complications with

ligation.

Balloon tamponade is used less frequently as a temporiz-

ing measure, showing an efficacy of approximately 60–70%,

comparable with that of vasopressin and sclerotherapy but

associated with a high complication rate. In a Sengstaken-

Blakemore tube, the gastric balloon is passed into the stomach

and inflated; the esophageal balloon is inflated only if bleed-

ing is not controlled by the gastric balloon to 35–50 mm Hg

of pressure using manometer control. The lowest pressure

possible that will control hemorrhage should be used.

Serious complications, with a 5% mortality, include aspira-

tion pneumonia, esophageal rupture, and mucosal ulcera-

tion. The risk of complications increases with prolonged use.

However, use of a Blakemore-Sengstaken tube or a Linton

tube can be a lifesaving maneuver if medical and endoscopic

measures fail to stop bleeding.

C. Nonsurgical Shunts (Transjugular Portosystemic

Shunt [TIPS])—This technique is used widely in the setting

of acute variceal bleeding because it offers a rapid decom-

pressive shunt that does not require laparotomy. It is used as

primary treatment for patients with bleeding gastric varices

and for patients with hypertensive portal gastropathy—

mainly because of the difficulty and poor results with endo-

scopic management.

D. Surgical Treatment—Surgery plays a role in the manage-

ment of patients who fail medical, endoscopic, and TIPS

management of acute variceal bleeding. The surgical options

are either shunt or nonshunt operations.

Shunt procedures are either total (eg, portacaval shunt,

mesocaval shunt, and central splenorenal shunt) or selective

(eg, distal splenorenal shunt). These procedures are so

named because they theoretically divert all (total) or only

part (selective) of the portal blood flow. The most commonly

used operation in the emergency setting is a portacaval

shunt. It is very effective in controlling acute bleeding and

preventing rebleeding, but the mortality rate is as high as

50%. All surgical procedures have some undesirable side

effects, including encephalopathy and/or ascites. The selec-

tive procedures loose their selective nature over time and also

have undesirable side effects.

Gastroesophageal devascularization (Sugiura operation)

is a nonshunt operation. It has fallen into disfavor because

the recurrence rate of bleeding is high, but it is indicated in a

selected subset of patients with portal vein thrombosis or

segmental portal hypertension with an acute bleeding

episode.



Ascites

ESSENTIALS OF DIAGNOSIS



History: abdominal distention.



Physical examination: fluid wave, shifting dullness, and

dullness to percussion.



Abdominal ultrasound may detect up to 100 mL of

ascitic fluid; ultrasound is useful in the diagnosis of

patients with minimal ascites.



Paracentesis; serum ascites albumin gradient >1.1 g/dL.

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CHAPTER 34

718

General Considerations

A typical circulatory dysfunction characterized by arterial

vasodilation and high cardiac output coupled with increased

sinusoidal pressure and hepatic insufficiency is the cause of

ascites in cirrhotic patients. In addition, there is renal sodium

and water retention caused by stimulation of the renin-

angiotensin-aldosterone axis and activation of antidiuretic

hormone (ADH) secretion by the relative underfilling of the

arterial vascular compartment.

Over 50% of patients with cirrhosis will develop ascites. It

is therefore one of the most common complications of cir-

rhosis. Once ascites develops, the median survival is approx-

imately 1 year.

Clinical Features

A. Symptoms and Signs—Patients with large-volume

ascites complain of increasing abdominal girth and abdomi-

nal pressure. Some patients complain of anorexia, early sati-

ety, and nausea or flank pain. Clinical findings of abdominal

distention and shifting dullness and demonstration of a fluid

wave support the diagnosis of ascites. Other stigmata of liver

disease that aid in diagnosis are jaundice, spider angiomas,

and large periumbilical collateral veins in the abdominal wall

(caput medusae).

B. Laboratory Findings—Diagnostic paracentesis is essen-

tial in the evaluation and management of patients with

ascites. Inspection of the fluid in patients with portal

hypertension reveals clear, straw-colored fluid. Laboratory

evaluation includes cell count, cytologic examination, albu-

min and protein concentrations, and bacteriologic analysis.

The serum-to-ascites albumin gradient, calculated by sub-

tracting the ascitic fluid albumin level from the serum albu-

min level, has been shown to be effective in differentiating

portal hypertensive from nonportal hypertensive ascites.

Patients with a gradient of more than 1.1 g/dL can be diag-

nosed as having portal hypertension with a reliability of

97%. A gradient of less than 1.1 g/dL suggests nonportal

hypertensive etiology. Further differentiation of the ascitic

fluid as a transudate or exudate provides insight into the

origin of ascites.

C. Imaging Studies—Ultrasonography may be helpful in

the detection of small volumes of ascitic fluid. Duplex

ultrasound of the portal and hepatic venous system is indi-

cated if portal vein thrombosis or hepatic vein thrombosis

is suspected. CT scanning is also helpful in the detection of

small volumes of ascites, usually as an incidental finding

when x-rays are requested for evaluation of intraabdominal

pathology.

