perioperative multiple organ dysfunction syndrome

Perioperative Multiple Organ Dysfunction Syndrome Ken Wood, Lisa Conner,/, and Douglas B. Coursin

A SIGNIFICANT number of our patients are critically ill at the time of surgery or are at

risk for perioperative critical illness (Table 1). 1-6 The spectrum of care these patients require includes preoperative examination, evaluation, and counseling; intraoperative monitoring and management; acute postoperative therapy in the recovery room or intermediate care unit; and postoperative treatment in the intensive care unit (ICU). Many anesthesiologists remain hospital-based physicians and some choose to be hospitalists or intensivists. 7's Therefore, it is timely to review the systemic inflammatory response syndrome (SIRS), which is frequently initiated by perioperative stress or traumatic insult, and multiple organ dysfunction syndrome (MODS), the most devastating sequelae of severe inflammation. 9

This report presents a case management approach to care of adults with evolving SIRS and MODS. The case scenarios touch on the epidemiology, pathophysiology, natural history, as well as conventional, innovative, controversial, and future therapies in patients with SIRS/MODS.

CASE SCENARIOS AND THERAPEUTIC ISSUES

The perioperative patients presented in the following case scenarios are at risk of developing MODS. All of them undergo elective, urgent, or emergent surgery. Anesthesiologists have the potential to impact outcome. It is crucial to remember that we have dramatically limited the intraoperative and immediate postoperative morbidity and mortality associated with anesthesia. However, there is increasing data that there are delayed implications of intraoperative therapy on patient outcome, length of hospital stay, and cost of care. Something as relatively simple as a moderate intraoperative decline in an elective surgical pa- tent 's temperature is associated with an increased incidence of postoperative wound infection, length of hospitalization, and total costs) ~ 1 Periopera- tive hypothermia in trauma patients also is associated with increased morbidity and mortality. The benefit of short- and long-term outcome of perioperative beta-blockade administration in patients

with known coronary disease undergoing major noncardiac surgery is well-reported. 12'13

With improved surgical techniques, safer anesthetic agents, and enhanced monitoring, our ability to pilot very ill and compromised patients through surgery has increased. However, we must remain vigilant to the sequelae of perioperative insult and the risk of developing severe SIRS with progression to M O D S . 14"17

Case 1

Case 1 is a 19-year-old man who was involved in a motor vehicle accident and sustained a closed head injury (CHI), pulmonary contusion, lacerated spleen, and femur fracture. He presented with systolic blood pressure 90 mm Hg, Sao2 92% on a 100% non-rebreather, Glasgow coma scale 9, TM

hematocrit 26 mL/dL, blood alcohol 0.2 g/dL, and Pao 2 74 mm Hg.

Risks. Head trauma, polytrauma, alcohol use, shock, and large volume resuscitation.

Issues. Trauma remains a leading cause of death in the United States. w Although most commonly thought of as a disease of the young, as the population ages, there are more elderly trauma victims. 2~ Older trauma victims more frequently have co-morbid pathology and suffer greater morbidity and mortality than their comparably injured younger counterparts. 2~

There is increased morbidity and mortality in patients with CHI if anemia, hypotension, hypox- emia, or hypercarbia develop in the perioperative period, z1'22 Therefore, our initial and ongoing aggressive interventions to assure adequate fluid resuscitation, gas exchange, and correct anemia are warranted. 23,24

From the Trauma and Life Support Center and the Depart- ments of Anesthesiology and Internal Medicine, University of Wisconsin Hospitals and Clinics, Madison, WI.

Address reprint requests to Douglas B. Coursin, MD, De- partment of Anesthesiotogy and Internal Medicine, B6/319 Uni- versity of Wisconsin Hospitals and Clinics, Madison, W153792- 3272.

Copyright �9 1999 by W.B. Saunders Company 0277-0326/99/1801-0008510.00/0

Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 18, No 1 (March), 1999: pp 27-43 27

28

Table 1. Risk factors and Clinical Diagnoses That Precede Multiple Organ Dysfunction Syndrome

Age >65 yr Chronic organ compromise Pulmonary (chronic obstructive

pulmonary disease) Cardiovascular system: chronic

heart failure/valvular Hepatic: cirrhosis Renal: renal failure Immunosuppression

Major operations Prolonged hypoperfusion or shock (delayed or inadequate resuscitation)

Cardiothoracic Hemorraghic Vascular Distributive Abdominal Cardiogenic

Septic Severe infections or Burns

sepsis Trauma Pancreatitis

Massive, blunt, or Cancer penetrating Head, chest Massive fluid resuscititation/ transfusion therapy

Aspiration Malnutrition Emergency surgery Alcohol abuse Surgical

misadventure

Multiple controversies surround the care of CHI victims. 25'26 Efforts to protect the ischemic pre- numbra to enhance cell survival and recovery are considered paramount. 26 Application of "routine" therapy such as hyperventilation is under close scrutiny. 25 Various investigators have questioned the logic of globally decreasing cerebral blood flow in a brain at risk for additional ischemic insult. Newer neurologic monitoring techniques such as transcranial Doppler and mixed venous jugular oxygen saturation have evolved as means of guiding proper use of hyperventilation.

A host of innovative therapies have been evaluated in the CHI population, including intravenous corticosteroids, lazaroids, N-methyl-D-aspartate (NMDA) antagonists, calcium channel blockade, and barbiturate-induced coma. 27 None of these have been shown to be consistently effective. 27 Several small studies have reported improved outcome in CHI patients treated with modest induced hypothermia (approximately 35~ for 24 hours after insult. In one study, hypothermia was effective in moderately severe to severe CHI (Glasgow

WOOD, CONNERY, AND COURSIN

coma scale 5 to 8), but not devastating injuries (Glasgow coma scale <5). 28

Case 2

Case 2 is an 80-kg, 45-year-old woman with a history of fatty food intolerance and a recent diagnosis of choMithiasis documented by ultrasound. She presented to the emergency department with 12 hours of intermittent, severe, abdominal pain, fever, and blood pressure of 80 mm Hg that was minimally responsive to volume expansion and dopamine. She was oliguric. The white blood cell count was 19,000 K//xL with a marked bandemia, international normalized ratio - 3 , platelet count 99,000 K//xL, and Pao 2 70 mm Hg on 60% oxygen by face mask. 29-34

Risks. Septic shock, potential peritonitis, renal insufficiency, disseminated intravascular coagulation, and early acute lung injury/acute respiratory distress syndrome (ARDS).

