Multiple Organ Failure

INTRODUCTION

Major burns are relatively common injuries that require multidisciplinary treatment

for patient survival and recovery. Statistics indicate that one million people

are burned every year in the United States. Of these, 60,000-80,000 require admission

to a specialized burn center with 5,000 associated deaths each year. Many of

these deaths are due to “sepsis” and multiple organ failure.

Early aggressive resuscitation regimens have improved survival dramatically

over the past four decades. With the advent of vigorous fluid resuscitation, irreversible

burn shock has been replaced by sepsis and subsequent multiple organ

failure as the leading cause of death associated with burns. In our pediatric burn

population with burns over 80% total body surface area (TBSA), 17.5% of the

children developed sepsis defined by bacteremia.1 The mortality rate in the whole

group was 33%, most of which succumbed to multiple organ failure. Some of the

patients who died were bacteremic and “septic”, but the majority were not. These

findings highlight the observation that the development of multiple organ failure

is often associated with infectious sepsis, but it is by no means required to develop

this syndrome. What is required is an inflammatory focus, which in severe burns

is the massive skin injury that requires inflammation to heal. It has been postulated

that the progression of patients to multiple organ failure exists in a continuum

with the systemic inflammatory response syndrome (SIRS).2 Nearly all

burn patients meet the criteria for SIRS as defined by the consensus conference of

the American College of Chest Physicians and the Society of Critical Care Medicine3

(Fig. 8.1). It is therefore not surprising that multiple organ failure is common

in burned patients.

ETIOLOGY AND PATHOPHYSIOLOGY

The progression from the systemic inflammatory response syndrome to multiple

organ failure is not well explained, although some of the responsible mechanisms

in some patients are recognized. Most of these are found in patients with

inflammation from infectious sources. In the burn patient, these infectious sources

most likely emanate from invasive wound infection or from lung infections

(pneumonias). As organisms proliferate out of control, endotoxins are liberated

from gram-negative bacterial walls and exotoxins from gram-positive and gramnegative

bacteria are released. Their release causes the initiation of a cascade of

inflammatory mediators that can result, if unchecked, in organ damage and progression

toward organ failure. Occasionally, failure of the gut barrier with penetration

of organisms into the systemic circulation may incite a similar reaction.

However, this phenomena has only been demonstrated in animal models, and it

remains to be seen if this is a cause of human disease.

Inflammation from the presence of necrotic tissue and open wounds can incite

a similar inflammatory mediator response to that seen with endotoxin. The

mechanism by which this occurs, however, is not well understood. Regardless, it is

known that a cascade of systemic events is set in motion either by invasive organisms

or from open wounds that initiates the systemic inflammatory response syndrome

which may progress to multiple organ failure. Evidence from animal studies

and clinical trials suggests that these events converge to a common pathway,

which results in the activation of several cascade systems. Those circulating mediators

can, if secreted in excessive amounts, damage organs distal from their site

of origin. Among these mediators are endotoxin, the arachidonic acid metabolites,

cytokines, neutrophils and their adherence molecules, nitric oxide, complement

components, and oxygen free radicals (Table 8.1).

ENDOTOXIN

Endotoxin, a component of the wall of gram-negative bacteria, is released upon

lysis of bacteria and activates a variety of cells via its receptor CD14. Endotoxemia

causes fever, hypotension, and activation of liver cells to release acute phase proteins.

It also stimulates monocytes, the predominant source of cytokines, to produce and secrete excessive amounts of cytokines. Paradoxically, appropriate antibiotic

treatment may initially even increase the levels of circulating endotoxin

through lysis of the pathogens

Table 8.1. Etiology and prevention of multiple organ failure

Factors in the development of multiple organ failure

Endotoxin

Burn Wound

Pneumonia

Bacterial Translocation

Arachidonic Acid Metabolites

Cytokines

Neutrophils and their Adherence Molecules

Nitric Oxide

Oxygen Free Radicals

Prevention Measures

Aggressive Resuscitation

Early and Complete Burn Wound Excision

Routine Central Line Changes

Directed Antimicrobial Therapy

Pulmonary Toilet

Continued Infection Surveillance

Enteral Feedings

Immunomodulation

ARACHIDONIC ACID METABOLITES

Arachidonic acid is the precursor for prostaglandins and thromboxanes through

the cyclooxygenase pathway and for the leukotrienes through the lipoxygenase

pathway. Prostaglandins (PGE), especially PGE2, is a powerful endogenous immunosuppressant.