Differential Diagnosis

Cirrhosis and chronic liver disease are the most common

causes of ascites (approximately 70–80% of patients). The

differential diagnosis of ascites is set forth in Table 34–4.

Spontaneous bacterial peritonitis is a frequent complica-

tion of cirrhotic patients with ascites. It has a 1-year mortal-

ity of 40% despite treatment with antibiotics. Because its

inception can be subclinical, bacteriologic analysis should be

done on every patient with new-onset ascites. Culture of

ascitic fluid in blood culture bottles is more reliable and is

successful in approximately 80% of patients.

Treatment

The treatment of ascites is directed at the underlying

pathogenesis.

A. Medical Treatment—Patients with mild ascites may be

managed with fluid (1.5 L/day) and sodium restriction (88

meq/day). Addition of an inhibitor of aldosterone (eg,

spironolactone) provides a slow sodium loss with preserva-

tion of potassium. Initial doses are 100 mg/day but may be

elevated progressively up to 400 mg/day. Monitoring of

weight and electrolytes is important so that adjustments can

be made to the initial therapy.

Patients with moderate ascites should, in addition, receive

loop diuretics (eg, furosemide). An initial dose of 40 mg/day

generally is well tolerated and may be increased up to

160 mg/day in adults. Careful monitoring of weight, elec-

trolytes, and serum creatinine may prevent complications

from diuretic therapy. Any rise in serum creatinine or urea

nitrogen warrants reduction of the diuretic dosage. An initial

daily weight loss of 500 g/day is acceptable in patients with

moderate ascites. If patients have peripheral edema, a weight

loss of approximately 1 kg/day is acceptable.

Patients with tense ascites in addition should be treated

with paracentesis. Up to 4–5 L may be removed safely.

Organ System Cause

Hepatic Cirrhosis

Veno-occlusive disease

Cardiac Right ventricular failure

Constrictive pericarditis

Renal Nephrotic syndrome

Renal failure

Malignancy Ovarian

Gastric

Colorectal

Pancreatic

Immunologic Tuberculosis

Pancreas Pancreatitis

Lymphatic Congenital anomaly

Trauma

Digestive Malnutrition

Endocrine Myxedema

Table 34–4. Differential diagnosis of ascites.

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HEPATOBILIARY DISEASE

719

Attention to salt and water restriction is also a critical com-

ponent of management. Patients who require large-volume

paracentesis may develop rapid contraction of the intravascu-

lar space after fluid shifting. Clinical trials have documented a

better outcome after large-volume paracentesis with the

simultaneous infusion of intravenous albumin. Intravenous

salt-poor albumin should be used routinely in patients under-

going large-volume paracentesis. As a rule of thumb, salt-poor

albumin (~10 g/L of ascitic fluid) is infused concomitantly

intravenously. Spontaneous bacterial peritonitis must be sus-

pected in patients with known liver disease who present with

fever, leukocytosis, and abdominal pain. Cell count of the

ascitic fluid is diagnostic if the polymorphonuclear neutrophil

count is 250 in the absence of a visceral source of infection.

Treatment should be initiated empirically on diagnosis. A

third-generation cephalosporin such as ceftriaxone or cefo-

taxime generally is the first-line therapy until a specific organ-

ism has been selected on the basis of ascitic fluid culture. A

5-day course generally is therapeutic. Most common organ-

isms are Escherichia coli, Klebsiella, and Streptococcus pneumo-

niae. Other organisms are Enterococcus, Bacteroides, and

Enterobacter. Antibiotics with a nephrotoxic profile, such as

aminoglycosides, should be avoided if at all possible.

B. Surgical Treatment—Ten percent of patients develop

intractable ascites. Refractory ascites may be treated by the

placement of a transjugular intrahepatic portosystemic

shunt. Transjugular intrahepatic portosystemic shunt inser-

tion lowers the rate of ascites recurrence and the risk of

developing hepatorenal syndrome compared with paracente-

sis plus albumin administration in patients with refractory

ascites. However, a recent meta-analysis documented

increased encephalopathy and absence of improvement in

survival. Transjugular intrahepatic portosystemic shunt

insertion is also recommended in the treatment of patients

with severe ascites and imminent rupture of umbilical/ven-

tral hernia or hepatic hydrothorax.

Operative therapy with placement of a peritoneovenous

shunt may be considered in patients with mild, stable liver

dysfunction who are otherwise refractory to less invasive

therapies. Although shunting is a simple surgical procedure,

the incidence of postoperative complications is high, related

to infection, coagulopathy, congestive heart failure, and early

shunt occlusion.

Patients with severe or rapidly deteriorating liver dys-

function should be considered for liver transplantation.



Hepatorenal Syndrome

ESSENTIALS OF DIAGNOSIS



Chronic liver disease.



Renal failure.



Circulatory abnormalities (low systemic vascular resist-

ance and blood pressure).