Issues. Timely, definitive treatment and elimination of the infectious source of shock is man- datory. Appropriate antibiotic therapy of enteric gram-negative organisms and Enterococcus sp combined with emergency surgery are required. 35 Increasing resistance to gram-negative bacteria has developed over the past 10 to 20 years. 36'37 More recently, vancomycin-resistant and vancomycin-/ ampicillin-resistant Enterococcus have become widespread, especially in hospitalized patients who have received heavy antibiotic pressure. 37

This woman has ongoing shock despite fluid resuscitation, inotrope support, and definitive therapy. She appears to have sepsis-induced myocardial depression and vasodilation. She is coagulopathic with marginal oxygenation and evolving renal insufficiency. 34 Aggressive intravascular monitoring is initiated with arterial and pulmonary artery catheters, which guide fluid resuscitation, choice of vasopressor, and the application of positive end-expiratory pressure and ventilatory maneuvers such as inverse ratio ventilation, permissive hypercapnia, or high-fre- quency ventilation. Although the incidence of acute tubular ratio has decreased in some populations, morbidity and mortality associated with renal failure remain high. 3s The recent evaluation of a synthetic atrial naturetic factor in patients with suspected renal insufficiency did not limit the development or severity of renal failure. 39

PERIOPERATIVE MODS 29

Case 3

Case 3 is a 66-year-old man who smoked 1.5 packs of cigarettes per day for 50 years, drank several six-packs daily, and had a variceal bleed 6 months previously that was treated with endo- scopic variceal banding. He had mild ascites, which improved while on spironolactone; he also had an international normalized ratio of 1.3 that was unresponsive to vitamin K. His albumin was mildly decreased at 3.1. He was classified as Child's B. 4~ He was admitted to first-day surgery for elective resection of a colon carcinoma.

Risks. Co-morbid pulmonary and hepatic compromise, cancer, ethanol abuse, and malnutrition.

Issues. Optimization of this patient's current status started with his cessation of smoking and alcohol 6 months previously at the time of the variceal bleed. This limited some of his perioperative pulmonary risk 41 and eliminated the complications associated with alcohol withdrawal. He responded to diuretics with a decrease in the ascites, which may decrease intraoperative fluid dis- equilibrium and respiratory compromise. He still has evidence of advanced liver dysfunction with a prolongation of prothrombin time and a decrease in serum albumin, which increases the patient's perioperative risk of complications.

Case 4

Case 4 is a 72-year-old sedentary man who sustained a myocardial infarction 2 years previously. He was taking baby aspirin, lisinopril, and mevacor daily. He had taken glipizide for 4 years to control his type II diabetes mellitus. Intermit- tently, he has had severe abdominal and lower back pain. His blood pressure was 150/100 mm Hg and his heart rate was 100 beats/min with intact pulses. An electrocardiogram revealed sinus tachycardia with Q waves in lead II, III, and avF, and new nonspecific T-wave changes in lead 1 and avL. Ultrasound and abdominal computed tomography revealed a 7-cm abdominal aortic aneurysm that was suspected to be leaking. Glucose was 425 mg/dL, creatinine 1.5 mg/dL, and hematocrit 45%. He was to undergo an urgent infrarenal aneurys- mectomy with tube graft.

Risks. Perioperative myocardial ischemia, renal insufficiency, diabetes, and abdominal aortic aneurysm repair.

Issues. This man has a life-threatening process and is at risk for multiple end-organ ischemic

insults. 14,42 He has compromise of his kidneys and cardiac function, which is incompletely quanti- fied. 43 With his history of diabetes and his sedentary life-style, we must assume that he has myo- cardium at risk, particularly during cross-clamping of his aorta. 44-46 He requires control of his hyper- glycemia with insulin by infusion. This will limit further metabolic derangement, osmotic dehydra- tion, and enhance white blood cell function. The use of an epidural anesthetic is probably not indicated because of his extreme illness. Intraoperative use of a pulmonary artery catheter or transesoph- ageal echograph is probably indicated along with serial postoperative electrocardiograms and creat- ine kinases.

BACKGROUND

Systemic inflammatory response syndrome and multiple organ dysfunction syndrome are terms coined by an American College of Chest Physicians- Society of Critical Care Medicine Consensus Confer- ence held in 1991 to standardize terminology 9 and facilitate clinical assessment, management, prognosis, communication, and investigation of the most critically ill. However, SIRS and related definitions of sepsis, sepsis-induced hypotension, or shock are not universally accepted as adequate descriptions of infectious or noninfectious inflammation (Fig 1). The term SIRS has been criticized as too general and not sufficiently specific for effective application. 33"47 At- tempts at refining inflammatory definitions such as compensated or excessive responses are evolving. 33

Sepsis remains a major cause of morbidity and mortality in patients admitted directly to the ICU as well as secondary to nosocomial infections in hospitalized individuals. Approximately 400,000 to 500,000 patients per year develop sepsis from blood-borne infection, with an overall mortality rate of 30% to 40%. 31 Systemic inflammatory response syndrome from an infectious or noninfectious cause is considered the key driving force in the progression to multiple organ dysfunction with its potentially lethal consequence.

Multiple organ dysfunction syndrome was first recognized within the past 25 to 30 years. 4'42 Pa- tients who develop MODS survive their original insult only to be plagued by lethal progression of severe multiple organ dysfunction. The term MODS replaces other terms that denote organ failure, such as sequential system failure, multisystem

30 WOOD, CONNERY, AND COURSIN

bacteria / - A I\ fungus A / I \~ ;~Ste / ~ /~

Fig 1. Definitions of SIRS and SIRS schematic relationship and associated etiologies. Initiated by a variety of severe infectious and noninfectious insults, SIRS may result in a normal or excessive proinflammatory response. The syndrome manifests when two or more of the following are present: temperature >38~ or <36~ heart rate >90 beats/rain, respiratory rate >20 breaths/min or Paco 2 <32 mm Hg, or white blood cell count >12,000 cells/mm 3, <4,000 cells/mm 3, or > 10 immature forms (bands). Infec- tion is characterized by inflammatory response to microorganisms, bacteremia is viable bacteria in the blood, and sepsis is a systemic response to infection. Sepsis-induced hypotension is characterized by a systolic blood pressure <90 mm Hg or a >40 mm Hg decrease from baseline and septic shock is sepsis-induced hypotension despite adequate fluid resuscitation requiring vasopressor support.