Thromboxane A2 and other metabolites of the cyclooxygenase

pathway are potent vasoconstrictors in both the splanchnic and pulmonary microvasculature.

Leukotrienes affect vascular tone and increase vascular permeability,

contributing to edema formation and pulmonary dysfunction.

CYTOKINES

Cytokines are a group of signaling proteins produced by a variety of cells that

are thought to be important for host defense, wound healing and other essential

host functions. Although cytokines in low physiologic concentrations preserve

homeostasis, excessive production may lead to widespread tissue injury and organ

dysfunction. Four of these cytokines, tumor necrosis factor alpha (TNF-α),

interleukin 1 beta (IL-1β, interleukin 6 (IL-6) and interleukin 8 (IL-8) have been

most strongly associated with sepsis and multiple organ failure. IL-1β and IL-6

are most consistently found to be elevated inpatients with septic episodes.

OXYGEN FREE RADICALS AND NITRIC OXIDE

The effects of the toxic products of oxygen free radical formation are only now

being elucidated. From in vitro models and in vivo animal models, we know that

tissues that initially were in shock and are then reperfused produce oxygen free

radicals that are known to damage a number of cellular metabolism processes.

This process occurs throughout the body during burn resuscitation, but the significance

of these free radicals in human burn injury is unknown. It was found

that free radical scavengers such as superoxide dismutase improve survival in animal

models; however, this has not been established in human patients.4 Oxygen

free radicals oxidize membrane lipids, resulting in cellular dysfunction. Endogenous

natural antioxidants, such as vitamins C and E, are low in patients with

burns, suggesting that therapeutic interventions may be beneficial.5 Augmenting

the effects of the primary endogenous antioxidant glutathione might also lead to

improved outcomes.

Nitric oxide, a metabolite of the amino acid arginine, is one of the major mediators

of the hypotensive response to sepsis. However, its has complex interactions

with other mediators, and further work in determining its role in the pathogenesis

of SIRS and multiple organ failure need to be performed before therapies

to modify its effects are widely adopted.6 Inhaled nitric oxide at 5-15 ppm will

improve oxygenation and lower pulmonary artery pressures during ARDS, presumably

by selectively dilating those pulmonary vessels that flow past open alveoli.

This results in an increase in flow to the open airways, allowing for better air

exchange and a decrease in pulmonary shunting.

PREVENTION

This brief outline of the proposed mediators of multiple organ failure shows

the complexity of the problem. Since different cascade systems are involved in the

pathogenesis, it is so far impossible to pinpoint a single mediator that initiates the

event. Thus, since the mechanisms of progression are not well known, specific

intervention to treat the cause is not possible. Therefore, prevention is likely to be

the best solution (Table 8.1).

The great reduction of mortality in our institution from large burns was seen

with early excision and an aggressive surgical approach to deep wounds. Early

removal of devitalized tissue prevents wound infections and decreases the inflammation

associated with the wound. In addition, it eliminates small-colonized foci

which are a frequent source of transient bacteremia. Those transient bacteremias

during surgical manipulations of the burn wound may prime immune cells to

react in an exaggerated fashion to subsequent insults, leading to whole body inflammation

and remote organ damage. We recommend complete early excision

of clearly full-thickness wounds within 48 h of the injury.

Oxidative damage from reperfusion after low flow states make early aggressive

fluid resuscitation imperative. This is particularly important during the initial

phases of treatment and operative excision with its attendant blood losses. Furthermore,

the volume of fluid may not be as important as the timeliness with

which it is given. In the study of children with greater than 80% TBSA burns, it

was found that one of the most important contributors to survival was the time

required to start intravenous resuscitation, regardless of the initial volume given.1

Topical and systemic antimicrobial therapy have significantly diminished the

incidence of invasive burn wound sepsis. Perioperative antibiotics clearly benefit

patients with injuries greater than 30% TBSA burns. Vigilant and scheduled replacement

of intravascular devices will minimize the incidence of catheter-related

sepsis. We recommend changes of indwelling catheters every three days. The

first can be done over a wire using sterile Seldinger technique, but the second

change requires a new site. This protocol should be kept as long as intravenous

access is required. Where possible, peripheral veins should be used for cannulation,

even through burned tissue. The saphenous vein, however, should be avoided

because of the high incidence of thrombophlebitis.

Pneumonia, which contributes significantly to mortality in burned patients,

should be vigilantly anticipated and aggressively treated. Every attempt should be

made to wean patients as early as possible from the ventilator in order to reduce

the risk of ventilator associated nosocomial pneumonia. Furthermore, early

ambulation is an effective means of preventing respiratory complications. With

sufficient analgesics, even patients on continuous ventilatory support can be out

of bed and in a chair.

