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Organ Failure Avoidance and Mitigation Strategies in Surgery
O r g a n F a i l u re Av o i d a n c e an d Mitigation Strategies in Surgery Kevin W. McConnell,
MD
a
, Craig M. Coopersmith,
MD
b,
*
KEYWORDS Organ failure Sepsis Resuscitation Critical care
ORGAN FAILURE AND MULTIORGAN DYSFUNCTION SYNDROME
The ability of physicians to treat failing organs is a recent development in the history of medicine. For most of human history, the development of organ failure resulted in the quick demise of the patient. It was not until the second half of the twentieth century, around the same time as the initial description of multiple organ failure, that the ability to support failing organs evolved from the realm of theory into a host of interventions that could be used at the bedside.1,2 The initial description of multiorgan dysfunction syndrome (MODS) came in a 1991 consensus conference between the American College of Chest Physicians and the Society of Critical Care Medicine, which produced definitions of the systemic inflammatory response syndrome (SIRS), sepsis, and MODS.3 SIRS is defined as the presence of at least 2 of the following 4 criteria: (1) body temperature greater than 38 C or less than 36 C; (2) heart rate greater than 90 beats per minute; (3) respiratory rate greater than 20 breaths per minute or hyperventilation with PaCO2 less than 32 mm Hg; or (4) white blood cell count greater than 12,000/mm3, less than 4000/mm3, or greater than 10% immature neutrophils. If these changes occur in the setting of an infectious source, then the process is defined as sepsis. MODS is defined as an acutely ill patient with altered organ function in whom homeostasis cannot be maintained without intervention. Studies now indicate that MODS is the leading cause of death in noncoronary intensive care units (ICUs), accounting for 50% to 81% of deaths,4–7 and its incidence is increasing.8 Surgical patients represent a subpopulation at significant risk for MODS because of the increased risk associated with sepsis, polytrauma, burns, pancreatitis, The authors have nothing to disclose. a Acute and Critical Care Surgery, Emory University School of Medicine, Atlanta, GA, USA b Emory Center for Critical Care, Emory University School of Medicine and Emory Healthcare, Atlanta, GA, USA * Corresponding author. 101 Woodruff Circle, Suite WMB 5105, Atlanta, GA 30322. E-mail address: [email protected] Surg Clin N Am 92 (2012) 307–319 doi:10.1016/j.suc.2012.01.001 surgical.theclinics.com 0039-6109/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
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aspiration, severe hemorrhage, massive transfusion, ischemia-reperfusion, and other complications.7,9,10 Although the number of organs failing and the severity of failure correlate strongly with patient outcomes,6,11,12 defining the pathophysiology of MODS continues to be challenging. Most agree that alterations in systemic inflammation lead, at least in part, to the development of MODS. However, the severity, balance between hyperinflammation/hypoinflammation, and time course of inflammation are all incompletely understood and therefore represent topics of intense research interest.13 The initial definition of MODS served to capture individuals with systemic inflammation and organ dysfunction for clinical trials, but may have contributed to the failure of these trials by including a broad distribution of patients with different ages, severities, sources, and genetics.14–16 Although further efforts were made to update the definitions of sepsis, severe sepsis, and septic shock, they remain nonspecific.17 Several scoring systems have been developed to characterize the degree of MODS and predict mortality. Of these, Multiorgan Dysfunction Score, Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE II and III), and Simplified Acute Physiology Score (SAPS) are some of the most commonly used.18 The individual strengths and weaknesses of each scoring system are beyond the scope of this article, but many are used without a clearly accepted gold standard, which implies variable usefulness and a lack of consensus on which might best identify patients for potential new interventions. CURRENT STRATEGIES FOR PREVENTION AND MITIGATION
Developing strategies to prevent or treat MODS has proved to be challenging. The reasons behind this are complex. On a cellular/subcellular level, there are many mechanisms known to contribute to MODS. Microvascular thrombosis, apoptosis, neutrophil-induced damage, bacterial translocation, cytokine release, endothelial dysfunction, enteric barrier dysfunction, and other mechanisms have been implicated in the process.19–28 Each of these (and multiple other) mechanisms have been shown to be important in animal models, but none has translated into targeted therapy for MODS that is useful at the bedside. On a whole-body level, each patient with critical illness is subjected to the injury or infection causing SIRS, which can frequently cause dysfunction or failure in 1 or multiple organs. The health care team responds to this with supportive care and/or potentially therapeutic interventions. However, these interventions may cause inadvertent harm to the patient, exacerbating the underlying insult.29 For instance, mechanical ventilation can be lifesaving but, depending on the settings on the ventilator, it may also injure the lung and adversely affect host defense mechanisms, secondarily affecting the function of other organs, and ultimately leading to a preventable increase in mortality.30,31 GENERALIZED PREVENTION
As with any disease, the best treatment of MODS is preventing it from occurring in the first place. In the surgical patient, MODS prevention can occur by identifying high-risk groups before elective surgery, and weighing the risk/benefit ratio of proceeding with an operation. There are numerous scoring systems that identify a patient’s risk for postoperative cardiac or respiratory complications. Surgeons and anesthesiologists (as well as medical specialty consultants, if indicated) are ultimately responsible for ensuring that surgery is being performed only on candidates who have an acceptable risk profile. In addition, preoperative status may need to be optimized before agreeing
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to operate on a patient. This optimization may take the form of improved nutrition, weight loss, respiratory rehabilitation, quitting smoking, and so forth. Once an operation has occurred (either elective or emergent), a certain number of patients have organ dysfunction, which progresses to MODS in a subset of them. However, this risk is modifiable by adherence to best practice, which can prevent development of further complications. For floor (and at times ICU) patients, this means rapid ambulation and deep breathing/incentive spirometer. For high-risk patients (studied most notably in vascular patients), perioperative b-blockade may prevent cardiovascular complications.32 Initiating appropriate prophylaxis against deep venous thrombosis and (if indicated) stress ulceration may also prevent complications that can lead to MODS. Removing central venous catheters, arterial lines, Foley catheters, and endotracheal tubes as soon as possible can prevent development of central line–associated bloodstream infection, catheter-associated urinary tract infection, and ventilator-associated pneumonia (VAP), respectively. ONCE MODS SETS IN, WHAT THERAPIES ARE AVAILABLE TO THE PATIENT?