General Considerations

Hepatorenal syndrome is a clinical condition that occurs in

patients with chronic liver disease, advanced hepatic failure,

and portal hypertension characterized by impaired renal

function. The prevalence of hepatorenal syndrome in patients

with end-stage cirrhosis ranges between 7% and 15%. It is

associated with marked abnormalities in the arterial circula-

tion and activity of the endogenous vasoactive system. Severe

renal vasoconstriction causes a low glomerular filtration rate

(GFR), whereas in the extrarenal circulation there is predom-

inance of arterial vasodilation, which results in reduction of

total systemic vascular resistance and arterial hypotension.

Hepatorenal syndrome is caused by severe vasoconstric-

tion of the renal circulation. A number of vasoactive media-

tors are implicated in the development of vasoconstriction,

such as angiotensin II, norepinephrine, neuropeptide Y,

endothelin, adenosine, and cysteine leukotrienes. The most

commonly accepted explanation is the arterial vasodilation

theory, which proposes that renal hypoperfusion represents

the extreme manifestation of underfilling of the arterial cir-

culation secondary to massive vasodilation of the splanchnic

circulation. Splanchnic vasodilation is caused by nitric oxide,

prostaglandins, and vasodilator peptides. In the early phase,

urine output and renal function are maintained by renal

vasodilator factors. Hepatorenal syndrome develops later,

when vasoconstriction ensues from relative hypovolemia.

Hepatorenal syndrome may be precipitated by concomi-

tant illnesses or may occur spontaneously. Spontaneous bac-

terial peritonitis is the most common precipitating factor of

hepatorenal syndrome in patients with cirrhosis.

Clinical Features

A. Symptoms and Signs—Hepatorenal syndrome occurs as

a complication of cirrhosis, more commonly in patients with

ascites. Two types are recognized. Type I is characterized by

rapid and progressive impairment of renal function.

Dominant features are marked renal failure, oliguria or

anuria, and high levels of urea and creatinine. Most patients

have hyperbilirubinemia, coagulopathy, and encephalopathy.

The median survival is only 2 weeks. Type II consists of mild

and stable reduction in renal function. These patients typi-

cally present with diuretic-resistant ascites.

Four major criteria must be present to establish the diag-

nosis of hepatorenal syndrome: (1) low GFR (creatinine

clearance <40 mL/min or serum creatinine >1.5 mg/dL),

(2) absence of shock with ongoing bacterial infection, fluid

loss, and current treatment with nephrotoxic drugs, (3) no

improvement in renal function after withdrawal of diuretics,

and (4) no evidence of obstructive uropathy and absence of

proteinuria (<500 mg/day).

B. Laboratory Findings—Laboratory findings in hepatorenal

syndrome include a creatinine clearance of less than 40 mL/min

or a serum creatinine concentration of more than 1.5 mg/dL,

a urine sodium concentration of less than 10 meq/L, a urine



CHAPTER 34

720

osmolality that is greater than plasma osmolarity, urine red

blood cells fewer than 50/hpf, and a serum sodium concen-

tration of less than 130 meq/L.

Differential Diagnosis

Other causes of renal failure that must be excluded prior to

making a diagnosis of hepatorenal syndrome include hypov-

olemia causing prerenal failure (eg, use of diuretics or bleed-

ing), acute tubular necrosis (eg, following hypotension or

sepsis), drug-induced nephrotoxicity (eg, NSAIDs or amino-

glycosides), and glomerulonephritis (commonly associated

with proteinuria) secondary to autoimmune disease.

Treatment

Initial management requires volume replacement and reach-

ing a euvolemic state. Once hepatorenal syndrome is sus-

pected, medical management is difficult and more often than

not unsuccessful. Basic management requires monitoring of

urine output, patient weight, blood pressure, evaluation and

replacement of electrolytes, and possibly dialysis.

Intravenous clonidine has been shown to lower renal vas-

cular resistance and increase the GFR by as much as 25%.

Dopamine has been proposed as a selective vasodilator of the

renal circulation in selected reports, but the literature sug-

gests that there is only a very mild effect in increasing GFR.

Liver transplantation causes a dramatic improvement in

renal function. Recovery of renal function typically is seen

within 48–72 hours of transplantation. Long-term survival

after transplantation is very good—approximately 60% after

3 years. The perioperative phase may be more complicated

owing to a 30% requirement of temporary hemodialysis and

the higher incidence of morbidity and mortality than in

patients transplanted without hepatorenal syndrome.



Preoperative Assessment & Perioperative

Management of Patients With Cirrhosis

There is high perioperative morbidity and a high mortality

risk in patients with cirrhosis undergoing abdominal surgery

for any indication. Liver function may deteriorate from general

anesthesia. Anesthesia reduces cardiac output, induces

splanchnic vasodilation, and causes a 30–50% reduction in

hepatic blood flow.

The 30-day mortality for patients with cirrhosis undergo-

ing celiotomy is 30%. A 60% major complication rate also

was reported. The risk depends on a number of factors.