organ failure, multiple system organ failure, and multiple organ failure. 6

The incidence of MODS in critically ill medical-surgical patients is approximately 10%. Over 90% of the patients dying in surgical ICUs have MODS. 2'6 Multiple organ dysfunction syndrome is reported to develop in 7% to 22% of patients undergoing emergency surgery (cases 1, 2, and 4) and 30% to 50% of patients undergoing surgery for intra-abdominal sepsis (case 2). 2,6

Medical advances over the past 50 years have increased longevity; enhanced survival of patients with predominantly single-organ disease such as cardiac ischemia, renal insufficiency, and chronic obstructive lung disease; and improved therapy of systemic processes such as diabetes or connective tissue disease. However, such compromised individuals are at increased risk of developing MODS when they suffer a

surgical or traumatic insult. Multiple innovative therapies have been evaluated in patients with SIRS and evolving MODS. Unfortunately, most of these have had limited, if any, success. Pre- vention remains the key. Anesthesiologists and intensivists therefore play a crucial role in limiting events that increase the risk of MODS. 6

MULTIPLE ORGAN DYSFUNCTION SYNDROME EPIDEMIOLOGY

Epidemiologic description of MODS has been a challenge because of variable definitions of the syndrome. The American College of Chest Physi- cians-Society of Critical Care Medicine consensus proposed the term multiple organ dysfunction to define the continuum of physiologic changes during which the end-organ is not capable of maintaining homeostasis without external support. 9 Studies before this definition was proposed were frequently limited by their retrospective nature and lack of standard definition of end-organ dysfunction. At present, criteria used to define MODS are predominantly related to physiologic abnormalities in the cardiovascular, respiratory, renal, hemato- logic, and neurologic systems. 19'48 Consensus regarding the degree of physiologic aberrancy that defines organ dysfunction is variable, but is supe- rior to defining overt organ failure and allows more subtle gradation and scoring of MODS. Currently, most systems of assessment of MODS use scoring systems weighed proportionately by the degree of organ dysfunction. 48

Retrospective epidemiologic surveys have identified diagnoses or events that often precede the development of MODS (Fig 2). 49 Patients with these problems are encountered on a daily basis in our practices.

Previously, MODS was uniformly thought to be secondary to an underlying infectious process. 5 Recent data suggest that an uncontrolled systemic inflammatory response (infectious or noninfectious in etiology), termed autodestructive or malignant intravascular, is the common culprit. 5~ This process may be secondary to excessive proinflammatory mediator effect, lack of an adequate anti- inflammatory response, or unfavorable balance of pro- and anti-inflammatory forces.

In an 8-year survey of over 2,000 patients with MODS, nonoperative diagnoses accounted for approximately 75% of the cases while 25% were associated with operative stresses, s~ The majority


Fig 2. The MODS is the final common pathway of severe SIRS. 1As patient progresses to end-organ dysfunction, the likelihood of survival decreases. 2If enc~organ dysfunction is severe and an increasing number of organs are compromised for a prolonged period, the likelihood of mortality increases, approaching 100%.

~ I Normal response'~ eliminate stimulus damaged |

tissue and start repair /

1

1 ( "ocovor, 1

I Secondary diffuse process

Prim~-'v develops e~ly

local then systemic inflammation

Systemic microeirculatory injury ("endothelialitis") (severe SIRS)

WBC, eomplement, humoral, coagulation, mediator activationl

1 Multiple organ dysfunction2 I I +

of nonoperative MODS admissions were second~ ary to cardiac arrest, sepsis, pneumonia, congestive heart failure, or upper gastrointestinal (GI) bleeding from ulcers or varices. The most common postoperative admissions who developed MODS were after surgery for head trauma (case 1), elective abdominal aortic aneurysm repair (case 4), GI perforation, GI inflammatory diseases, aortic dissection or rupture, GI carcinoma (case 3), and valvular surgery. 5~

Conventional wisdom proposes two discrete scenarios from which MODS can evolveS: primary MODS develops as a result of an initial insult and occurs early in the course of the critical illness, whereas secondary MODS is not the result of the initial insult but rather a consequence of an abnormal host response to an insult. Indicators of the severity of the initial insult have been shown to correlate with the development of MODS. In the

trauma population, the injury severity score has been shown to be a good predictor of postinjury MODS. 19'52 Shock as an initial insult has been shown to predict organ failure and corresponding ICU mortality. Surrogate measures of the depth of shock, such as base deficit and lactate concentra- tion, particularly if present in the early phase of the patient resuscitation, predict multiple organ dysfunction, s3 Initial blood transfusion requirements correlate with the evolution of MODS. 53 Although too sensitive to function as a predictor for multiple organ dysfunction, the presence of the systemic inflammatory response appears to represent a continuum of the immunologic response to the inciting insult and is frequently viewed as a precursor to MODS.47

The outcome of MODS is usually determined by the severity of the associated disease and the number and duration of organs that fail in conjunction

32

with the age of the patient. 54 The presence of chronic disease, advanced age (case 4), malnutrition (case 3), and alcohol abuse (case 3) are considered risk factors that contribute to poor outcome in MODS patients. 4s'5~ The APACHE database has reported that patients with a single organ failure lasting more than 1 day had a hospital mortality rate of approximately 40%, patients with two organ failures for more than 1 day had a hospital mortality rate of 60%, and the mortality rate in patients with three or more organ failures on the fourth day in the ICU was over 98%. 54

Recently, a specific multiple organ dysfunction score has been developed. It defines graded abnormalities in the respiratory, renal, hepatic, hemato- logic, central nervous, and cardiovascular sys- temsY Abnormalities in organ function were graded on a scale from 0 to 4, with 4 representing marked functional derangement. Organ dysfunction on ICU admission and over the ICU course correlated in a graded fashion with ICU mortality. Calculation of the change in the multiorgan dysfunction score during the critical illness reflected organ dysfunction that developed in the ICU and was an additional predictor of outcome. 55

In summary, it appears that the magnitude of the initial insult in conjunction with specific co-morbid conditions and age defines the patient's ability to survive MODS. Recognition of perioperative situ- ations when patients, such as those represented in cases 1 to 4, are at significant risk of developing SIRS/MODS has become increasingly refined and require our appropriate attention and intervention.

