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InternalMed_Harrison. CSA, which is less common than OSAHS, may occur in isolation or, more often, in combination with obstructive events in the form of “mixed” apneas. CSA is often caused by an increased sensitivity to pCO2, which leads to an unstable breathing pattern that manifests as hyperventilation alternating with apnea. A prolonged circulation delay between the pulmonary capillaries and carotid chemoreceptors is also a contributing cause; thus individuals with congestive heart failure are at risk for CSA. With prolonged circulation delay, there is a crescendo-decrescendo breathing pattern known as Cheyne-Stokes respiration (Fig. 319–2B). Other risk factors for CSA include opioid medications (which appear to have a dose-dependent effect on CSA) and hypoxia (e.g., breathing at high altitude). In some individuals, CPAP— particularly at high pressures—seems to induce central apnea; this condition is referred to as complex sleep apnea. Rarely, CSA may be caused by blunted chemosensitivity due to


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InternalMed_Harrison. individuals, CPAP— particularly at high pressures—seems to induce central apnea; this condition is referred to as complex sleep apnea. Rarely, CSA may be caused by blunted chemosensitivity due to congenital disorders (congenital central hypoventilation syndrome) or acquired factors. Treatment of CSA is difficult and depends on the underlying cause. Limited data suggest that supplemental oxygen can reduce the frequency of central apneas, particularly in patients with hypoxemia. Cheyne-Stokes respiration is treated by optimizing therapy for heart failure and, in some cases, using CPAP with or without supplemental oxygen. Adaptive servoventilation, a form of ventilatory support that dynamically changes inspiratory support levels across periods of apnea and hypopnea, can minimize large fluctuations in PCO2 that produce central apnea and can be effective for the treatment of CSA.


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InternalMed_Harrison. Lung transplantation Elbert P. Trulock Lung transplantation is a therapeutic consideration for many patients with nonmalignant end-stage lung disease, and it prolongs survival and improves quality of life in appropriately selected recipients. Since 1985 almost 40,000 procedures have been recorded worldwide, and 320e since 2009 more than 3000 transplants have been reported annually. The indications span the gamut of lung diseases, but in some respects the distribution of indications differs among countries. According to aggregate international data, the most common indications in the last few years have been chronic obstructive pulmonary disease (COPD), ~29%; idiopathic pulmonary fibrosis (IPF), ~28%; cystic fibrosis (CF), ~16%; α1-antitrypsin deficiency emphysema, ~3.5%; and idiopathic pulmonary arterial hypertension (IPAH), ~3%. Other diseases have made up the balance of primary indications, and retransplantation has accounted for ~3% of procedures.


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InternalMed_Harrison. Transplantation should be considered when other therapeutic options have been exhausted and when the patient’s prognosis is expected to improve as a result of the procedure. Survival rates after transplantation can be compared with predictive indices for the patient’s disease, but each patient’s clinical course must be integrated into the assessment as well. Moreover, quality of life is a primary motive for transplantation for many patients, and the prospect of improved quality-adjusted survival is often attractive even if the survival advantage itself may be marginal.


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InternalMed_Harrison. Disease-specific consensus guidelines for referring patients for evaluation and for proceeding with transplantation are summarized in Table 320e-1 and are linked to clinical, physiologic, radiographic, and pathologic features that influence the prognosis of the respective diseases. Candidates for lung transplantation are also thoroughly screened for comorbidities that might affect the outcome adversely. Conditions such as systemic hypertension, diabetes mellitus, gastroesophageal reflux, and osteoporosis are not unusual; however, if uncomplicated and adequately managed, they do not disqualify patients from transplantation. The upper age limit is ~70 years at most centers, but the median age of recipients has been increasing steadily over the last decade. In the United States in 2009, 22% of recipients were ≥65 years old.