A. Physiologic Status—The Child-Turcotte-Pugh classifi-

cation of surgical risk is summarized in Table 34–5. This clas-

sification was first proposed (by Child) as a means of

predicting the operative mortality associated with portacaval

shunt surgery. The presence of ascites, encephalopathy, and

coagulopathy predicts mortality. There is a 10% mortality

rate for patients with Child class A cirrhosis, 30% for Child

class B, and 75% for Child class C.

Another model predictive of outcomes in patients with cir-

rhosis is the Model for End-Stage Liver Disease (MELD),

which is a numerical scale based on the etiology of cirrhosis,

bilirubin, creatinine, and international normalization ratio

(INR). Scores range from 6 (less ill) to 40 (gravely ill), and the

model is used for liver transplant candidates aged 12 and older.

B. Type of Surgery—The overall hospital mortality rate was

estimated at 21% for biliary surgery, 35% for peptic ulcer

disease, and 55% for colectomy. Newer techniques such as

laparoscopy and better patient selection have contributed to

a reduced mortality rate in recent reports of laparoscopic

cholecystectomy and appendectomy.

C. Other Factors—Active infection, a higher number of

blood transfusions, pulmonary complications, GI bleeding,

and the need for emergency surgery have a negative impact

on the outcome of surgery in patients with cirrhosis.



Liver Resection in Patients

with Cirrhosis

Hepatectomy is a major operation that induces a severe cata-

bolic response and immunosuppression. Cirrhotic patients

already suffer from underlying catabolism and immunosup-

pression. Liver resection in patients with underlying liver

Clinical Variable 1 Point 2 Points 3 Points

Encephalopathy None Stage 1–2 Stage 3–4

Ascites Absent Slight Moderate

Bilirubin (mg/dL) <2 2–3 >3

Albumin (g/dL) 3.5 2.8–3.5 <2.8

Prothrombin time

(seconds prolonged or INR)

<4 s or

INR <1.7

4–6 s or

INR 1.7–2.3

>6 s or

INR >2.3

Interpretation: Child class A = 5–6 points, Child class B = 7–9 points, Child class C = 10–15 points.

Table 34–5. Child-Turcotte-Pugh estimate of surgical risk.



HEPATOBILIARY DISEASE

721

insufficiency carries the risk of postoperative liver failure. In

experienced hands, the mortality rate after hepatectomy

ranges from 5–50%.

Other postoperative complications are common, such as

the development of ascites (5%), encephalopathy (20%),

renal failure (15%), and upper GI bleeding (5%). Factors

that contribute to this great variability are the extent of resec-

tion and the patient’s underlying physiologic status.

Preoperative patient selection and perioperative manage-

ment are critical to successful outcome after liver resection in

patients with cirrhosis.

Preoperative Evaluation

Prior to operation, attention is directed to identification of

patients in whom the complication rate or mortality risk

is prohibitive. Numerous methods of identification have been

proposed. The clinical classification of patients according to

their Child score is a time-tested approach and is used most

commonly. Patients with Child A liver function have a hospi-

tal mortality risk for major hepatectomy of 3–15%. Patients

with Child B or C liver function tolerate liver resection poorly,

and that procedure should be withheld except in highly

selected individuals who require minimal surgery. Others have

proposed the use of the indocyanine green clearance test, the

lidocaine clearance test, and measuring the degree of fibrosis

in the unaffected liver as predictors of morbidity and mortal-

ity. Another factor that must be considered in selection of

patients is the volume of remaining liver estimated by CT scan.

As before any other major surgery, a good clinical history

and examination should alert the clinician to the presence of

any significant pulmonary, cardiac, hematologic, or renal

disorders. Screening of hematologic, biochemical, renal, pul-

monary, and cardiac function is essential.

Operative Management

Metabolic and hematologic derangements must be corrected

prior to surgery. Intraoperative monitoring of blood loss,

hemodynamics, and urine output is crucial. Patients with

hepatic dysfunction suffer from peripheral vasodilation and

are less responsive to catecholamines. It is therefore impor-

tant to maintain the circulatory volume. Maintaining liver

perfusion during surgery is critical to the prevention of any

further impairment of hepatic function. Therefore, anes-

thetic agents that do not impair hepatic perfusion and oxy-

genation should be selected.

Liver transection must be performed with two issues in

mind, minimizing blood loss and having adequate hemostasis

and securing biliary radicles to avoid postoperative biliary leak-

age, which is a cause of postoperative morbidity and sepsis.

Postoperative Care

Postoperative monitoring should include hemodynamics,

oxygen saturation, vital signs, fluid balance, electrolytes, and

blood glucose. Postoperative pain must be controlled to

avoid cardiopulmonary complications. Careful fluid man-

agement is a critical component of postoperative care.

Maintaining euvolemia is a priority. Owing to alterations in

the renin-angiotensin-aldosterone axis, cirrhotic patients

have a propensity for salt retention and third spacing of

extracellular water. This, in turn, manifests as ascites. When

salt restriction is required, 0.25% saline solution should be

used instead of 0.5%.