The mainstays of prevention of MODS include early recognition/resuscitation, removal of the inciting source, and prevention of iatrogenic injury. Once organ failure sets in, most treatment is supportive, allowing the host to heal without causing additional iatrogenic injury. In a global view, most care provided in the ICU is not intended to cure but to support. Pressors do not cure shock, but instead potentially prevent inadequate tissue perfusion until the body is able to maintain its own blood pressure. Mechanical ventilation does not cure respiratory failure but instead supports the lungs until the body is able to regulate ventilation and oxygenation on its own. Similarly, renal replacement therapy does not cure acute renal failure but supports the body until the kidneys recover to the point that they are able to clear both toxins and volume. As such, the best that can be offered to many patients is to effectively support them, with the hope that prevention of further decompensation will allow their bodies to have sufficient time to heal from the initial insults. STRATEGIES BY ORGAN SYSTEM
Despite most treatment in MODS being supportive rather than curative, it is helpful to be fully versed in strategies that may result in positive outcomes for critically ill patients. Because the most common cause of organ failure is sepsis, the Surviving Sepsis guidelines are an excellent resource for an evidence-based approach that identifies key interventions to improve survival in patients with this complex process.33,34 Neurologic Conditions
Effective management centers on maintaining patient comfort (generally, although not always, with narcotics or an epidural, when appropriate) while minimizing common sequelae of MODS including delirium and agitation. Although sedation may be necessary to safely ventilate a subset of patients, unchecked sedative use can lead to iatrogenic harm. This harm can be broken down into direct neurologic complications and indirect complications caused by an inability to liberate patients from mechanical ventilation. Delirium is an important measure of organ dysfunction and has been shown to be a predictor of mortality in the ICU.35 However, studies indicate that delirium is underrecognized in the ICU, especially hypoactive delirium. Patient should be screened for delirium each day using a validated screen such as the Confusion Assessment Method
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for the ICU (CAM-ICU).36 Minimization of benzodiazepines by either avoidance or using other agents may reduce delirium and ICU length of stay.37,38 If patients do develop delirium, initial treatment should be nonpharmacologic, using frequent reorientation of the patient and attempts to correct sleep-wake cycle deficits. If unsuccessful, antipsychotic agents such as haloperidol or newer atypical agents may be beneficial. Delirium is best treated with a protocol using evidence-based standards and adopted for local usage. The use of excessive sedation medicines can have secondary effects outside the neurologic system. Patients who do not wake up once their sedatives are stopped have continued need for mechanical ventilation, with the concordant risk of VAP. For this reason, sedation protocols are recommended because they have been shown to conclusively reduce duration of mechanical ventilation, ICU length of stay, and need for tracheostomy.39,40 In addition, a daily sedation holiday, allowing the patient to wake, is also strongly supported.39,41,42 Although historically there have been concerns about daily awakening in surgical patients, all patients in the ICU, including postoperative patients, should have a sedation holiday assuming they are physiologically able to have one. Surgeons also need to be cognizant of the potential for the development of neuropathy/myopathy of critical illness. Use of neuromuscular blocking agents is generally discouraged because they exacerbate neuropathy and require additional sedation. This problem is further exacerbated in patients receiving steroids.43 This concern should not prevent steroid usage in patients who may potentially benefit from them, such as patients with acute respiratory distress syndrome (ARDS)44 or septic shock; however, a careful weighing of available literature and the risk/benefit ratio should be undertaken before their initiation. Cardiovascular Conditions
Cardiovascular organ failure support primarily consists of hemodynamic stabilization and fluid resuscitation. Surgical patients often have significant blood loss or dehydration reducing their intravascular fluid volume, ultimately leading to hypovolemic shock. This condition may be further complicated by the inflammatory response, which can cause worsened capillary permeability and decreased vascular resistance (distributive shock). The treatment of cardiovascular failure depends on the underlying cause. The treatment of hypovolemia is volume. The treatment of bleeding is resuscitation with blood and/or blood products. The treatment of distributive shock is multifactorial as described in early goaldirected therapy.45 Although additional studies are ongoing to further optimize early goal-directed therapy, current guidelines for septic shock recommend resuscitation to a central venous pressure of 8 to 12 mm Hg (12–15 mm Hg in mechanically ventilated patients) with desired end points of a mean arterial pressure greater than 65 mm Hg, urine output 0.5 mL/kg/h, and central venous oxygen saturation greater than 70%.33,45 If patients are not volume responsive and are intravascularly resuscitated, vasopressors are recommended to keep a mean arterial pressure greater than 65 mm Hg, although the goal pressure needed for adequate perfusion may vary with individual patients and data to support this number are limited.46 Norepinephrine and dopamine have traditionally been the vasopressors of choice, but norepinephrine has become the preferred agent at many centers because of fewer adverse events.47 If patients continue to have a low central venous oxygen saturation despite adequate volume status and mean arterial pressure, the next step is to transfuse to a hemoglobin greater than 10 mg/dL. If, despite all these steps, the patient continues to have a low
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central venous oxygen saturation, consideration should be given to the addition of an inotrope. Myocardial function may be decreased in the perioperative period as a result of either myocardial infarction or a globally decreased left ventricular function that is mediated by an inflammatory response. High-risk vascular patients and those on preoperative b-blockers should have b-blockers continued in the perioperative period. Patients with perioperative myocardial infarctions should receive rapid cardiology consults. Therapy includes aspirin, b-blockade, oxygen, adequate oxygen-carrying capacity with transfusion if indicated, and statin therapy.32 The determination of whether to begin anticoagulation and/or to send the patient for a cardiac catheterization is an individualized decision. Right ventricular dysfunction is more rare but is frequently seen in the setting of a physiologically significant pulmonary embolism. Treatment includes anticoagulation or lytics if indicated or an inferior vena cava filter if the risk for bleeding is too high to safely anticoagulate the patient. The myocardium should be supported with inotropic support if needed, with minimization of fluid resuscitation. Another common cause of shock in the patient with trauma is spinal cord injury. Pressors to maintain vascular tone are appropriate in this setting. Clinicians must be concerned about obstructive shock secondary to tension pneumothorax, pericardial tamponade, or pulmonary embolism. Treatment includes a high index of suspicion when clinically indicated, followed by needle decompression, pericardiocentesis, and/or window and anticoagulation or inferior vena cava filter, respectively. Respiratory Conditions