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InternalMed_Harrison. Standard exclusions include HIV infection, chronic active hepatitis B or C infection, uncontrolled or untreatable pulmonary or extrapulmonary infection, uncured malignancy, active cigarette smoking, drug or alcohol dependency, irreversible physical deconditioning, chronic nonadherence with medical care, significant disease of another vital organ (e.g., heart, liver, or kidney), and psychiatric or psychosocial situations that could substantially interfere with post-transplantation management. Other problems that may compromise outcome constitute relative contraindications. Some typical issues are ventilator-dependent respiratory failure, previous thoracic surgical procedures, obesity, and coronary artery disease. Chronic infection with antibiotic-resistant Pseudomonas species, Burkholderia species, Aspergillus species, or nontuberculous mycobacteria is a unique concern in some patients with CF. The potential impact of these and other factors must be judged in the clinical context to


InternalMed_Harrison

InternalMed_Harrison. species, Aspergillus species, or nontuberculous mycobacteria is a unique concern in some patients with CF. The potential impact of these and other factors must be judged in the clinical context to determine an individual candidate’s suitability for transplantation.


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InternalMed_Harrison. Organ allocation policies are influenced by medical, ethical, geographic, and political factors, with systems varying from country to country. Regardless of the system, potential recipients are placed on a waiting list and must be matched for blood group compatibility and, with some latitude, for lung size with an acceptable donor. Most lungs are procured from deceased donors after total brain failure (“brain Any of the following criteria: Hospitalization for exacerbation, with PaCO2 >50 mmHg Pulmonary hypertension or cor pulmonale, despite oxygen therapy FEV1 <20% with either DLCO <20% or diffuse emphysema Referral FEV1 <30% or rapidly declining FEV1 Hospitalization in ICU for exacerbation Increasing frequency of exacerbations Refractory or recurrent pneumothorax Recurrent hemoptysis not controlled by bronchial artery embolization Referral Pathologic or radiographic evidence of UIP, regardless of vital capacity Transplantation Pathologic or radiographic evidence of UIP


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InternalMed_Harrison. Referral Pathologic or radiographic evidence of UIP, regardless of vital capacity Transplantation Pathologic or radiographic evidence of UIP Any of the following criteria: DLCO <39% Decrement in FVC ≥10% during 6 months of follow-up Decrease in SpO2 to <88% during a 6-min walk test Honeycombing on HRCT (fibrosis score >2) NYHA functional class III or IV, regardless of therapy Failure of therapy with IV epoprostenol (or equivalent drug) Abbreviations: BODE, body mass index (B), airflow obstruction (O), dyspnea (D), exercise capacity (E); DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HRCT, high-resolution computed tomography; ICU, intensive care unit; NYHA, New York Heart Association; PaCO2, partial pressure of carbon dioxide in arterial blood; SpO2, arterial oxygen saturation by pulse oximetry; UIP, usual interstitial pneumonitis.


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InternalMed_Harrison. Source: Summarized from JB Orens et al: J Heart Lung Transplant 25:745, 2006. For BODE index, BR Celli et al: N Engl J Med 350:1005, 2004. death”), but only ~15–20% of brain-death organ donors yield either one or two lungs suitable for transplantation. Lungs from donors after cardiac death have been utilized to a limited extent (~2% of lung donors in the United States in 2009). Recently, ex vivo lung perfusion has been used by some centers to assess donor lungs that are marginal or high-risk for implantation by standard criteria; if the results of ex vivo testing are satisfactory, these lungs have been transplanted successfully.


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InternalMed_Harrison. In the United States, a lung allocation scoring system is used to prioritize patients on the waiting list. The lung allocation score (LAS) for a patient is based on the patient’s risk of death during 1 year on the waiting list and the patient’s likelihood of survival for 1 year after transplantation. The LAS can range from 0 to 100, and precedence for transplantation is ranked from highest to lowest scores. Both the lung disease and its severity affect a patient’s LAS; parameters in the LAS must be updated biannually but can be submitted for recalculation whenever the patient’s condition changes. The median LAS for all candidates on the waiting list is usually ~35, but the LAS tends to be higher among patients with IPF and CF than among patients with COPD and IPAH.