PATHOPHYSIOLOGY

General

Although elderly patients and those with co- morbid conditions are more likely to develop MODS than their robust counterparts, the latter are not immune, as evidenced by the significant incidence of MODS in the trauma population. A common sequence of clinical events leading to MODS involves a severe injury or illness (Table 2) associated with a period of shock and circulatory in- stability with decreased ~splanchnic and renal perfusion, followed by resuscitation and therapy of the underlying process. The respiratory system frequently is compromised first, followed by pulmonary hypertension, right heart failure, and biventricular failure (especially in sepsis), with subsequent inadequate perfusion of the brain, kid-

W O O D , CONNERY, A N D COURSIN

Table 2. Common Clinical Characteristics Involved in Events Leading to Multiple Organ Dysfunction Syndrome

Severe metabolic insult (ie, trauma, operation, both, or sepsis)

Unrecognized clinical or technical insult (ie, continued postoperative bleeding, wound infection, anastomatic leak, fluid collections in the chest or abdomen, or massive wound contaminationl

The presence of underlying infection (secondary to inadequate drainage of pus, inadequate treatment of primary injury, line sepsis, or nosocomial pneumonia, etc)

Underlying baseline end organ dysfunction (ie, atherosclerotic heart disease, chronic obstructive pulmonary disease, peripheral vascular disease, immunosuppression, or organ transplantation)

ney, and liver. Hepatic dysfunction tends to develop later in MODS. 6

Multiple organ dysfunction syndrome is believed to be a byproduct of a diffuse inflammatory state initiated by several arms of the body's defense mechanisms. The underlying pathophysio- logic mechanisms of MODS appear to be a nonspecific expression during various critical illnesses with a complex interaction of the following:

1. hypoperfusion of vital organs and an inadequate 0 2 supply and demand balance to meet subcellular 0 2 requirements,

2. adrenergic nervous system activation, 3. excessive or uncontrolled activation of

inflammatory mediators and acute-phase reactants,

4. cellular reactions with activation of leuko- cytes, macrophages, lymphocytes, platelets, and others that amplify humorally mediated factors and release reactive oxygen species (free radicals),

5. ischemia-reperfusion injury, and 6. metabolic derangements and catabolism

related to stress. 6

This constellation of events results in subcellular dysfunction with resultant cell injury and end- organ failure. If this process is of sufficient magnitude and duration, it results in death.

Pinsky and Matuschak 51 attribute much of the overall devastation of MODS to a "malignant" intravascular inflammation. Investigators following this line of reasoning feel that normal host defense, which operates to control, limit, and de- stray infecting organisms or to clear damaged tis-


sue or foreign material, goes awry and results in the previously described clinical scenario. In addition, the GI tract is felt to be a potential common source of occult bacteremias or inflammation in patients at risk for progressive multiple organ dysfunction, while occult pulmonary infections may be a source of ongoing SIRS/MODS in those with acute lung injury/ARDS.

The central inflammatory reaction may be a primary process from a localized insult, such as aspiration or pulmonary contusion, or as a secondary systemic response, such as occurs with bacteremia or hypotension/hypoperfusion. These initial stim- uli are referred to as the "first hit. ''5 When the balance between pro- and anti-inflammatory systems go awry, amplification of a dysregulated system causes cellular hypoxia, which leads to organ dysfunction and cellular death. Further insults or "second hits," such as hypotension, hypermetabo- lism, or nosocomial infection, perpetuate and ag- gravate the initial insult and amplify the cascade of progressive end-organ dysfunction. 5

Development of dysfunction in one organ appears to predispose the dysfunction and failure of another. Some speculate that organs are interlinked in ways not yet understood. Others have invoked mathematical models, such as entropy and chaos theory, in an attempt to understand this phenome- non. Our understanding of this extremely complex system is incomplete.

Cellular Response

Endothelial cells, polymorphonuclear leuko- cytes, macrophages, multiple mediators, the coagulation system, and the oxidative stress response are all felt to play roles in microvascular inflammation, ts Inflammatory mediators, which are capable of amplifying their own responses, are normally counterbalanced by anti-inflammatory mediators (Table 3). 13 When this balance goes awry, severe SIRS develops and may progress to MODS (Fig 3).

The initial inflammatory process in evolving MODS results in a panendothelial insult (endothelialitis) and interstitial edema. 56 Hypoperfusion, histamine release, and complement activation re- suits in endothelial cell expression of selections, adhesion molecules, and platelet-activating factor. These cause adhesion, sequestration, and activation of white blood cells in the microcirculation ("leukostasis). s7 Stimulation of macrophages ini-

Table 3. Suspected Proinflammatory and Anti- inflammatory Mediators in Systemic Inflammatory

Response Syndrome and Multiple Organ Dysfunction Syndrome

Promediators Antimediators

Complement (C3a, C5a) White blood cell products Proteases

Elastase Collagenases

Oxgyen-free radicals Superoxide (02.') Hydrogen peroxide (H202)

Hydroxyl radical (OH.-)

Arachadonic acid derivatives

Prostanoids: thromboxane Leukotrienes

Cytokines Interleukins Tumro necrosis factor

Coagulation cascade Platelet-activating factor Kallikrein-kinins Macrophage-derived growth

factor Lysosomal enzymes Stress hormones

Catecholamines Glucagon Insulin Thyroxin Growth hormone Steroids

Nitric oxide

Steroids Monoclonal antibodies Antioxidants

Vitamins A and E Glutathione/glutathion

peroxidase Catalase Super-oxide dismutase

Prostanoids - prostaglandin 12

Nonsteroidal anti- inflammatory agents

Cytokine receptor antagonists

Nitric oxide synthase inhibitors

tiates a cascade release of other inflammatory mediators, including tumor necrosis factor, interleukins (IL-1 to IL-16), platelet activating factor, prostanoids (thromboxane, prostacyclin), and leukotrienes. Tumor necrosis factor is believed to be an especially important mediator; it initiates cytokine release and expression of adhesion molecules on the endothelial surface. These exacerbate mi- crocirculatory dysfunction and may be the basis of amplification of an autoexcessive inflammation, ss