The key aspects of organ failure prevention involve minimization of volutrauma and barotrauma to the lung, minimization of VAP, and minimization of volume overload. There are strong data to support the use of a lung-protective, low-tidal-volume (starting at 6 mL/kg ideal body weight) ventilation strategy in patients with acute lung injury, maintaining a plateau pressure less than 30 mm Hg, because higher tidal volumes worsen organ failure and mortality.34,48–50 The use of positive end-expiratory pressure to prevent atelectasis and recruit closed alveoli in patients with ARDS is also well supported.51,52 All ventilated patients are at risk for VAP. Elevating the head of the bed to 30 to 45 , oral care, and early liberation from the ventilator decreases the incidence of VAP.53 Several studies show that patients who are given a daily spontaneous breathing trial have a reduction in the duration of mechanical ventilation.54–56 Recent studies show that a positive fluid balance is associated with longer mechanical ventilation and increased mortality,57,58 which can be especially challenging in postoperative patients who have significant third spacing, especially when they are critically ill. Although it is difficult to have a single rule of thumb for these patients, the best practice is to ensure that patients have adequate intravascular volume without excessive volume resuscitation. Assaying volume status in surgical patients can be difficult. In patients who are less sick, noninvasive methods such as following urine output are adequate. In more critically ill patients, additional monitoring may be appropriate. The simplest method is the use of central venous pressure; however, there are multiple studies indicating that this correlates poorly with intravascular volume status, despite its common usage. Newer technologies, such as those assessing stroke volume variance from an arterial line tracing and esophageal Dopplers, may play a role in assessing volume status. Bedside echocardiography is also being increasingly used for this purpose. Historically, pulmonary artery catheters have been used to aid in management of
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volume status, but several trials suggest that these should not be used on a routine basis for this indication.59–61 Renal Conditions
Protection of the kidneys in the surgical patient can be challenging. Acute kidney injury still occurs in up to 65% of septic shock and is an independent risk factor for death in patients with MODS.62 The mainstay of therapy involves ensuring adequate hemodynamic resuscitation and, if possible, avoidance of iodinated contrast and nephrotoxic drugs. Although several agents have been proposed, there are no proven therapies that improve renal function in patients with MODS. However, there are unequivocal data that renal-dose dopamine is not effective in preventing acute renal failure, and its use cannot be supported.33 A certain subset of patients with MODS require an intravenous dye load in the setting of a computed tomography scan or angiography. Prevention of contrastinduced nephropathy has received significant attention recently. As with other causes of renal failure in MODS, the most important factor in protecting kidney function is adequate hydration. In addition, there are some data that suggest that bicarbonate may be useful in preventing contrast-induced nephropathy, although the largest trial to date suggests that there is no benefit to n-acetylcysteine, an agent commonly used for this purpose.63 In general, there is no advantage to using crystalloids or colloids in preventing perioperative renal failure. The SAFE (Saline vs Albumin Fluid Evaluation) study suggests that the choice of crystalloid versus albumin as the resuscitation fluid in patients in the ICU makes no difference except in patients with head injury, for whom albumin may be worse.64 There are some patient population–specific data to suggest that albumin may be beneficial in patients with liver failure, acute lung injury (when given with furosemide), and sepsis.65,66 Unless a patient is in a specific subcategory in which albumin has been shown to have benefit compared with crystalloid, it should be avoided if possible because it is significantly more expensive. When using crystalloids for resuscitation, it is important to choose a balanced solution. For this reason, it is important that practitioners be aware that normal saline is associated with a significant incidence of hyperchloremic metabolic acidosis.67 Despite optimal medical therapy, some surgical patients progress to anuric renal failure and require dialysis. Hypotensive patients who require dialysis are generally placed on continuous renal replacement therapy rather than intermittent hemodialysis because it causes less hemodynamic instability. However, the optimal timing and rate of renal replacement therapy continues to be controversial and is therefore a topic of active research.68,69 In addition, there are experimental protocols to use alternative hemofiltration to remove inflammatory mediators, a technique that is commonly used in select ICUs outside the United States.70 Gastrointestinal Conditions
The intestine is often described as the motor of the systemic inflammatory response.71 The most well-supported intervention associated with the gut and prevention of organ failure in the postoperative setting is early enteral nutrition. There have been several randomized trials, including enteral feeding versus total parenteral nutrition, that show improved outcomes and decreased organ failure in patients given early enteral nutrition.72–75 In contrast, there does not seem to be a benefit of early parenteral nutrition in critically ill patients.76 Immunonutrition is an evolving field. Although an exhaustive review of the literature is beyond the scope of this article, there is strong evidence that supplemental enteral
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glutamine should be considered in patients with burns and trauma, and supplemental glutamine is recommended for critically ill patients receiving parental nutrition.77 Supplemental combined vitamins, trace elements, and selenium supplementation should also be considered in critically ill patients. In contrast, diets supplemented with arginine should not be used in critically ill patients based on current data. Although many surgical patients receive stress ulcer prophylaxis, data support their use only in patients with significant risk factors. These risk factors include mechanical ventilation for longer than 48 hours and coagulopathy. Other relative indications include acute kidney injury, sepsis, burn, and head injury. For patients who meet these indications, there is more evidence to support the usage of H2 blockers than proton pump inhibitors. Both classes of agents are associated with complications including development of Clostridium difficile infections and pneumonia and should be avoided unless a clear indication is present. Endocrine Conditions
Although panendocrine dysfunction can occur in critical illness, the most well-studied abnormalities include those involving glucose control and adrenocorticoid secretion.78 Although a single-center study in 2001 showed a significant mortality improvement in critically ill patients after cardiac surgery with tight glucose control (80–110 mg/dL),79 multiple large-scale trials have failed to reproduce this benefit.80–82 In addition, tight glucose control has been associated with a marked increase in hypoglycemia. Current recommendations suggest keeping blood glucose levels at less than 150 mg/dL. Steroid use in critically ill patients remains controversial. A multicenter randomized trial showed improvement of shock and mortality in patients with relative adrenal insufficiency.83 However, a subsequent larger trial did not show a mortality benefit, but did have a more rapid resolution of shock in patients treated with steroids.84 Thus, current recommendations suggest supplementing patients with refractory septic shock with hydrocortisone.33 However, the definition of refractory shock is unclear, so the appropriate trigger for initiating steroid therapy in patients with septic shock is not known. Obtaining an adrenocorticotropic hormone stimulation test is not indicated in patients with septic shock. Hematology
The treatment of bleeding is transfusion of blood and blood products. When a surgical patient or a patient with trauma is bleeding, transfusion should be initiated immediately and can be a lifesaving therapy. However, although blood has historically been transfused to improve oxygen-carrying capacity in nonbleeding patients, there are significant data in critically ill patients that transfusing patients to a hemoglobin of 10 mg/dL is not beneficial and is potentially harmful.85,86 Patients should generally have a hemoglobin of 7 mg/dL before transfusion, likely because of the immunosuppressive effects of blood and the underrecognized complication of transfusion-associated acute lung injury. Although most patients can safely be anemic, higher hemoglobin levels should be targeted in patients having an acute myocardial infarction, those with unstable angina, and those with class 3 or 4 congestive heart failure. In addition, the protocol for early goal-directed therapy for sepsis includes transfusion to a hemoglobin of 10 mg/dL if the patient has a central venous oxygen saturation less than 70% despite adequate fluid resuscitation and pressors. Although this is controversial and is the topic of a current study funded by the National Institutes of Health,87 following this protocol is a reasonable evidenced-based approach.