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InternalMed_Harrison. Under this system in the United States, the median waiting time for transplantation has been ~135 days. The overall death rate on the waiting list has been ~6.5%, but death rates vary substantially with the diagnosis (e.g., COPD, ~3%; IPF, ~7%) and with the LAS (e.g., 40–49, ~7%; 50–59, ~15%; ≥60, ~25%). The indications for transplantation depend not only on the prevalence and natural history of the various lung diseases but also on the LAS typically associated with these diseases. While patients with IPF constitute ~20% of the waiting list, they make up ~34% of recipients because their allocation scores are typically higher than those of patients with other diseases.


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InternalMed_Harrison. Bilateral transplantation is mandatory for CF and other forms of bronchiectasis because the risk of spillover infection from a remaining native lung precludes single-lung transplantation. Heart-lung transplantation is obligatory for Eisenmenger syndrome with complex anomalies that cannot readily be repaired in conjunction with lung transplantation and for concomitant end-stage lung and heart disease. However, cardiac replacement is not necessary for cor pulmonale because right ventricular function will recover when pulmonary vascular afterload is normalized by lung transplantation.


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InternalMed_Harrison. Either bilateral or single-lung transplantation is an option for other diseases unless there is a special consideration, but bilateral transplantation has been utilized increasingly for most indications. Recently, ~65% of procedures in the United States have been bilateral, and ~70% of transplants for COPD, ~55% of those for IPF, and ~95% of those for IPAH in the international registry have been bilateral. Living-donor lobar transplantation has had a limited role in adult lung transplantation but is now rarely performed. It has been used predominantly for teenagers or young adults with CF and has usually been reserved for patients who were unlikely to survive the wait for a deceased-donor organ.


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InternalMed_Harrison. Induction therapy with an antilymphocyte globulin or an interleukin 2 receptor antagonist is utilized by ~55% of centers, and a three-drug maintenance immunosuppressive regimen that includes a calcineurin inhibitor (cyclosporine or tacrolimus), a purine synthesis antagonist (azathioprine or a mycophenolic acid precursor), and prednisone is traditional. Subsequently, other drugs (e.g., sirolimus) may be substituted into the regimen for various reasons. Prophylaxis against Pneumocystis jirovecii pneumonia is standard, and prophylaxis against cytomegalovirus (CMV) infection and fungal infection is part of many protocols. The dose of cyclosporine, tacrolimus, or sirolimus is adjusted by blood-level monitoring. All of these agents are metabolized by the hepatic cytochrome P450 system, and interactions with medications that affect this pathway can significantly alter their clearance and blood level.


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InternalMed_Harrison. Routine management focuses on monitoring of the allograft, regulation of immunosuppressive therapy, and expeditious detection of problems or complications. Regular contact with a nurse coordinator, physician follow-up, chest radiography, blood tests, and spirometry are customary, and periodic surveillance bronchoscopies are employed in some programs. If recovery is uncomplicated, lung function rapidly improves and then stabilizes by 3–6 months after transplantation. Subsequently, the variation in spirometric measurements is small, and a sustained decline of ≥10–15% signals a potentially significant problem.


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InternalMed_Harrison. OUTCOMES Survival Major registries publish survival rates (Table 320e-2) and other outcomes annually (www.ishlt.org; www.srtr.org). In the international registry, the survival half-life for recipients with IPF is 4.4 years; IPAH, 5 years; COPD, 5.3 years; and CF, 7.5 years. However, age and transplantation procedure have a significant impact on outcome. For recipients 18–59 years of age, the survival half-life is 5–6 years, but this figure decreases to 4.4 years among patients 60–65 years old and to 3.6 years for those >65 years old. Survival rates at >15 years have been significantly higher after bilateral transplantation than after unilateral transplantation for COPD, α1-antitrypsin deficiency emphysema, IPF, and IPAH.