Parenteral nutritional support is provided in the form of

branched-chain amino acids because they reduce the cata-

bolic response and promote hepatic protein synthesis and

liver regeneration in cirrhosis. Adequate calories and fatty

acids are also provided. Perioperative nutritional support

reduces overall postoperative morbidity by decreasing septic

complications, the incidence of ascites, and deterioration of

liver function.

Potassium phosphate is used in the parenteral solution to

avoid hypophosphatemia, which occurs commonly after

hepatectomy. Phosphate is necessary for production of ATP

in the liver.

At least one study supports the use of salt-poor albumin

in septic cirrhotic patients as a means of reducing renal com-

plications and mortality.

Hyperbilirubinemia occurs commonly and generally is

transient, but progressive hyperbilirubinemia is an ominous

sign. Decreased sensorium, hypoglycemia, and acidosis are

present in severe hepatic failure and portend a poor prognosis.

Hepatic failure is complicated by a noncorrectable coagulopa-

thy and sepsis. Use of the bioartificial liver is potentially a life-

saving measure, but this resource is not yet widely available.

Liver transplantation is the only option (see Chapter 35).

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

723

0035

Burns

David W. Mozingo, MD

William G. Cioffi, Jr., MD

Basil A. Pruitt, Jr., MD

∗

Burns represent particularly challenging and difficult man-

agement problems. This chapter addresses the most common

causes, including thermal, electrical, and chemical burns.

Because of the far-reaching implications for care, additional

aspects of electrical injuries such as lightning strikes and

electrocution are discussed further with environmental

injuries in Chapter 37.

I. THERMAL BURN INJURY

Approximately 1.25 million burn injuries occur each year

in the United States. House and structure fires account for

81% of the 3600 burn- and fire-related deaths that occur

each year. Flame injury following a house fire or ignition of

clothing is the most common burn injury in patients

admitted to burn centers. Scald burns, the most common

burn injury in children, are responsible for about 30% of

patients requiring hospitalization for burns. Most burn

injuries are treated adequately on an outpatient basis; how-

ever, approximately 60,000 patients per year require hospi-

tal care because of the extent of their injury, the presence of

comorbid factors, or extremes of age. Approximately 20,000

patients have injuries of such significance that care is best

undertaken in a designated burn care facility. The American

Burn Association has developed criteria to identify patients

who require treatment in a burn center. These criteria assess

the severity of injury and the need for specialized burn cen-

ter treatment based on the age of the patient; the extent,

depth, and location of the burn; the type of injury; and the

presence of preexisting comorbid factors or associated

injuries (Table 35–1).

Thermal burn injury initiates a deleterious pathophys-

iologic response in every organ system, with the extent

and duration of organ dysfunction proportionate to the

size of the burn. Direct cellular damage is manifested by

coagulation necrosis, with the magnitude of tissue destruc-

tion determined by the temperature to which the tissue is

exposed and the duration of contact.



Histopathologic Characteristics of Burned

Tissue

Following thermal injury, the region of the burn in which

protein coagulation and cell death has occurred has been

referred to as the zone of necrosis. In full-thickness injury, all

dermal elements are destroyed, whereas partial-thickness

burns are characterized by a variable and incomplete dermal

necrosis. Extending radially from the zone of necrosis are

areas of cellular damage referred to as the zones of stasis and

hyperemia. The zone of stasis is characterized by a decreased

microvascular blood flow, which may be restored to normal

with successful resuscitation or converted to necrosis follow-

ing inadequate perfusion, desiccation, or infection. Minimal

thermal injury induces a zone of hyperemia characterized by

an immediate inflammatory response and increased

microvascular blood flow. These early histopathologic

changes are depicted as concentric tissue zones about the

point of thermal contact. Coagulation necrosis of the skin

and skin appendages results in loss of normal skin functions;

the antimicrobial barrier is destroyed, control of water evap-

oration is lost, and regulation of body temperature is

impaired.



Mechanisms of Edema Formation

Following thermal injury, edema formation in the burn

wound and in unburned tissues is greatest in the first 6 hours

following injury and continues to a lesser extent for the first

24 hours postburn. Postcapillary venular constriction results

in a marked increase in capillary hydrostatic pressure and

the production of interstitial edema in the early postinjury

phase. In an animal model of burn injury, a strongly nega-

tive interstitial fluid hydrostatic pressure has been shown

to occur within 30 minutes of injury. The duration and

∗

The views of the authors do not purport to reflect the position of

the Department of the Army and the Department of Defense.