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Infectious Disease
The one organ system that is unequivocally amenable to curative (as opposed to supportive) care is infectious disease. This care involves appropriate source control when appropriate via surgery, interventional radiology drainage, or removal of an infected catheter. Source control should occur in the least invasive manner possible. Administration of appropriate antibiotics can be lifesaving. In the setting of septic shock, a delay in the administration of appropriate antibiotics results in an 8% per hour increase in mortality.88,89 Patients should initially receive broad-spectrum antibiotics targeted to suspected microorganisms (this varies based on the anatomic site of infection). Antibiotics should then be narrowed, based on culture results, to prevent generation of resistant organisms. Apart from antibiotics, there are no biological adjuncts that are known to be beneficial for the treatment of MODS. Previously, drotrecogin a (Xigris) had US Food and Drug Administration approval for the treatment of septic shock. However, follow-up studies showed a lack of efficacy for this agent and it was recently withdrawn from the market worldwide.90,91 THE FUTURE
In the last decade, there has been increasing interest in studying homogenous subgroups of critically ill patients, rather than looking at a large heterogeneous population, in which important differences may be masked by the diversity of the group as a whole. A commonly used analogy is that no oncologist would enroll patients with stage I melanoma and stage IV pancreatic cancer in the same trial independently of disease state; however, to some degree, this is what has historically be done in critical care research. As a framework for future studies, the PIRO system has been advocated as a method for developing more patient-based therapies. In this acronym, P stands for predisposition (including age, genetic factors, and baseline comorbidities), I refers to the insult or infection that brought on the organ dysfunction (including site, whether hospital or community acquired, and microbiology), R is the response (evaluated by laboratory values and vital signs), and O is organ dysfunction (with evaluation of number of organs failing).14,92,93 The hope is that this new approach will help stage patients with organ failure so that trials can be more effectively designed and more effective therapies can be designed to mitigate or treat MODS. SUMMARY
Postoperative organ failure is a challenging disease process that is better prevented than treated. Providers should use close observation and clinical judgment, and checklists of best practices to minimize the risk of organ failure in their patients. The treatment of MODS generally remains supportive, outside of rapid initiation of source control (when appropriate) and targeted antibiotic therapy. More specific treatments may be developed as the complex pathophysiology of MODS is better understood and more homogenous patient populations are selected for study. REFERENCES
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3. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20(6):864–74. 4. Barie PS, Hydo LJ. Epidemiology of multiple organ dysfunction syndrome in critical surgical illness. Surg Infect 2000;1(3):173–85 [discussion: 185–6]. 5. Martin CM, Hill AD, Burns K, et al. Characteristics and outcomes for critically ill patients with prolonged intensive care unit stays. Crit Care Med 2005;33(9): 1922–7 [quiz: 1936]. 6. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34(2):344–53. 7. Dewar D, Moore FA, Moore EE, et al. Postinjury multiple organ failure. Injury 2009; 40(9):912–8. 8. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348(16):1546–54. 9. Barie PS, Hydo LJ, Pieracci FM, et al. Multiple organ dysfunction syndrome in critical surgical illness. Surg Infect 2009;10(5):369–77. 10. Kallinen O, Maisniemi K, Bohling T, et al. Multiple organ failure as a cause of death in patients with severe burns. J Burn Care Res 2011. [Epub ahead of print]. 11. Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995;23(10):1638–52. 12. Le Gall JR, Klar J, Lemeshow S, et al. The Logistic Organ Dysfunction System. A new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group. JAMA 1996;276(10):802–10. 13. Hotchkiss RS, Opal S. Immunotherapy for sepsis–a new approach against an ancient foe. N Engl J Med 2010;363(1):87–9. 14. Vincent JL, Martinez EO, Silva E. Evolving concepts in sepsis definitions. Crit Care Nurs Clin North Am 2011;23(1):29–39. 15. Marshall JC. Sepsis research: where have we gone wrong? Crit Care Resusc 2006;8(3):241–3. 16. Carlet J, Cohen J, Calandra T, et al. Sepsis: time to reconsider the concept. Crit Care Med 2008;36(3):964–6. 17. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31(4):1250–6. 18. Ferreira AM, Sakr Y. Organ dysfunction: general approach, epidemiology, and organ failure scores. Semin Respir Crit Care Med 2011;32(5):543–51. 19. Coopersmith CM, Stromberg PE, Dunne WM, et al. Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis. JAMA 2002;287(13):1716–21. 20. Marshall JC. Modeling MODS: what can be learned from animal models of the multiple-organ dysfunction syndrome? Intensive Care Med 2005;31(5):605–8. 21. Dorinsky PM, Gadek JE. Mechanisms of multiple nonpulmonary organ failure in ARDS. Chest 1989;96(4):885–92. 22. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348(2):138–50. 23. Paulus P, Jennewein C, Zacharowski K. Biomarkers of endothelial dysfunction: can they help us deciphering systemic inflammation and sepsis? Biomarkers 2011;16(Suppl 1):S11–21. 24. Fink MP. Gastrointestinal mucosal injury in experimental models of shock, trauma, and sepsis. Crit Care Med 1991;19(5):627–41. 25. Marshall JC. Neutrophils in the pathogenesis of sepsis. Crit Care Med 2005; 33(Suppl 12):S502–5.
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26. Patel KN, Soubra SH, Lam FW, et al. Polymicrobial sepsis and endotoxemia promote microvascular thrombosis via distinct mechanisms. J Thromb Haemostasis 2010;8(6):1403–9. 27. Dixon B. The role of microvascular thrombosis in sepsis. Anaesth Intensive Care 2004;32(5):619–29. 28. Suliburk J, Helmer K, Moore F, et al. The gut in systemic inflammatory response syndrome and sepsis. Enzyme systems fighting multiple organ failure. Eur Surg Res 2008;40(2):184–9. 29. Marshall JC. Critical illness is an iatrogenic disorder. Crit Care Med 2010; 38(Suppl 10):S582–9. 30. Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999;282(1):54–61. 31. Imai Y, Parodo J, Kajikawa O, et al. Injurious mechanical ventilation and endorgan epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 2003;289(16):2104–12. 32. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. Circulation 2007;116(17):e418–99. 33. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36(1):296–327. 34. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342(18):1301–8. 35. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291(14):1753–62. 36. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001;286(21):2703–10. 37. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301(5):489–99. 38. Pichot C, Ghignone M, Quintin L. Dexmedetomidine and clonidine: from secondto-first-line sedative agents in the critical care setting? J Intensive Care Med 2011. [Epub ahead of print]. 39. Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med 1999;27(12):2609–15. 40. MacLaren R, Plamondon JM, Ramsay KB, et al. A prospective evaluation of empiric versus protocol-based sedation and analgesia. Pharmacotherapy 2000;20(6):662–72. 41. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled Trial): a randomised controlled trial. Lancet 2008;371(9607):126–34.