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InternalMed_Harrison. The main sources of perioperative mortality include technical complications of the operation, primary graft dysfunction, and infections. Acute rejection and CMV infection are common problems in the first year, but neither is usually fatal. Beyond the first year, chronic rejection and non-CMV infections cause the majority of deaths. Risk factors for mortality have been analyzed in the international and U. S. registries. In these analyses, factors associated with an increased risk of death, especially in the first year after transplantation, have included the following: recipients hospitalized at the time of transplantation; recipients supported by mechanical ventilation, extra-corporeal membrane oxygenation, inotropic drugs, or dialysis at the time of transplantation; and recipients undergoing retransplantation. taBLe 320e-2 reCipient survivaL, By pretranspLantation DiaGnosis (1990–2010) Survival Rate, %


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InternalMed_Harrison. taBLe 320e-2 reCipient survivaL, By pretranspLantation DiaGnosis (1990–2010) Survival Rate, % However, other factors have contributed as well. The mortality risk has been higher at centers with <20–30 transplantations per year. Function Regardless of the disease, successful transplantation impressively restores cardiopulmonary function. After bilateral transplantation, pulmonary function tests are typically normal; after unilateral transplantation, a mild abnormality characteristic of the remaining diseased lung is still apparent. Formal exercise testing usually demonstrates some impairment in maximal work rate and maximal oxygen uptake, but few recipients report any limitation to activities of daily living.


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InternalMed_Harrison. Quality of Life Both overall and health-related quality-of-life scores are enhanced. With multidimensional profiles, improvements extend across most domains and are sustained longitudinally unless chronic rejection or some other complication develops. Other problems that detract from quality of life include renal dysfunction and drug side effects.


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InternalMed_Harrison. Cost The cost of transplantation depends on the health care system, other health care policies, and economic factors that vary from country to country. In the United States in 2011, the average billed charge for the period from 30 days before bilateral lung transplantation until 180 days after discharge from the transplantation admission was $797,300. The total cost included the following charges: all care during 30 days before transplantation, $21,400; organ procurement, $90,300; hospital transplantation admission, $458,500; physician fees during transplantation admission, $56,300; all inpatient and outpatient care for 180 days after discharge, $142,600; and all outpatient drugs (including immunosuppressants) for 180 days after discharge, $28,200. Lung transplantation can be complicated by a variety of problems (Table 320e-3). Aside from predicaments that are unique to transplantation,


InternalMed_Harrison

InternalMed_Harrison. Lung transplantation can be complicated by a variety of problems (Table 320e-3). Aside from predicaments that are unique to transplantation, Allograft Primary graft dysfunction; anastomotic dehiscence or stenosis; ischemic airway injury with bronchostenosis or bronchomalacia; rejection; infection; recurrence of primary disease (sarcoidosis, lymphangioleiomyomatosis, giant cell interstitial pneumonitis, diffuse panbronchiolitis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis) Gastrointestinal Esophagitis (especially Candida, herpesvirus, or cytomegalovirus [CMV]); gastroparesis; gastroesophageal reflux; diarrhea (Clostridium difficile; medications, especially mycophenolate mofetil and sirolimus); colitis (C. difficile; CMV) side effects and toxicities of immunosuppressive medications can cause 320e-3 new medical problems or aggravate preexisting conditions.


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InternalMed_Harrison. Graft Dysfunction Primary graft dysfunction (PGD), an acute lung injury, is a manifestation of multiple potential insults to the donor organ that are inherent in the transplantation process. The principal clinical features are diffuse pulmonary infiltrates and hypoxemia within 72 h of transplantation; however, the presentation can be mimicked by pulmonary venous obstruction, hyperacute rejection, pulmonary edema, and pneumonia.


InternalMed_Harrison

InternalMed_Harrison. The severity is variable, and a standardized grading system has been established. Up to 50% of lung transplant recipients may have some degree of PGD, and ~10–20% have severe PGD. The treatment follows the conventional supportive paradigm for acute lung injury. Inhalation of nitric oxide and extracorporeal membrane oxygenation have been used in severe cases; retransplantation has also been performed, but when undertaken in the first 30 days this procedure is associated with a poor survival rate (~30% at 1 year). Most recipients with mild PGD recover, but the mortality rate for severe PGD has been ~40–60%. PGD is also associated with longer postoperative ventilator support, longer intensive care unit and hospital stays, higher costs, and excess morbidity, and severe PGD is a risk factor for the later development of chronic rejection (see below).