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724

magnitude of the negative hydrostatic pressure change were

proportional to the size of the burn. An early increase in the

interstitial fluid colloid osmotic pressure following burn

injury resulting in a reversal of the transcapillary osmotic

pressure gradient also has been reported. Following initial

changes in the physical characteristics of burn tissue, subse-

quent edema formation generally has been attributed to an

increase in microvascular permeability owing to the effects of

humoral factors liberated from burned tissue and cytokines

produced by activated leukocytes. The plasma concentration

of histamine, a potent regulator of vascular permeability

present in abundance in mast cells, rises in proportion to

burn size immediately following injury. Many inflammatory

mediators, including activated proteases, prostaglandins,

leukotrienes, fibrin degradation products, and substance P,

have been reported to increase microvascular permeability

following burn injury. Specific antagonists to these agents

have been shown to decrease but not eliminate edema forma-

tion when administered prior to burn injury. The efficacy of

inflammatory mediator antagonists in decreasing microvas-

cular permeability when administered following burn injury

has not been demonstrated conclusively.

Leukocyte activation results in the production of

cytokines and other factors capable of increasing microvas-

cular permeability. Lysosomal enzymes, increased xanthine

oxidase activity, products of complement activation, and

oxygen radicals are generated following thermal injury and

are capable of increasing microvascular permeability and

burn wound edema. Interleukin 2 (IL-2)–activated human

killer lymphocytes have been shown to increase albumin flux

across monolayers of cultured endothelial cells in vitro. Even

though neutrophil depletion has been reported to protect

against postburn lung injury, it did not reduce burn wound

edema formation. The response of the leukocyte appears to

depend on the agent of injury, the proximity to the site of

injury, and exposure to humoral mediators.

Edema formation also occurs in unburned tissues follow-

ing a major burn. Conflicting reports exist concerning the

mechanism of this edema formation. In animal studies, an

increase in the ratio of lymph to plasma protein measured in

uninjured extremities following burn injury, as well as an

increase in extravasation of radiolabeled albumin into unin-

jured tissue, has been described. Others were unable to

demonstrate a change in ratios of lymph to serum protein

from an uninjured sheep extremity following burn injury,

implying that no change in vascular permeability in the

uninjured extremity had occurred. Edema accumulation

may be massive in unburned tissue following thermal injury,

and despite the conflicting reports, it is most likely due to

changes in oncotic pressure and the dilutional effects result-

ing from the infusion of large volumes of crystalloid fluid

required for burn resuscitation. Edema formation is charac-

terized by a shift of fluid and protein from the intravascular

into the extravascular compartment. Volume shifts occur in

proportion to the extent of burn, resulting in decreased

blood volume and decreased cardiac output, which, if

untreated, progress to hypovolemic shock.



Organ System Responses to Burn Injury

The magnitude and duration of the prototype organ

response to thermal injury of early hypofunction and later

hyperfunction depend on the extent of injury.

Cardiovascular System

During the resuscitative phase, the initial cardiovascular

response to thermal injury is manifested by decreased cardiac

output and increased peripheral vascular resistance followed

by a progressive increase in cardiac output and decrease in

peripheral vascular resistance during the hypermetabolic

flow phase. The fall in cardiac output is proportional to the

size of the burn and attributable to the loss of fluid and pro-

tein from the intravascular into the extravascular compart-

ment. There is a corresponding reflex increase in peripheral

vascular resistance as a consequence of the neurohumoral

response to hypovolemia. A myocardial depressive factor has

been implicated as the cause of initial impaired myocardial

performance; however, this factor has not been identified.

Clinical studies have demonstrated that in the absence of

heart disease, the ventricular ejection fraction and velocity of

myocardial fiber shortening were increased following thermal

injury and that hypovolemia, as measured by decreased left

ventricular end-diastolic volume, was the cause of depressed

cardiac output. Fluid resuscitation following burn injury

improves cardiac performance as hypovolemia is corrected.

Table 35–1. American Burn Association burn center

referral guidelines.

Partial-thickness burns greater than 10% total body surface area

Burns that involve the face, hands, feet, genitalia, perineum, or major

joints

Third-degree burns in any age group

Electrical burns, including lightning injury

Chemical burns

Inhalation injury

Burn injury in patients with preexisting medical disorders that could

complicate management, prolong recovery, or affect mortality

Any patients with burns and concomitant trauma (such as fractures) in

which the burn injury poses the greatest risk of morbidity or

mortality. In such cases, if the trauma poses the greater immediate

risk, the patient may be initially stabilized in a trauma center before

being transferred to a burn unit. Physician judgment will be neces-

sary in such situations and should be in concert with the regional

medical control plan and triage protocols.

Burned children in hospitals without qualified personnel or equipment

for the care of children

Burn injury in patients who will require special social, emotional, or

long-term rehabilitative intervention

TBSA=total surface area.



BURNS

725

As microvascular permeability decreases, the plasma volume

deficit is replenished in the second 24 hours, and cardiac out-

put increases to supranormal levels. Peripheral vascular

resistance decreases below normal, and the postburn hyper-

metabolic state, which peaks in the second postburn week

and slowly recedes thereafter, is established. Studies have

demonstrated that the postresuscitation increase in cardiac

output is directed primarily toward the burn wound; that is,

the blood flow to a burned extremity is significantly

increased compared with an unburned extremity in the same

patient, and the increase is proportional to the extent of burn

on the involved extremity. As a consequence, a decrease in

cardiac output secondary to hypovolemia or pharmacologic

intervention may reduce the flow of oxygen and nutrients to

the wound and impair wound healing.