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42. Devlin JW, Boleski G, Mlynarek M, et al. Motor Activity Assessment Scale: a valid and reliable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit. Crit Care Med 1999;27(7):1271–5. 43. De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288(22):2859–67. 44. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363(12):1107–16. 45. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345(19):1368–77. 46. Bourgoin A, Leone M, Delmas A, et al. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Crit Care Med 2005;33(4):780–6. 47. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362(9):779–89. 48. Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med 1998;338(6):355–61. 49. Tobin MJ. Culmination of an era in research on the acute respiratory distress syndrome. N Engl J Med 2000;342(18):1360–1. 50. Marini JJ, Gattinoni L. Ventilatory management of acute respiratory distress syndrome: a consensus of two. Crit Care Med 2004;32(1):250–5. 51. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive endexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351(4):327–36. 52. Amato MB, Barbas CS, Medeiros DM, et al. Beneficial effects of the “open lung approach” with low distending pressures in acute respiratory distress syndrome. A prospective randomized study on mechanical ventilation. Am J Respir Crit Care Med 1995;152(6 Pt 1):1835–46. 53. Kollef MH. Prevention of hospital-associated pneumonia and ventilatorassociated pneumonia. Crit Care Med 2004;32(6):1396–405. 54. Ely EW, Baker AM, Dunagan DP, et al. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996;335(25):1864–9. 55. Esteban A, Alia I, Tobin MJ, et al. Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med 1999;159(2):512–8. 56. Esteban A, Alia I, Gordo F, et al. Extubation outcome after spontaneous breathing trials with T-tube or pressure support ventilation. The Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med 1997;156(2 Pt 1):459–65. 57. Flori HR, Church G, Liu KD, et al. Positive fluid balance is associated with higher mortality and prolonged mechanical ventilation in pediatric patients with acute lung injury. Crit Care Res Pract 2011;2011:854142. 58. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006;354(24):2564–75. 59. Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354(21):2213–24. 60. Sandham JD, Hull RD, Brant RF, et al. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 2003; 348(1):5–14.
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61. Richard C, Warszawski J, Anguel N, et al. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2003;290(20):2713–20. 62. Bagshaw SM, Lapinsky S, Dial S, et al. Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy. Intensive Care Med 2009;35(5):871–81. 63. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT). Circulation 2011;124(11):1250–9. 64. Myburgh J, Cooper DJ, Finfer S, et al. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 2007;357(9):874–84. 65. Martin GS, Mangialardi RJ, Wheeler AP, et al. Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med 2002;30(10): 2175–82. 66. Delaney AP, Dan A, McCaffrey J, et al. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med 2011;39(2):386–91. 67. Yunos NM, Kim IB, Bellomo R, et al. The biochemical effects of restricting chloride-rich fluids in intensive care. Crit Care Med 2011;39(11):2419–24. 68. Ricci Z, Polito A, Ronco C. The implications and management of septic acute kidney injury. Nat Rev Nephrol 2011;7(4):218–25. 69. Honore PM, Jacobs R, Joannes-Boyau O, et al. Septic AKI in ICU patients. diagnosis, pathophysiology, and treatment type, dosing, and timing: a comprehensive review of recent and future developments. Ann Intensive Care 2011;1(1):32. 70. Oda S, Sadahiro T, Hirayama Y, et al. Non-renal indications for continuous renal replacement therapy: current status in Japan. Contrib Nephrol 2010;166: 47–53. 71. Clark JA, Coopersmith CM. Intestinal crosstalk: a new paradigm for understanding the gut as the “motor” of critical illness. Shock 2007;28(4):384–93. 72. Moore FA, Moore EE, Kudsk KA, et al. Clinical benefits of an immune-enhancing diet for early postinjury enteral feeding. J Trauma 1994;37(4):607–15. 73. Moore FA, Feliciano DV, Andrassy RJ, et al. Early enteral feeding, compared with parenteral, reduces postoperative septic complications. The results of a metaanalysis. Ann Surg 1992;216(2):172–83. 74. Moore FA, Moore EE, Jones TN, et al. TEN versus TPN following major abdominal trauma–reduced septic morbidity. J Trauma 1989;29(7):916–22 [discussion: 922–3]. 75. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding. Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215(5):503–11 [discussion: 511–3]. 76. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365(6):506–17. 77. Available at: http://www.criticalcarenutrition.com/docs/cpg/srrev.pdf. Accessed August 1, 2011. 78. Vanhorebeek I, Langouche L, Van den Berghe G. Endocrine aspects of acute and prolonged critical illness. Nat Clin Pract Endocrinol Metab 2006;2(1):20–31. 79. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345(19):1359–67. 80. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360(13):1283–97.
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81. Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ 2009;180(8):821–7. 82. Marik PE, Preiser JC. Toward understanding tight glycemic control in the ICU: a systematic review and metaanalysis. Chest 2010;137(3):544–51. 83. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288(7):862–71. 84. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358(2):111–24. 85. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340(6):409–17. 86. Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med 2009;37(12): 3124–57. 87. Available at: http://clinicaltrials.gov/ct2/show/NCT00510835?term5process&rank51. Accessed August 1, 2011. 88. Iregui M, Ward S, Sherman G, et al. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 2002;122(1):262–8. 89. Dickinson JD, Kollef MH. Early and adequate antibiotic therapy in the treatment of severe sepsis and septic shock. Curr Infect Dis Rep 2011;13(5):399–405. 90. Laterre PF, Abraham E, Janes JM, et al. ADDRESS (ADministration of DRotrecogin alfa [activated] in Early stage Severe Sepsis) long-term follow-up: one-year safety and efficacy evaluation. Crit Care Med 2007;35(6):1457–63. 91. Dhainaut JF, Laterre PF, Janes JM, et al. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med 2003;29(6):894–903. 92. Rubulotta F, Marshall JC, Ramsay G, et al. Predisposition, insult/infection, response, and organ dysfunction: a new model for staging severe sepsis. Crit Care Med 2009;37(4):1329–35. 93. Moreno RP, Metnitz B, Adler L, et al. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med 2008;34(3):496–504.