Blood cultures may be necessary to identify specific bacteria if a source cannot

be identified. This is particularly true for the operating room, where transient

bacteriemia and endotoxemia are common. For ongoing evidence of inflammation

outside of intraoperative fluid shifts and transient hypotension, common

sources are the wound and tracheobronchial trees, and efforts to identify causative

organisms for sepsis should be concentrated there. Weekly cultures from the

burn wound should guide specific perioperative antibiotic coverage.

The gastrointestinal tract is a natural reservoir for bacteria. Starvation and

hypovolemia shunt blood from the splanchnic bed and promote mucosal atrophy

and failure of the gut barrier.7 Early enteral feeding reduces septic morbidity and

prevents failure of the gut barrier.8 In our institution, patients are fed immediately

via a nasogastric tube with Vivonex TEN®, although other enteral feedings may

suffice, including milk. Early enteral feedings are tolerated in burn patients and

preserve the mucosal integrity and may reduce the magnitude of the hypermetabolic

response to injury. Support of the gut goes along with carefully monitored

hemodynamics since sufficient splanchnic blood flow is essential to prevent translocation

of bacteria.9

Specific immunomodulation to prevent the onset of multiple organ failure

does not yet exist. Clinical trials with antibodies against endotoxin have not proven

efficacy, safety and cost-effectiveness.10-12 Although, animal studies have shown

that pretreatment with monoclonal antibodies against tumor-necrosis factor alpha

(TNFα) increases survival, clinical results were disappointing.13

ORGAN FAILURE

Even with the best efforts at prevention, the presence of the systemic inflammatory

syndrome that is ubiquitous in burn patients may progress to organ failure.

The general development begins either in the renal or pulmonary systems and

can progress through the liver, gut, hematologic system, and central nervous system.

The development of multiple organ failure does not preclude mortality, however,

and efforts to support the organs until they heal are justified.

RENAL FAILURE

With the advent of early aggressive resuscitation, the incidence of renal failure

coincident with the initial phases of recovery has diminished significantly in severely

burned patients. However, a second period of risk for the development of

renal failure, 2-14 days after resuscitation, is still present.14 Renal failure is hallmarked

by decreasing urine output, fluid overload, electrolyte abnormalities including

metabolic acidosis and hyperkalemia, the development of azotemia, and

increased serum creatinine. Treatment is aimed at averting complications associated

with the above conditions.

Urine output of 1 cc/kg/h is sufficient. When the output falls below this level,

initial efforts should be concentrated on discerning the status of the intravascular

volume. Initial fluid boluses should be given and if these go without response,

atrial filling and pulmonary artery pressures should be measured with a Swan-

Ganz catheter. If it appears to be primary renal dysfunction with an adequate

intravascular volume and cardiac output, loop diuretics should be given to maintain

urine output (up to 1 mg/kg of lasix every 4 h). Oftentimes in primary renal

insufficiency, these measures will fail requiring other treatments.

Fluid overload in burned patients can be alleviated by decreasing the volume

of fluid being given. These patients have increased insensible losses from the wounds

which can be roughly calculated (see resuscitation chapter). Decreasing the infused

volume of intravenous fluids and enteral feedings below the expected insensate

losses will alleviate fluid overload problems. Electrolyte abnormalities can

be minimized by decreasing potassium administration in the enteral feedings and

giving oral bicarbonate solutions such as Bicitra. Almost invariably, severely burned

patients require exogenous potassium because of the heightened aldosterone response

which results in potassium wasting, therefore hyperkalemia is rare even

with some renal insufficiency.

Should the problems listed above overwhelm the conservative measures, some

form of dialysis may be necessary. The indications for dialysis are fluid overload

or electrolyte abnormalities not amenable to other treatments. We usually begin

with peritoneal dialysis through catheters placed in the operating room. We instill

one liter of infusate into the peritoneum which is tailored to treat the treat the

problem at hand. Hypertonic solutions are used to treat fluid overload, and the

concentrations of potassium and bicarbonate are modified to produce the desired

results. The dwell time is usually 30 minutes followed by drainage for 30 minutes.

This treatment can be repeated in cycles until the problem is resolved. For maintenance,

4-6 such cycles a day with prolonged dwell times (1 h) are usually sufficient

during the acute phase.

Occasionally, hemodialysis will be required. Continuous veno-venous hemodialysis

is often indicated in these patients because of the fluid shifts that occur.

These patients are not stable hemodynamically and therefore we prefer this method.