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InternalMed_Harrison. Airway Complications The bronchial blood supply to the donor lung is disrupted during procurement. Bronchial revascularization during transplantation is technically feasible in some cases, but it is not widely practiced. Consequently, after implantation, the donor bronchus is dependent on retrograde bronchial blood flow from the pulmonary circulation and is vulnerable to ischemia. The spectrum of airway problems includes anastomotic necrosis and dehiscence, occlusive granulation tissue, anastomotic or bronchial stenosis, and bronchomalacia. The incidence has been in the range of 7–18%, but the associated mortality rate has been low. These problems usually can be managed bronchoscopically with techniques such as simple endoscopic debridement, laser photoresection, balloon dilation, and bronchial stenting.


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InternalMed_Harrison. Rejection Rejection is the main deterrent to higher mediumand long-term survival rates. In this immunologic response to alloantigen recognition, both cell-mediated and antibody-mediated (humoral) cascades can play a role. Cellular rejection is effected by T lymphocyte interactions with donor alloantigens, mainly in the major histocompatibility complex (MHC), whereas humoral rejection is driven by antibodies to donor MHC alloantigens or possibly to non-MHC antigens on epithelial or endothelial cells. Rejection is often categorized as acute or chronic without reference to the underlying mechanism. Acute rejection is cell-mediated, and its incidence is highest in the first 6–12 months after transplantation. In contrast, chronic rejection generally emerges later, and both alloimmune and non-alloimmune fibroproliferative reactions may contribute to its pathogenesis.


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InternalMed_Harrison. Acute Cellular Rejection With current immunosuppressive regimens, ~30–40% of recipients experience acute rejection in the first year. Acute cellular rejection (ACR) can be clinically silent or can be manifested by nonspecific symptoms or signs that may include cough, low-grade fever, dyspnea, hypoxemia, inspiratory crackles, interstitial infiltrates, and declining lung function; however, clinical impressions are not reliable. The diagnosis is confirmed by transbronchial biopsies showing the characteristic lymphocytic infiltrates around arterioles or bronchioles, and a standardized pathologic scheme is used to grade the biopsies.


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InternalMed_Harrison. Minimal ACR on a surveillance biopsy in a clinically stable recipient is often left untreated, but higher grades generally are treated regardless of the clinical situation. Treatment usually includes a short course of high-dose glucocorticoids and adjustment of the maintenance immunosuppressive regimen. Most episodes respond to this approach; however, more intensive therapy is sometimes necessary for persistent or recurrent episodes.


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InternalMed_Harrison. Chronic Rejection This complication is the main impediment to longterm survival and is the source of substantial morbidity because of its impact on lung function and quality of life. Clinically, chronic rejection is characterized physiologically by airflow limitation and pathologically by bronchiolitis obliterans; the process is designated bronchiolitis obliterans syndrome (BOS). Transbronchial biopsies are relatively insensitive for detecting bronchiolitis obliterans, and pathologic confirmation is not required for diagnosis. Thus, after other causes of graft dysfunction have been excluded, the diagnosis of BOS is based primarily on a sustained decrement (≥20%) in forced expiratory volume in 1 s (FEV1), although smaller declines in FEV1 (≥10%) or in midexpiratory flow rate (FEF ) may presage BOS. Spirometric cri teria for diagnosis and staging of BOS have been standardized.