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a
, Craig M. Coopersmith,
MD
b,
*
KEYWORDS Organ failure Sepsis Resuscitation Critical care
ORGAN FAILURE AND MULTIORGAN DYSFUNCTION SYNDROME
The ability of physicians to treat failing organs is a recent development in the history of medicine. For most of human history, the development of organ failure resulted in the quick demise of the patient. It was not until the second half of the twentieth century, around the same time as the initial description of multiple organ failure, that the ability to support failing organs evolved from the realm of theory into a host of interventions that could be used at the bedside.1,2 The initial description of multiorgan dysfunction syndrome (MODS) came in a 1991 consensus conference between the American College of Chest Physicians and the Society of Critical Care Medicine, which produced definitions of the systemic inflammatory response syndrome (SIRS), sepsis, and MODS.3 SIRS is defined as the presence of at least 2 of the following 4 criteria: (1) body temperature greater than 38 C or less than 36 C; (2) heart rate greater than 90 beats per minute; (3) respiratory rate greater than 20 breaths per minute or hyperventilation with PaCO2 less than 32 mm Hg; or (4) white blood cell count greater than 12,000/mm3, less than 4000/mm3, or greater than 10% immature neutrophils. If these changes occur in the setting of an infectious source, then the process is defined as sepsis. MODS is defined as an acutely ill patient with altered organ function in whom homeostasis cannot be maintained without intervention. Studies now indicate that MODS is the leading cause of death in noncoronary intensive care units (ICUs), accounting for 50% to 81% of deaths,4–7 and its incidence is increasing.8 Surgical patients represent a subpopulation at significant risk for MODS because of the increased risk associated with sepsis, polytrauma, burns, pancreatitis, The authors have nothing to disclose. a Acute and Critical Care Surgery, Emory University School of Medicine, Atlanta, GA, USA b Emory Center for Critical Care, Emory University School of Medicine and Emory Healthcare, Atlanta, GA, USA * Corresponding author. 101 Woodruff Circle, Suite WMB 5105, Atlanta, GA 30322. E-mail address: [email protected] Surg Clin N Am 92 (2012) 307–319 doi:10.1016/j.suc.2012.01.001 surgical.theclinics.com 0039-6109/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
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aspiration, severe hemorrhage, massive transfusion, ischemia-reperfusion, and other complications.7,9,10 Although the number of organs failing and the severity of failure correlate strongly with patient outcomes,6,11,12 defining the pathophysiology of MODS continues to be challenging. Most agree that alterations in systemic inflammation lead, at least in part, to the development of MODS. However, the severity, balance between hyperinflammation/hypoinflammation, and time course of inflammation are all incompletely understood and therefore represent topics of intense research interest.13 The initial definition of MODS served to capture individuals with systemic inflammation and organ dysfunction for clinical trials, but may have contributed to the failure of these trials by including a broad distribution of patients with different ages, severities, sources, and genetics.14–16 Although further efforts were made to update the definitions of sepsis, severe sepsis, and septic shock, they remain nonspecific.17 Several scoring systems have been developed to characterize the degree of MODS and predict mortality. Of these, Multiorgan Dysfunction Score, Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE II and III), and Simplified Acute Physiology Score (SAPS) are some of the most commonly used.18 The individual strengths and weaknesses of each scoring system are beyond the scope of this article, but many are used without a clearly accepted gold standard, which implies variable usefulness and a lack of consensus on which might best identify patients for potential new interventions. CURRENT STRATEGIES FOR PREVENTION AND MITIGATION
Developing strategies to prevent or treat MODS has proved to be challenging. The reasons behind this are complex. On a cellular/subcellular level, there are many mechanisms known to contribute to MODS. Microvascular thrombosis, apoptosis, neutrophil-induced damage, bacterial translocation, cytokine release, endothelial dysfunction, enteric barrier dysfunction, and other mechanisms have been implicated in the process.19–28 Each of these (and multiple other) mechanisms have been shown to be important in animal models, but none has translated into targeted therapy for MODS that is useful at the bedside. On a whole-body level, each patient with critical illness is subjected to the injury or infection causing SIRS, which can frequently cause dysfunction or failure in 1 or multiple organs. The health care team responds to this with supportive care and/or potentially therapeutic interventions. However, these interventions may cause inadvertent harm to the patient, exacerbating the underlying insult.29 For instance, mechanical ventilation can be lifesaving but, depending on the settings on the ventilator, it may also injure the lung and adversely affect host defense mechanisms, secondarily affecting the function of other organs, and ultimately leading to a preventable increase in mortality.30,31 GENERALIZED PREVENTION
As with any disease, the best treatment of MODS is preventing it from occurring in the first place. In the surgical patient, MODS prevention can occur by identifying high-risk groups before elective surgery, and weighing the risk/benefit ratio of proceeding with an operation. There are numerous scoring systems that identify a patient’s risk for postoperative cardiac or respiratory complications. Surgeons and anesthesiologists (as well as medical specialty consultants, if indicated) are ultimately responsible for ensuring that surgery is being performed only on candidates who have an acceptable risk profile. In addition, preoperative status may need to be optimized before agreeing
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to operate on a patient. This optimization may take the form of improved nutrition, weight loss, respiratory rehabilitation, quitting smoking, and so forth. Once an operation has occurred (either elective or emergent), a certain number of patients have organ dysfunction, which progresses to MODS in a subset of them. However, this risk is modifiable by adherence to best practice, which can prevent development of further complications. For floor (and at times ICU) patients, this means rapid ambulation and deep breathing/incentive spirometer. For high-risk patients (studied most notably in vascular patients), perioperative b-blockade may prevent cardiovascular complications.32 Initiating appropriate prophylaxis against deep venous thrombosis and (if indicated) stress ulceration may also prevent complications that can lead to MODS. Removing central venous catheters, arterial lines, Foley catheters, and endotracheal tubes as soon as possible can prevent development of central line–associated bloodstream infection, catheter-associated urinary tract infection, and ventilator-associated pneumonia (VAP), respectively. ONCE MODS SETS IN, WHAT THERAPIES ARE AVAILABLE TO THE PATIENT?
The mainstays of prevention of MODS include early recognition/resuscitation, removal of the inciting source, and prevention of iatrogenic injury. Once organ failure sets in, most treatment is supportive, allowing the host to heal without causing additional iatrogenic injury. In a global view, most care provided in the ICU is not intended to cure but to support. Pressors do not cure shock, but instead potentially prevent inadequate tissue perfusion until the body is able to maintain its own blood pressure. Mechanical ventilation does not cure respiratory failure but instead supports the lungs until the body is able to regulate ventilation and oxygenation on its own. Similarly, renal replacement therapy does not cure acute renal failure but supports the body until the kidneys recover to the point that they are able to clear both toxins and volume. As such, the best that can be offered to many patients is to effectively support them, with the hope that prevention of further decompensation will allow their bodies to have sufficient time to heal from the initial insults. STRATEGIES BY ORGAN SYSTEM
Despite most treatment in MODS being supportive rather than curative, it is helpful to be fully versed in strategies that may result in positive outcomes for critically ill patients. Because the most common cause of organ failure is sepsis, the Surviving Sepsis guidelines are an excellent resource for an evidence-based approach that identifies key interventions to improve survival in patients with this complex process.33,34 Neurologic Conditions
Effective management centers on maintaining patient comfort (generally, although not always, with narcotics or an epidural, when appropriate) while minimizing common sequelae of MODS including delirium and agitation. Although sedation may be necessary to safely ventilate a subset of patients, unchecked sedative use can lead to iatrogenic harm. This harm can be broken down into direct neurologic complications and indirect complications caused by an inability to liberate patients from mechanical ventilation. Delirium is an important measure of organ dysfunction and has been shown to be a predictor of mortality in the ICU.35 However, studies indicate that delirium is underrecognized in the ICU, especially hypoactive delirium. Patient should be screened for delirium each day using a validated screen such as the Confusion Assessment Method