Tissue injury activates complement by the alternate complement pathway. Endotoxemia or bacteremia can activate complement through the classic or alternate pathways. Complement also is activated in low-flow states, which can result in intestinal hypoperfusion and bacterial translocation or


Identify those at risk of developing

Head or multiple trauma Burn Elective aortic aneurysm repair Aortic dissection Infection

Sepsis GI perforation/peritonitis Pneumonia Necrotizing soft

tissue infection Endocarditis Meningitis

GI cancer Valve surgery Hematoma Inflammation

pancreatitis Pre-eclampsia /HELLP syndrome

Intoxication ethanol drug poison

Drug reaction

postoperative MODS

Ago >65 y/o Baseline end-organ compromise Perioperative shock Large perloperative fluid or

transfusion therapy Ischemia-reperfusion insult latrogenic Immunosuppression

steroids transplant patient

1. Adequate and ongoing resuscitation monitor vital signs assess arterial, central venous, pulmonary artery pressures as needed evaluate tissue oxygenation

lactate MV0a gastric tonometry

if suspected oxygen dependence, increase D02

2. Adequate gas exchange maintain adequate intravasealar volume avoid baro-volutrauma role of PEEP

3. Antimicrobials directed therapy at most likely pathogens take into consideration increasing resistance patterns take into consideration immune reserve and risk for unusual organisms

4. Definitive surgery/radiologic procedure 5. Surveillance for nosocomial infection

aseptic technique eliminate excessive antibiotic prophylaxis catheter care eliminate invasive monitors as able

6. Use GI tract as soon as possible enteral nutrition

Fig 3. Prevention strategies against perioperatlve MODS.

endotoxin release across ischemic intestinal mu- cosa into the portal and systemic circulations. Bac- terial endotoxin binds to macrophage receptors and triggers mediator release. 59 Gut-associated lym- phoid tissue may also stimulate release of a variety of cytokines, interleukins, and tumor necrosis factor when activated by a hypovolemic state. Persis- tent intestinal dysfunction and hypoperfusion has been speculated to cause ongoing insult. 59

Demargination of polymorphonuclear leuko- cytes into the general circulation occurs rapidly during shock states because of the surge in cate- cholamine levels. 58 In the low flow or hypoper- fused shock state, white blood cells are seques- tered, particularly in the lung and liver. This leukostasis occurs within the first hour of shock.

Degranulation of polymorphonuclear leuko- cytes releases toxic enzymes, including proteases, collagenases, and free radicals or reactive oxygen species (superoxide [0 2 �9 - ] ) , hydrogen peroxide (H202), and peroxyl radical (OOH �9 ). These reactive oxygen species damage endothelial cell membranes, inactivate sulfhydryl enzymes, and damage native DNA, 6~ and contribute to cellular injury, apoptosis (cell death), and capillary leak.

Ischemic insult results in an excess of cytosolic calcium. This excess of calcium activates proteases, which convert xanthine dehydrogenase to xanthine oxidase. When (and if) reperfusion occurs, xanthine oxidase metabolizes 0 2 to 02 " - , which then generates other ROSs that exacerbate


reperfusion injury. The coagulation system is also activated by the shock state, resulting in fibrin deposition in the microvascular bed with potential organ injury. 34

A combination of factors may result in myocardial depression, cz- and/3-adrenoreceptor dysfunction, and vasodepression. 31'61 The latter occurs in part from the increased expression of the inducible isoenzyme of nitric oxide synthetase from injured endothelial cells, 62'63 which dramatically increases NO levels and may play a rote in the refractory vasodilatation encountered in patients with progressive SIRS/MODS.

PREVENTION AND THERAPY OF MULTIPLE ORGAN DYSFUNCTION SYNDROME

Given the dismal prognosis of established MODS, it is crucial to develop strategies targeted at preventing MODS in high-risk patients. There is a biphasic character of disease in critical care. The initial insult may be of such magnitude to provoke MODS, or the subsequent acquisition of a nosocomial complication, particularly infectious, in an otherwise stable ICU patient may represent a second avenue to MODS. The latter is best prevented by vigilance and surveillance for nosocomial complications.

The first step in the prevention of MODS is to identify and correct the underlying culprit process whenever possible. The preventative strategy of ensuring adequacy of resuscitation and abolition of ischemia is common to all high-risk patients. Ad- equate resuscitation as defined by clinical indices, blood pressure, tissue perfusion, organ function, and elimination of a serum lactate or base deficit should be established. When it is unclear that oxygen transport is sufficient, invasive monitoring and measurement of oxygen transport parameters should be performed. Subgroups, such as high-risk surgical patients and trauma patients, have improved outcome if supranormal DO 2 is provid- ed. 64-67 However, supranormal D O 2 in other populations has not been beneficial. 6s

Infection control is another major area of prevention. Critical illness produces a well-recognized depression in immune function. Although infection is frequently the initiating process in MODS, infection also commonly represents an acquired process leading to the development of MODS. A vigilant search for infection should be made with adequate debridement of dead and devitalized tis-

sue and drainage of infected body cavities or ab- scesses. Prophylaxis against nosocomial infection should be used. Infection control should consist of careful hand washing, infection surveillance for at-risk populations, and standard policies govern- ing urinary catheters, nosocomial pneumonia, and catheter-related infections.

Once MODS is established, the primary therapy is supportive. The bulk of supportive care of MODS is directed toward maintenance of major systems: neurologic, cardiovascular, pulmonary, renal, and gastrointestinal. This requires careful use of sedative, analgesic, and paralytic drugs. Vasoactive drugs are infused as needed to enhance tissue perfusion and end-organ function. 69 Me- chanical ventilatory strategies are applied that minimize oxygen toxicity and limit barotrauma and volutrauma produced by positive pressure ventilation. 7~ Appropriate selection and dosing of antimicrobials are required to avoid toxicity, drug reaction, and nosocomial or resistant infection. Re- nal insufficiency is managed with judicious fluid replacement, acid-base and electrolyte control, appropriate nutrition, and avoidance of further renal insults, particularly nephrotoxin exposure or hypoperfusion. Improved dialytic techniques continue to evolve with the application of slow continuous ultrafiltration, continuous venovenous hemofiltration or hemodialysis, or conventional hemodialysis as needed. Coagulopathy is corrected as able and peripheral blood counts are monitored to identify bone marrow suppression or immune effect on platelets and on white or red blood cells. It is speculated that the GI tract is the motor of multiple organ dysfunction with translocation of both gut bacteria and bacterial byproducts. A compromised reticuloendothelial system and liver allows access of these products into the systemic circulation. Early use of enteral feedings is advocated to improve GI blood flow, maintain microvillus function, and limit the translocation of bacteria or endotoxin into the systemic circulation. Use of nonabsorbable oral antibiotics with selective digestive decontamination is hypothesized to minimize the reflux of pathogenic organisms in the respiratory system and translocation reservoir in the gut. Although selective digestive decontamination re- duced the incidence of nosocomial pneumonia, there are no prospective or randomized trials that demonstrated improved survival.