All hemodialysis techniques should be done in conjunction with experienced

nephrologists.

After beginning dialysis, renal function may return, especially in those patients

that maintain some urine output. Therefore, patients requiring such treatment

may not require lifelong dialysis. It is a clinical observation that whatever urine

output was present will decrease once dialysis is begun, but it may return in several

days to weeks once the acute process of closing the burn wound nears completion.

PULMONARY FAILURE

Many of these patients require mechanical ventilation to protect the airway in

the initial phases of their injury. We recommend that these patients be extubated

as soon as possible after this risk is diminished. A trial of extubation is often warranted

in the first few days after injury, and re-intubation in this setting is not a

failure. To perform this technique safely, however, requires the involvement of

experts in obtaining an airway. At our institutions, these maneuvers are done in

conjunction with an experienced anesthesiologist. The goal is extubation as soon

as possible to allow the patients to clear their own airways, as they can perform

their own pulmonary toilet better than we can through an endotracheal tube or

tracheostomy.

The first sign of impending pulmonary failure is a decline in oxygenation. This

is best followed by continuous oximetry, and a fall in saturation below 92% is

indicative of failure. Increasing concentrations of inspired oxygen will be necessary,

and when ventilation begins to fail denoted by increasing respiratory rate

and hypercarbia, intubation will be needed. Various maneuvers described in the

inhalation injury chapter may then be required.

HEPATIC FAILURE

The development of hepatic failure in burned patients is a very challenging

problem that does not have many solutions. The liver functions to synthesize circulating

proteins, detoxify the plasma, produce bile, and provide immunologic

support. When the liver begins to fail, protein concentrations of the coagulation

cascade will fall to critical levels and these patients will become coagulopathic.

Toxins will not be cleared from the bloodstream, and concentrations of bilirubin

will increase. Complete hepatic failure is not compatible with life, but a gradation

of liver failure with some decline of the functions is common. Efforts to prevent

hepatic failure are the only effective methods of treatment.

With the development of coagulopathies, treatment should be directed at replacement

of factors II, VII, IX, and X until the liver recovers. Albumin replacement

may also be required. Attention to obstructive causes of hyperbilirubinemia

such as acalculous cholecystitis should be entertained as well. Initial treatment of

this condition should be gallbladder drainage which can be done percutaneously.

HEMATOLOGIC FAILURE

Burn patients may become coagulopathic via two mechanisms, either through

depletion/impaired synthesis of coagulation factors or through thrombocytopenia.

Factors associated with factor depletion are through disseminated intravascular

coagulation (DIC) associated with sepsis. This process is also common with

coincident head injury. With breakdown of the blood-brain barrier, brain lipids

are exposed to the plasma which activates the coagulation cascade. Varying penetrance

of this problem will result in differing degrees of coagulopathy. Treatment

of DIC should include infusion of fresh frozen plasma and cryoprecipitate to

maintain plasma levels of coagulation factors. For DIC induced by brain injury,

following the concentration of fibrinogen and repleting levels with cryoprecipitate

is the most specific indicator. Impaired synthesis of factors from liver failure

is treated as alluded to above.

Thrombocytopenia is common in severe burns from depletion during burn

wound excision. Platelet counts of below 50,000 are common and do not require

treatment. In general, we withhold platelet transfusions regardless of platelet count

in the absence of clinical bleeding. Even in those who are bleeding from the wounds,

most of the loss is from open vessels in the excised wound which require surgical

control. Only when the bleeding is diffuse and is also noted from the IV sites

should consideration for exogenous platelets be given. Patients with severe burns

will often have several instances of thrombocytopenia. Our reluctance to give platelets

is based on the development of anti-platelet antibodies, which will make platelet

transfusions ineffective later when they are truly required.

CENTRAL NERVOUS SYSTEM FAILURE

Obtundation is one of the hallmarks of sepsis, and in burns this is not excepted.

The new onset of mental status changes not attributed to sedative medications

in a severely burned patient should incite a search for a septic source. Treatment

is supportive.

SUMMARY

All burn patients are by definition affected of the systemic inflammatory response

syndrome (SIRS), characterized by hyperthermia, increased respiratory

rate, and tachycardia. Efforts to prevent the progression to multiple organ failure

are chronicled above. Carefully monitored hemodynamics, early excision of burn

wound, appropriate antibiotic coverage, early enteral feeding and good respiratory

care are so far most promising in the prevention of organ failure and in reducing

its morbidity. Once organ failure has developed, efforts at organ-specific

support will provide some survivors.

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