Lungs

Following thermal injury, even in the absence of associated

smoke inhalation, physiologic changes in pulmonary func-

tion occur. Immediately postburn, minute ventilation is

unchanged or slightly increased as a result of anxiety- and

pain-induced hyperventilation. With the initiation of fluid

resuscitation, respiratory rate and tidal volume increase pro-

gressively, resulting in a minute ventilation that may be two

to two and one-half times normal. The magnitude of this

increase is proportional to the extent of burn and is consid-

ered to reflect postinjury hypermetabolism. In patients with

circumferential burns of the thorax, the unyielding eschar

and underlying edema may restrict ventilation to the point of

requiring escharotomy incisions to relieve the restrictive ven-

tilatory defect.

Pulmonary vascular resistance increases immediately fol-

lowing thermal injury, and the increase is more prolonged

than the increase in peripheral vascular resistance. The

release of vasoactive amines and other mediators following

thermal injury may be responsible for the increased pul-

monary vascular resistance, and this process may exert a pro-

tective effect during fluid resuscitation by decreasing

pulmonary capillary hydrostatic pressure and thus prevent

pulmonary edema. Lung lymph flow studies have demon-

strated no change in pulmonary capillary permeability fol-

lowing cutaneous thermal injury. Complement activation

and generation of the chemotactic peptide C5A have been

shown to be temporally related to neutropenia, aggregation

of leukocytes in pulmonary capillaries, and intraalveolar

hemorrhages. In other laboratory studies, preburn depletion

of complement, neutrophils, and platelets was protective of

postinjury lung dysfunction. Preinjury treatment with cata-

lase and superoxide dismutase also improve postburn pul-

monary function, implicating toxic oxygen products

produced by activated neutrophils as mediators of the post-

burn pulmonary dysfunction.

Whether or not the infusion of large volumes of crystal-

loid solution associated with burn resuscitation causes post-

burn pulmonary changes remains controversial. The

accumulation of chest wall edema, exacerbated by infusion

of large volumes of resuscitation fluid, decreases total lung

compliance and promotes atelectasis and hypoxemia.

Furthermore, overzealous initial fluid resuscitation may

result in florid pulmonary edema as the edema fluid is

resorbed during the third to fifth postburn days. Consequently,

the smallest volume of resuscitation fluid that maintains ade-

quate organ perfusion should be administered to avoid

secondary pulmonary complications.

Kidneys

The renal response following thermal injury parallels the car-

diovascular response. In the immediate postburn period, renal

blood flow and the glomerular filtration rate are reduced in

proportion to the size of the burn and the magnitude of the

intravascular volume deficit. Delayed or inadequate fluid

resuscitation may cause inadequate renal perfusion and lead to

acute tubular necrosis and renal failure. Following a successful

resuscitation phase, cardiac output and renal blood flow are

increased as edema fluid is resorbed. A diuretic response is

observed during the period of edema resorption; however, this

response may be modified by a large evaporative loss of fluids

through the wound surface and slow rates of edema resorption

in patients with large-surface-area burns. Despite the

markedly increased cardiac output and renal plasma flow seen

in the flow phase of burn injury, the blood volume of patients

measured by

Cr red blood cell labeling was only 81% of pre-

dicted values. Plasma renin activity and antidiuretic hormone

levels are elevated, as predicted by the decreased blood vol-

ume, despite the findings of increased blood flow to the kid-

ney. This may explain in part the propensity for sodium

retention to occur during the course of treatment for thermal

injury. As in other organ systems, the duration of changes in

renal physiology is related to the timing of wound closure by

primary healing or autografting. Owing to the increased renal

blood flow, drugs excreted by the kidneys tend to have

markedly shortened half-lives, and appropriate dosing adjust-

ments of these drugs are necessary.

Gastrointestinal Tract and Liver

GI and hepatic dysfunction are also related to the magnitude

of thermal injury. In patients with burns of more than 25% of

the total body surface, ileus, resulting from the combined

effects of hypovolemia and neurohumoral changes, is a

prominent feature. Nasogastric intubation for gastric decom-

pression is usually required. Following resuscitation, normal

GI motility commonly returns by the third to fifth postburn

day. Focal ischemic mucosal lesions of the stomach and duo-

denum may be observed as early as 3–5 hours following burn

injury, and in the absence of stress ulcer prophylaxis, these

early lesions may progress to frank ulceration. Intestinal bac-

terial translocation following thermal injury has been studied

extensively in the laboratory, and increased intestinal perme-

ability to low-molecular-weight sugars has been identified as



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726

a prodrome to the onset of infection in thermally injured

patients. However, the clinical significance and therapeutic

implications of these findings are yet to be fully elucidated.