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for the ICU (CAM-ICU).36 Minimization of benzodiazepines by either avoidance or using other agents may reduce delirium and ICU length of stay.37,38 If patients do develop delirium, initial treatment should be nonpharmacologic, using frequent reorientation of the patient and attempts to correct sleep-wake cycle deficits. If unsuccessful, antipsychotic agents such as haloperidol or newer atypical agents may be beneficial. Delirium is best treated with a protocol using evidence-based standards and adopted for local usage. The use of excessive sedation medicines can have secondary effects outside the neurologic system. Patients who do not wake up once their sedatives are stopped have continued need for mechanical ventilation, with the concordant risk of VAP. For this reason, sedation protocols are recommended because they have been shown to conclusively reduce duration of mechanical ventilation, ICU length of stay, and need for tracheostomy.39,40 In addition, a daily sedation holiday, allowing the patient to wake, is also strongly supported.39,41,42 Although historically there have been concerns about daily awakening in surgical patients, all patients in the ICU, including postoperative patients, should have a sedation holiday assuming they are physiologically able to have one. Surgeons also need to be cognizant of the potential for the development of neuropathy/myopathy of critical illness. Use of neuromuscular blocking agents is generally discouraged because they exacerbate neuropathy and require additional sedation. This problem is further exacerbated in patients receiving steroids.43 This concern should not prevent steroid usage in patients who may potentially benefit from them, such as patients with acute respiratory distress syndrome (ARDS)44 or septic shock; however, a careful weighing of available literature and the risk/benefit ratio should be undertaken before their initiation. Cardiovascular Conditions
Cardiovascular organ failure support primarily consists of hemodynamic stabilization and fluid resuscitation. Surgical patients often have significant blood loss or dehydration reducing their intravascular fluid volume, ultimately leading to hypovolemic shock. This condition may be further complicated by the inflammatory response, which can cause worsened capillary permeability and decreased vascular resistance (distributive shock). The treatment of cardiovascular failure depends on the underlying cause. The treatment of hypovolemia is volume. The treatment of bleeding is resuscitation with blood and/or blood products. The treatment of distributive shock is multifactorial as described in early goaldirected therapy.45 Although additional studies are ongoing to further optimize early goal-directed therapy, current guidelines for septic shock recommend resuscitation to a central venous pressure of 8 to 12 mm Hg (12–15 mm Hg in mechanically ventilated patients) with desired end points of a mean arterial pressure greater than 65 mm Hg, urine output 0.5 mL/kg/h, and central venous oxygen saturation greater than 70%.33,45 If patients are not volume responsive and are intravascularly resuscitated, vasopressors are recommended to keep a mean arterial pressure greater than 65 mm Hg, although the goal pressure needed for adequate perfusion may vary with individual patients and data to support this number are limited.46 Norepinephrine and dopamine have traditionally been the vasopressors of choice, but norepinephrine has become the preferred agent at many centers because of fewer adverse events.47 If patients continue to have a low central venous oxygen saturation despite adequate volume status and mean arterial pressure, the next step is to transfuse to a hemoglobin greater than 10 mg/dL. If, despite all these steps, the patient continues to have a low
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central venous oxygen saturation, consideration should be given to the addition of an inotrope. Myocardial function may be decreased in the perioperative period as a result of either myocardial infarction or a globally decreased left ventricular function that is mediated by an inflammatory response. High-risk vascular patients and those on preoperative b-blockers should have b-blockers continued in the perioperative period. Patients with perioperative myocardial infarctions should receive rapid cardiology consults. Therapy includes aspirin, b-blockade, oxygen, adequate oxygen-carrying capacity with transfusion if indicated, and statin therapy.32 The determination of whether to begin anticoagulation and/or to send the patient for a cardiac catheterization is an individualized decision. Right ventricular dysfunction is more rare but is frequently seen in the setting of a physiologically significant pulmonary embolism. Treatment includes anticoagulation or lytics if indicated or an inferior vena cava filter if the risk for bleeding is too high to safely anticoagulate the patient. The myocardium should be supported with inotropic support if needed, with minimization of fluid resuscitation. Another common cause of shock in the patient with trauma is spinal cord injury. Pressors to maintain vascular tone are appropriate in this setting. Clinicians must be concerned about obstructive shock secondary to tension pneumothorax, pericardial tamponade, or pulmonary embolism. Treatment includes a high index of suspicion when clinically indicated, followed by needle decompression, pericardiocentesis, and/or window and anticoagulation or inferior vena cava filter, respectively. Respiratory Conditions
The key aspects of organ failure prevention involve minimization of volutrauma and barotrauma to the lung, minimization of VAP, and minimization of volume overload. There are strong data to support the use of a lung-protective, low-tidal-volume (starting at 6 mL/kg ideal body weight) ventilation strategy in patients with acute lung injury, maintaining a plateau pressure less than 30 mm Hg, because higher tidal volumes worsen organ failure and mortality.34,48–50 The use of positive end-expiratory pressure to prevent atelectasis and recruit closed alveoli in patients with ARDS is also well supported.51,52 All ventilated patients are at risk for VAP. Elevating the head of the bed to 30 to 45 , oral care, and early liberation from the ventilator decreases the incidence of VAP.53 Several studies show that patients who are given a daily spontaneous breathing trial have a reduction in the duration of mechanical ventilation.54–56 Recent studies show that a positive fluid balance is associated with longer mechanical ventilation and increased mortality,57,58 which can be especially challenging in postoperative patients who have significant third spacing, especially when they are critically ill. Although it is difficult to have a single rule of thumb for these patients, the best practice is to ensure that patients have adequate intravascular volume without excessive volume resuscitation. Assaying volume status in surgical patients can be difficult. In patients who are less sick, noninvasive methods such as following urine output are adequate. In more critically ill patients, additional monitoring may be appropriate. The simplest method is the use of central venous pressure; however, there are multiple studies indicating that this correlates poorly with intravascular volume status, despite its common usage. Newer technologies, such as those assessing stroke volume variance from an arterial line tracing and esophageal Dopplers, may play a role in assessing volume status. Bedside echocardiography is also being increasingly used for this purpose. Historically, pulmonary artery catheters have been used to aid in management of
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volume status, but several trials suggest that these should not be used on a routine basis for this indication.59–61 Renal Conditions