Finally, multiple approaches such as advances in monitoring, use of mediator antagonists, antioxidants, growth factors, blood purification, and inhi- bition of the anti-inflammatory process are available, but none have been shown to be an effective preventative strategy or to improve the mortality of patients with MODS.

CONTROVERSIES IN THERAPY Fluid Therapy

Choice of appropriate fluid, crystalloid, colloid, or blood product for resuscitation and maintenance infusion continues to remain under debate. Based on a meta-analysis from 1994 that evaluated outcome, cost factors, safety, and ease of administration, crystalloid is advocated as the initial resuscitation fluid of choice. TM However, recent data have shown enhanced survival in certain critically ill patients who received hypertonic solutions and medium chain colloids, such as pentastarch and pentafraction. 75,76

The quantity and timing of fluid administration remains open to question. Recent data in patients with penetrating torso trauma challenged the practice of routinely administering large amounts of fluids to such patients before definitive surgery. 77 Bickell et a177 reported that delaying massive fluid resuscitation in penetrating trauma victims until they were undergoing definitive surgery enhanced outcome and shortened length of hospital stay. It is crucial to recall that these were predominantly younger patients who received definitive care within an optimal time frame in a sophisticated trauma center. Whether such data are applicable to other settings, such as blunt trauma or stabilization of the injured patient in different circumstances, remains unresolved.

In case 1, important questions about fluid therapy in the young polytrauma patient with a CHI arise. All agree that infusion of dextrose-contain- ing fluid is not indicated unless the patient has significant hypoglycemia. 24 Most advocate infusion of an isotonic balanced salt solution (0.9% normal saline) with the key end point being adequate intravascular volume and avoidance of cerebral hypoperfusion or excessive hemodilution with dilutional coagulopathy. 24

Ideal Hemoglobin The use of blood products continues to change

stimulated by concerns over safety, infectious risk,

and immune alterations. 78'79 Identification of tighter transfusion triggers, whether it be for red blood cells or individual component therapy, is evolving. The American Society of Anesthesiolo- gists recently reviewed the state of transfusion in a consensus statement. 79 The application of such guidelines in the critically ill, particularly those with coronary or cerebral vascular compromise, patients with impaired oxygen consumption, and those at risk from bleeding, remains open to dis- cussion. 8~ One must evaluate oxygen delivery and utilization parameters, bleeding risk, and the presence of consumptive coagulopathy to guide therapy in the critically ill.

The use of recombinant erythropoietin in the critically ill is being explored. 8~ Erythropoietin kinetics may be altered in the critically ill. The earlier use of erythropoietin to enhance red blood cell mass without the potential sequelae of alloge- neic blood deserves consideration. 8~

Development of blood substitutes or oxygen- carrying colloids is receiving increasing attention. 81 Products such as cross-linked hemoglobins, recombinant hemoglobin, and second generation perfluorocarbons are undergoing phase II safety or phase III efficacy trials and are not available for clinical use. These drugs vary in their half-life (all relatively short), vasopressor effect (particularly with the hemoglobin-based products), and potential effect on immune function. 67 The ideal agent would be longer lasting, be nontoxic, have a long shelf-life, and be inexpensive; it has yet to be developed.

Optimal Oxygen Delivery The use of oxygen transport variables in the care

of patients with MODS remains controversial. 82 Initial clinical data suggested that deficiencies in oxygen delivery and the accompanying decrease in oxygen consumption were prime instigators in MODS. 83 Reconciling the oxygen transport controversy requires an understanding of the concept of supply-dependent consumption. Under normal circumstances, patients deliver far more oxygen than they need to fulfill their consumptive needs (supply independent oxygen consumption). Se- quential decreases in DO2 result in the maintenance of a constant oxygen consumption (VO2) facilitated by an increase in the extraction ratio. At a point defined as the critical DO 2, decreases in DO 2 result in decreased consumption. This is


termed supply-dependent oxygen consumption, s3 Initial data suggested that critically ill patients, particularly those with MODS and ARDS, mani- fested supply dependent consumption or patho- logic oxygen consumption throughout the entire domain of their oxygen delivery. 71 Using the mean of the oxygen transport indices of survivors as a goal for shock resuscitation, proponents of "supranormal" oxygen transport advocated increased oxygen delivery in an attempt to abolish the overt or covert oxygen debt. Several studies applied such a strategy in postoperative and surgical trauma patients with reported improvement in out- c o m e . 64-67

It is of note that the original studies which supported the hypothesis of supply dependent oxygen consumption were derived using indirect measurement of oxygen consumption. Subsequent data using direct measurements of oxygen consumption have suggested that the supply dependent oxygen relationship is secondary to mathematical coupling of the variables in the delivery and consumptive equations. 6s

A review of randomized controlled trials of supranormal DO 2 revealed that half the trials reported a decrease in morbidity or mortality while half did not. s2 The difference between the two groups is predominantly related to the heterogene- ity of the groups that were not responsive to supranormal titration and the application of therapy at a later time point in some studies. The patients who appeared to benefit received early supranormal therapy in the preoperative period or immedi- ately after trauma. Given the preceding, it seems appropriate to use supranormal levels of oxygen transport as therapeutic end points in certain subgroups of patient. However, to indiscriminently apply this strategy to all patients is not appropriate.