As the magnitude of a burn increases, so does the likeli-

hood of early postburn hepatic dysfunction. An initial

increase in hepatic aminotransferase is common following

burns of more than 50% of the body surface area. This is most

likely due to the acute reduction in cardiac output, increased

blood viscosity, and associated splanchnic vasoconstriction

that occur immediately following thermal injury. Following

successful fluid resuscitation, the hepatic enzymes promptly

return to normal in most patients. The magnitude of initial

enzyme derangements has not been predictive of outcome;

however, the early onset of jaundice following thermal injury

is associated with a poor prognosis, probably indicating

preinjury hepatic dysfunction or severely compromised

hepatic perfusion during the resuscitative phase. The onset of

hepatic dysfunction later in the postburn period usually is

manifested by hyperbilirubinemia and elevation of liver

enzymes in a cholestatic pattern. These changes are most

often associated with sepsis or multiple-organ failure.

Nervous System

Nonspecific neurologic changes such as increased anxiety

and disorientation are observed commonly in patients with

extensive thermal injury and are most likely due to the neu-

rohumoral stress response and ICU isolation. Specific neuro-

logic changes are observed more commonly in patients with

high-voltage electrical injury or mechanical trauma.

Changing neurologic symptoms and signs, manifested by

increasing disorientation, obtundation, or seizures, may be

the earliest indications of hypoxemia, electrolyte or fluid

imbalance, sepsis, or the toxic effects of medications.

Changes in neurologic findings require prompt intervention

to identify and correct such abnormalities.

Endocrine System

The metabolic response to thermal injury is also proportion-

ate to the extent of burn and follows the typical biphasic

response documented in other organ systems. Immediately

following burn injury, during the period of hypovolemia, the

metabolic rate decreases; however, as resuscitation pro-

gresses, a catabolic or hypermetabolic hormonal pattern

emerges. Serum levels of catecholamines, glucagon, and

cortisol increase, whereas insulin and triiodothyronine lev-

els are decreased. There is an increase in net glucose flow,

with relative peripheral insulin resistance and a markedly

negative nitrogen balance. As the burn wounds heal or are

closed by autografting, the catabolic hormone response

dissipates, an anabolic state is eventually attained, and

restoration of lean body mass ensues. Septic complications

superimposed on thermal injury initially exaggerate the

hypermetabolic response, but if the septic state persists,

progressive deterioration and multisystem organ failure,

characterized by hypometabolism, may occur.

Hematopoietic System

Destruction of red blood cells following thermal injury

occurs to an extent proportional to the size and depth of

burn. In areas of full-thickness burn, red blood cells are

immediately coagulated in the involved microvasculature.

There is a continuing red blood cell loss in patients with

extensive burns of 8–12% of the red blood cell mass per day

caused by the continued lysis of cells damaged by heat,

microvascular thrombosis in zones of ischemia that subse-

quently become necrotic, and repeated blood sampling. In

the early postburn period, platelet number and fibrinogen

levels are depressed, with a corresponding rise in fibrin split

products. Following resuscitation, platelets and serum levels

of fibrinogen and factors V and VIII rapidly increase to

supranormal levels. Erythropoietin levels are increased coin-

cident with the anemia following thermal injury. Recent

studies have suggested that the rate of erythropoiesis may be

further increased by the administration of recombinant ery-

thropoietin and iron. However, a decrease in transfusion

requirements has yet to be demonstrated.

Immunologic Response

Infection remains the major cause of death among burn

patients. Following injury, dysfunction of the cellular and

humoral immune response occurs that is related to the

extent of injury. Destruction of the normal skin barrier

results in loss of mechanical protection from microbial pro-

liferation and allows microbial invasion into normal tissues.

Modern burn care—with emphasis on effective topical

antimicrobial agents, infection control policies, and timely

excision with autograft closure of burn wounds—has signif-

icantly decreased the incidence of burn wound infection.

Other infectious complications, principally pneumonia,

remain the major source of morbidity and mortality, and

treatment may be made difficult by the generalized immune

system dysfunction following thermal injury.

During the first postburn week, the total white blood cell

count is elevated, although peripheral blood lymphocyte

counts are reduced. Burn injury also causes apoptosis of lym-

phocytes in various solid organs following burn injury. This

process is glucocorticoid-mediated and can be blocked

experimentally by the administration of glucocorticoid

receptor antagonists. This process is not TNF-α– or Fas

ligand–dependent and may represent a counterregulatory

mechanism to reduce inflammatory stimuli. Delayed hyper-

sensitivity reactions and peripheral blood lymphocyte prolif-

eration in the mixed lymphocyte reaction are both inhibited

following thermal injury. Alterations in lymphocyte subpop-

ulations have been described that normalize over the second

postburn week in patients whose course is uncomplicated.

Further alterations occur prior to and during the onset of

septic complications. Alterations in IL-2 production and

IL-2 receptor expression by lymphocytes have been measured

following burn injury, and direct correlation has been estab-

lished between the extent of burn and the decrease in IL-2