Protection of the kidneys in the surgical patient can be challenging. Acute kidney injury still occurs in up to 65% of septic shock and is an independent risk factor for death in patients with MODS.62 The mainstay of therapy involves ensuring adequate hemodynamic resuscitation and, if possible, avoidance of iodinated contrast and nephrotoxic drugs. Although several agents have been proposed, there are no proven therapies that improve renal function in patients with MODS. However, there are unequivocal data that renal-dose dopamine is not effective in preventing acute renal failure, and its use cannot be supported.33 A certain subset of patients with MODS require an intravenous dye load in the setting of a computed tomography scan or angiography. Prevention of contrastinduced nephropathy has received significant attention recently. As with other causes of renal failure in MODS, the most important factor in protecting kidney function is adequate hydration. In addition, there are some data that suggest that bicarbonate may be useful in preventing contrast-induced nephropathy, although the largest trial to date suggests that there is no benefit to n-acetylcysteine, an agent commonly used for this purpose.63 In general, there is no advantage to using crystalloids or colloids in preventing perioperative renal failure. The SAFE (Saline vs Albumin Fluid Evaluation) study suggests that the choice of crystalloid versus albumin as the resuscitation fluid in patients in the ICU makes no difference except in patients with head injury, for whom albumin may be worse.64 There are some patient population–specific data to suggest that albumin may be beneficial in patients with liver failure, acute lung injury (when given with furosemide), and sepsis.65,66 Unless a patient is in a specific subcategory in which albumin has been shown to have benefit compared with crystalloid, it should be avoided if possible because it is significantly more expensive. When using crystalloids for resuscitation, it is important to choose a balanced solution. For this reason, it is important that practitioners be aware that normal saline is associated with a significant incidence of hyperchloremic metabolic acidosis.67 Despite optimal medical therapy, some surgical patients progress to anuric renal failure and require dialysis. Hypotensive patients who require dialysis are generally placed on continuous renal replacement therapy rather than intermittent hemodialysis because it causes less hemodynamic instability. However, the optimal timing and rate of renal replacement therapy continues to be controversial and is therefore a topic of active research.68,69 In addition, there are experimental protocols to use alternative hemofiltration to remove inflammatory mediators, a technique that is commonly used in select ICUs outside the United States.70 Gastrointestinal Conditions
The intestine is often described as the motor of the systemic inflammatory response.71 The most well-supported intervention associated with the gut and prevention of organ failure in the postoperative setting is early enteral nutrition. There have been several randomized trials, including enteral feeding versus total parenteral nutrition, that show improved outcomes and decreased organ failure in patients given early enteral nutrition.72–75 In contrast, there does not seem to be a benefit of early parenteral nutrition in critically ill patients.76 Immunonutrition is an evolving field. Although an exhaustive review of the literature is beyond the scope of this article, there is strong evidence that supplemental enteral
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glutamine should be considered in patients with burns and trauma, and supplemental glutamine is recommended for critically ill patients receiving parental nutrition.77 Supplemental combined vitamins, trace elements, and selenium supplementation should also be considered in critically ill patients. In contrast, diets supplemented with arginine should not be used in critically ill patients based on current data. Although many surgical patients receive stress ulcer prophylaxis, data support their use only in patients with significant risk factors. These risk factors include mechanical ventilation for longer than 48 hours and coagulopathy. Other relative indications include acute kidney injury, sepsis, burn, and head injury. For patients who meet these indications, there is more evidence to support the usage of H2 blockers than proton pump inhibitors. Both classes of agents are associated with complications including development of Clostridium difficile infections and pneumonia and should be avoided unless a clear indication is present. Endocrine Conditions
Although panendocrine dysfunction can occur in critical illness, the most well-studied abnormalities include those involving glucose control and adrenocorticoid secretion.78 Although a single-center study in 2001 showed a significant mortality improvement in critically ill patients after cardiac surgery with tight glucose control (80–110 mg/dL),79 multiple large-scale trials have failed to reproduce this benefit.80–82 In addition, tight glucose control has been associated with a marked increase in hypoglycemia. Current recommendations suggest keeping blood glucose levels at less than 150 mg/dL. Steroid use in critically ill patients remains controversial. A multicenter randomized trial showed improvement of shock and mortality in patients with relative adrenal insufficiency.83 However, a subsequent larger trial did not show a mortality benefit, but did have a more rapid resolution of shock in patients treated with steroids.84 Thus, current recommendations suggest supplementing patients with refractory septic shock with hydrocortisone.33 However, the definition of refractory shock is unclear, so the appropriate trigger for initiating steroid therapy in patients with septic shock is not known. Obtaining an adrenocorticotropic hormone stimulation test is not indicated in patients with septic shock. Hematology
The treatment of bleeding is transfusion of blood and blood products. When a surgical patient or a patient with trauma is bleeding, transfusion should be initiated immediately and can be a lifesaving therapy. However, although blood has historically been transfused to improve oxygen-carrying capacity in nonbleeding patients, there are significant data in critically ill patients that transfusing patients to a hemoglobin of 10 mg/dL is not beneficial and is potentially harmful.85,86 Patients should generally have a hemoglobin of 7 mg/dL before transfusion, likely because of the immunosuppressive effects of blood and the underrecognized complication of transfusion-associated acute lung injury. Although most patients can safely be anemic, higher hemoglobin levels should be targeted in patients having an acute myocardial infarction, those with unstable angina, and those with class 3 or 4 congestive heart failure. In addition, the protocol for early goal-directed therapy for sepsis includes transfusion to a hemoglobin of 10 mg/dL if the patient has a central venous oxygen saturation less than 70% despite adequate fluid resuscitation and pressors. Although this is controversial and is the topic of a current study funded by the National Institutes of Health,87 following this protocol is a reasonable evidenced-based approach.
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Infectious Disease
The one organ system that is unequivocally amenable to curative (as opposed to supportive) care is infectious disease. This care involves appropriate source control when appropriate via surgery, interventional radiology drainage, or removal of an infected catheter. Source control should occur in the least invasive manner possible. Administration of appropriate antibiotics can be lifesaving. In the setting of septic shock, a delay in the administration of appropriate antibiotics results in an 8% per hour increase in mortality.88,89 Patients should initially receive broad-spectrum antibiotics targeted to suspected microorganisms (this varies based on the anatomic site of infection). Antibiotics should then be narrowed, based on culture results, to prevent generation of resistant organisms. Apart from antibiotics, there are no biological adjuncts that are known to be beneficial for the treatment of MODS. Previously, drotrecogin a (Xigris) had US Food and Drug Administration approval for the treatment of septic shock. However, follow-up studies showed a lack of efficacy for this agent and it was recently withdrawn from the market worldwide.90,91 THE FUTURE
In the last decade, there has been increasing interest in studying homogenous subgroups of critically ill patients, rather than looking at a large heterogeneous population, in which important differences may be masked by the diversity of the group as a whole. A commonly used analogy is that no oncologist would enroll patients with stage I melanoma and stage IV pancreatic cancer in the same trial independently of disease state; however, to some degree, this is what has historically be done in critical care research. As a framework for future studies, the PIRO system has been advocated as a method for developing more patient-based therapies. In this acronym, P stands for predisposition (including age, genetic factors, and baseline comorbidities), I refers to the insult or infection that brought on the organ dysfunction (including site, whether hospital or community acquired, and microbiology), R is the response (evaluated by laboratory values and vital signs), and O is organ dysfunction (with evaluation of number of organs failing).14,92,93 The hope is that this new approach will help stage patients with organ failure so that trials can be more effectively designed and more effective therapies can be designed to mitigate or treat MODS. SUMMARY
Postoperative organ failure is a challenging disease process that is better prevented than treated. Providers should use close observation and clinical judgment, and checklists of best practices to minimize the risk of organ failure in their patients. The treatment of MODS generally remains supportive, outside of rapid initiation of source control (when appropriate) and targeted antibiotic therapy. More specific treatments may be developed as the complex pathophysiology of MODS is better understood and more homogenous patient populations are selected for study. REFERENCES
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