In the future, improved organ-specific indices of the adequacy of oxygen transport will probably be available. Recently, gastric tonometric determina- tion of gastric intramucosal pH as a marker of tissue oxygen delivery and utilization has been evaluated. Although the use of this technique does not improve outcome in those who present in a compromised state, it has been shown to be beneficial in identifying those who develop gastric mu- cosal acidosis during their perioperative and ICU course. Subsequent intervention to improve gastric intramucosal pH in such patients is reported to improve outcome, s4

Vasopressors

The selection of appropriate vasoactive agent depends on an accurate assessment of the cardiovascular system. 69 The hydraulic pump model of the cardiovascular system has three discrete com- ponents: the capacitance or the volume in the system, the hydraulic pump or cardiac function, and the impedance or resistance to which that pump empties. The first step in determining the need for vasoactive support is to characterize the hemodynamic pattern and identify whether that pattern allows for adequate tissue perfusion. Therapy with vasoactive drugs should be as specific as possible to allow optimal tissue perfusion. The characteris- tic hemodynamic pattern of MODS is variable and needs to be defined for each patient. For example, capacitance/volume may be abnormal because of inadequate resuscitation, capillary leak, and third spacing or normal or hypervolemic from excessive fluids or pump dysfunction. Hydraulic pump function may be impaired because of septic depression and/or inadequate filling secondary to a depleted capacitance bed. Almost uniformly, the initial impedance of a patient with MODS is low with systemic vasodilatation.

Fluids are frequently administered to evaluate the Starling and end-organ response. Inadequate hydraulic pump function is best managed with a /3-agonist such as dobutamine. Excessive heart rate response or peripheral vasodilation may necessi- tate administration of an o-agent such as phenyl- ephrine or norepinephrine to maintain critical perfusion pressure. Noncatecholamine drugs such as milrinone may be useful in patients with receptor downregulation or excessive rate response.

In summary, the choice of vasoactive drug depends on the cardiovascular reserve of the patient and response to initial therapy. The goal is for specific therapy using the lowest dose possible with the end point being adequate organ perfusion. 69

Optimal Mode of Ventilation~Positive End- Expiratory Pressure

Given the common association of ARDS with MODS, ventilatory strategies for MODS are essentially those strategies used for ARDS patients. 7~ In the setting of diffuse lung injury, it is crucial to weigh the relative toxicity of oxygen therapy against the complications of barotrauma and volutrauma from high airway pressures and large


lung volumes. 72'73 The traditional practice of ventilatory management in diffuse lung-injured patients is based on the perception that the insult is homogeneous. The end point of therapy was nor- malization of arterial blood gases using normal or high tidal volumes and high airway pressures. 7~ Recent literature suggests that the pattern of injury in ARDS is far more heterogeneous than previously appreciated. 72'73 It is estimated that approximately one third of the lung is essentially normal, with well-preserved mechanics, gas-exchanging ability, and gas tissue ratios. Given this regional variation in distensibility and fragility, it has been recommended that the lungs in ARDS be perceived as small rather than stiff. Conventional strategies using large volumes and high pressures have been shown to expose endothelial areas to stress. This excess tidal volume relative to the size of the aeratable lung causes an excessive transalveolar inflation pressure that initiates damaging shearing forces. Recent literature suggests that these excessive inflation pressures may be quite damaging to the lung and produce a syndrome indistinguishable from ARDS. 73

Current ventilatory strategies are targeted at maximum alveolar recruitment. This approach ad- vocates limiting overdistention of normal lung while attempting to recruit the lung that is atelec- tatic and collapsed. It is speculated that the use of optimal positive end-expiratory pressure allows for alveolar recruitment and subsequent tidal volumes are dissipated into the open lung. Newer ventilatory strategies using pressure limited approaches and inflection points have suggested improved outcome. In these studies, the optimal positive end- expiratory pressure is defined by the inflection point method and the tidal volume occurs over the area of the pressure volume curve where the lung remains most compliant. The tidal volume is limited by the higher inflection point, beyond which overdistention occurs. As a consequence of the pressure limitation, tidal volumes are significantly less, characteristically around 6 mL/kg, and the patient is ventilated with a low respiratory rate to achieve low pressures. 72 A consequence to the pressure limited ventilation is CO 2 retention and permissive hypercapnia, which appears to be well- tolerated in most patients. Prone positioning in ARDS is another technique under investigation.

Catheter Infection and Care

The incidence of secondary blood stream infection from many sources has declined in the last decade. However, nosocomial bacteremia has increased twofold, primarily attributable to intravascular catheter, particularly central venous, infection. Catheter-related bacteremia is associated with a twofold to threefold increase in mortality. The use of maximal barrier precautions, sterile gloves, cap, mask, full length surgical gown, and full drapes during insertion has been shown to decrease catheter-related bacteremia in a cost-effective fashion. Local catheter infection is defined as a positive semiquantitative catheter culture, whereas catheter-related septicemia is defined by a positive semiquantitative catheter culture and blood cultures with the same species without another identifiable source. Molecular subtyping has identified a high concordance between skin organisms and infected catheters. This suggests that microorganisms from the skin invade the cutaneous track and precipitate infection. 85

The duration of catheterization undoubtedly plays a role in the genesis of infections. It has been shown that central venous or pulmonary artery (PAC) catheters have a low risk of catheter-related bacteremia during the first 4 days of use, but the incidence increases sharply thereafter. 86 Two schools of thought exist. The first recommends limiting catheter placement to 4 days. If continued use is necessary, the catheter site should be rotated or changed over a guidewire and a semiquantitative culture performed. Alternatively, it has been proposed that scheduled catheter changes are associated with a higher incidence of infection and mechanical complications either by guidewire changes or by establishing new sites. Those in accordance with the latter recommend that catheter changes be done when clinically indicated only (fever, infection, or catheter malfunction), s5'86

Steroid/Immunotherapy

Since their discovery half a century ago, corticosteroids have been proposed as a potential pan- acea in various critical illnesses, including early ARDS, sepsis, and traumatic brain injury. 87-90 However, only several life-threatening processes have stood the test of randomized, prospective analysis and shown steroid-associated benefit. These include its use in patients with acute spinal cord optimally within the first 8 hours of insult, just


before therapy for bacterial meningitis in children, and possibly in patients in the late or fibroprolif- erative phase of ARDS. 91'92

A host of immunologic and receptor therapies, including polyclonal and monoclonal antibodies against endotoxin, anti-tumor necrosis factor, in- terleukin receptor antagonists, and inflammatory mediators, have been tried in modulating SIRS and limiting the progression of MODS (Table 3) . 93

Despite initial enthusiasm, none of them has been consistently effective.

Monitoring Indications for invasive intravascular monitor-

ing, particularly with central venous catheters and PACs, catheters, remains under scrutiny. Monitors are helpful if they aid us in establishing diagnosis, guide appropriate therapy, and identify trends without undue risk.

The routine use of right heart catheterization or PAC placement is controversial. Recently, Con- nors et a194 from the SUPPORT group reported the outcome of over 5,000 patients who underwent PAC placement as part of their critical care. When these 5,000 were matched to an "equal" cohort of 5,000, the PAC patients had higher morbidity, mortality, and cost of c a r e . 94 This fueled an ongoing controversy about the PAC and some have called for a national moratorium on PAC use until a prospective, randomized study can be performed. The current general consensus of such august bod- ies as the American Society of Anesthesiologists, Society of Critical Care Medicine, and Food and Drug Administration is that a moratorium is not warranted. 95~ However, educational deficiencies in the proper application of the PAC have been well-outlined in the United States and Europe. 97'98

ANESTHETIC IMPLICATIONS Perioperative Planning

Anesthesiologists encounter patients at risk for MODS in the perioperative period most commonly in two general scenarios. The first occurs when the patient presents for surgery and the surgical stress/ insult is the inciting factor for MODS (ie, aortic aneurysm repair). The second situation, is surgical treatment of the "first hit" insult (ie, multiple trauma patient, resection of ischemic bowel), or subsequent "second hit insults" (ie, drainage of intraabdominal abscess 10 days after ischemic bowel resection).

Patients at risk for MODS or with evolving MODS frequently have minimal reserve. Although there are limited, if any, studies available regarding the effect of anesthesia on outcome, intuitively careful preparation, appropriate monitoring, safe transport, and avoidance of predictable complications seem to be crucial. The additional stress from surgery and anesthesia may overwhelm an already tenuous patient. A full review of the current clinical situation and how the present cause evolved is an important starting point. After reviewing the background information and physical examination, specific end-organ system review is undertaken.

The Operating Room

The operating room must be fully organized before patient transport. This includes a checked and fully equipped anesthesia machine, drugs, suc- tion, routine monitoring equipment, and any antic- ipated equipment that may be needed or is already in use in the emergency department or ICU (ie, specialized ventilator, intracranial monitor, trane- sophageal echocardiograph, or drug infusion). Spe- cial consideration should be given to (1) safe patient transport, (2) mode of ventilation and presence of an appropriate ventilator, (3) means of maintaining normothermia, (4) availability of a cell saver and rapid infuser, (5) ready access to previously ordered blood products, and (6) availability of sufficient personnel.

Transport

Safe patient transport is a major challenge. It may be more appropriate to perform certain pro- cedures, such as placing additional intravenous catheters, intensifying monitoring (ie, placing a PAC with x-ray documentation of proper position), or administering certain drugs (such as vancomycin or steroids) or blood products before transfer. It also may be beneficial to sedate or provide analgesia before transport. This is of particular benefit in the awake, anxious patient and those who will be markedly uncomfortable during the transport.

Various studies have reported multiple deleteri- ous effects on physiologic parameters such as heart rhythm, blood pressure, acid-base status, and temperature, and also increased risk of infection in critically ill patients who require transport within the hospital. 99'1~176 Therefore, adequate personnel and equipment with appropriate backup material is needed before patient transport.


Anesthetic

Controversy continues to surround the issue of the safest anesthetic to administer to the critically ill and those at risk for critical illness. TM The issue of choice between general, regional, and combined general and regional remains under debate. The concept of pre-emptive analgesia although attrac- tive, has not yet been shown to improve outcome and limit morbidity.

We propose the concept of preventive anesthesia. This approach strives to administer adequate analgesia, amnesia, and sufficient muscle relax- ation to insure patient safety, comfort, and provide optimal operating conditions. In addition, we must avoid or recognize and aggressively correct intraoperative complications such as hypoperfusion, hypothermia, and ischemi.a. Finally, infection control protocols should be applied to limit nosocomial infection as well as protect practitioners.

FUTURE DIRECTIONS AND SUMMARY

Multiple organ dysfunction syndrome is the major cause of protracted ICU patient care, morbidity, and mortality. Improved techniques to define the entity, identify the development of MODS, and establish methods to prevent or treat established MODS are needed to enhance survival. Anesthe- siologists must provide meticulous attention to de- tail, careful planning of perioperative management of these patients, and well-coordinated transport of MODS patients. The anesthetic management of these patients requires a complete knowledge of the patient's status and efforts to maintain fluid balance, gas exchange, and temperature homeostasis.

A host of innovative therapies have been tried in the past 10 to 20 years (Table 3). Only a few have withstood the test of time. Many proposed reme- dies have been single-shot or short-term therapies directed toward a specific mediator or time point in the evolution of a critical illness. It may be too simplistic to hope that a single monoclonal anti- body, receptor agonist/antagonist, antioxidant, anti-inflammatory, cellular modulator, or the like will prevent, stop, or reverse excessive systemic inflammation or organ damage. Therefore, a multimodal approach may be needed. Identification of the progression to irreversible end-organ dysfunction is needed to enhance development of effective therapies.

Systemic inflammatory response syndrome/ MODS will remain major causes of morbidity and mortality as our population ages, as an increasing number of patients are immunosuppressed, and as resources continue to be stretched. The backbone of successful care of those at risk for developing SIRS/MODS will continue to be prevention. Peri- operative physicians need to be aware of techniques to better identify at-risk patients; intervene preemptively; explore alternative therapeutic options if a surgical procedure has excessive risk; and anticipate delayed sequelae secondary to intraoperative events.

Multimodal therapy will hopefully be forthcom- ing. Unfortunately, the development of such approaches may be exorbitantly expensive. This calls for well-designed and executed multicenter, prospective studies. An example is the evolving data generated by the SUPPORT and ARDS net- works . 73,74

The application of molecular biologic techniques to diagnose and treat the most critically ill should be on the horizon. This may allow more specific targeting of therapy. Improved imaging and minimally invasive or percutaneous proce- dures continue to grow. Finally, the use of nutri- ceuticals, immune manipulation, hemofiltration or diafiltation, organ support systems (ie, artificial or temporary liver), site-specific drugs, and more selective sedatives and analgesics are under development.

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