InternalMed_Harrison

InternalMed_Harrison. The prevalence of BOS approaches 50% by 5 years after transplantation. Antecedent ACR is the main risk factor, but PGD, CMV pneumonitis, other community-acquired respiratory viral infections, and gastroesophageal reflux have been implicated as well. BOS can present acutely and imitate infectious bronchitis, or it can manifest as an insidious decline in lung function. The chest radiograph is typically unchanged; CT may reveal mosaic perfusion, air trapping, ground-glass opacities, or bronchiolectasis. Bronchoscopy is indicated to rule out other processes, but transbronchial biopsies identify bronchiolitis obliterans in a minority of cases.


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InternalMed_Harrison. BOS usually is treated with augmented immunosuppression, but there is no consensus about therapy. Strategies include changes in the maintenance drug regimen, including the addition of azithromycin, antilymphocyte globulin, photopheresis, and total lymphoid irradiation. Although therapy may stabilize lung function, the overall results of treatment have been disappointing; the median survival period after onset has been ~3–4 years. Retransplantation is a consideration if clinical circumstances and other comorbidities are not prohibitive, but survival rates have been inferior to those with primary transplantation.


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InternalMed_Harrison. Humoral Rejection Consensus on the role of antibody-mediated rejection is still evolving. Hyperacute rejection is caused by preformed HLA antibodies in the recipient, but it is minimized by pretransplantation antibody screening coupled with virtual or direct cross-matching with any potential donor. Donor-specific HLA antibodies develop after transplantation in up to 50% of recipients, and their presence has been associated with an increased risk of both ACR and BOS and with poorer overall survival. However, the mechanisms by which these antibodies could contribute to ACR or BOS or could otherwise be detrimental have not been unraveled. Formal criteria for antibody-mediated rejection have been defined for renal transplantation, but few cases in lung transplantation fulfill these criteria. Nonetheless, episodes of acute lung allograft dysfunction occasionally have been attributed directly to antibody-mediated injury. If treatment is indicated, potential therapies include plasmapheresis


InternalMed_Harrison

InternalMed_Harrison. Nonetheless, episodes of acute lung allograft dysfunction occasionally have been attributed directly to antibody-mediated injury. If treatment is indicated, potential therapies include plasmapheresis and administration of IV immune globulin, rituximab, bortezomib, or eculizumab.


InternalMed_Harrison

InternalMed_Harrison. Infection The lung allograft is especially susceptible to infection, which has been one of the leading causes of death in recipients. In addition to a blunted immune response from immunosuppressive drugs, other normal defenses are compromised: the cough reflex is diminished, and mucociliary clearance is impaired in the transplanted lung. The spectrum of infections includes both opportunistic and non-opportunistic pathogens. Bacterial bronchitis or pneumonia can occur at any time but is very common in the perioperative period. Later, bronchitis occurs frequently in recipients with BOS, and Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus is often the culprit.


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InternalMed_Harrison. CMV is the most common cause of viral infection. Although gastroenteritis, colitis, and hepatitis can occur, CMV viremia and CMV pneumonia are the main illnesses. Most episodes occur in the first 6 months, and treatment with ganciclovir is effective unless resistance develops. Other community-acquired viruses, such as influenza, parainfluenza, and respiratory syncytial viruses, also contribute to respiratory complications. The most problematic fungal infections are caused by Aspergillus species. The spectrum encompasses simple pulmonary colonization, tracheobronchitis, invasive pulmonary aspergillosis, and disseminated aspergillosis, and the clinical scenario dictates treatment.


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InternalMed_Harrison. Other Complications Other potential complications are listed in Table 320e-3. Many of them are related to side effects or toxicities of immunosuppressive drugs. Management of these general medical problems is guided by standard practices, but the complex milieu of transplantation requires close collaboration and good communication among health care providers.


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InternalMed_Harrison. Approach to the Patient with Critical Illness John P. Kress, Jesse B. Hall The care of critically ill patients requires a thorough understanding of pathophysiology and centers initially on the resuscitation of patients at the extremes of physiologic deterioration. This resuscitation is often fast-paced and occurs early, without a detailed awareness of the patient’s chronic medical problems. While physiologic stabilization is taking place, intensivists attempt to gather important background med-ical information to supplement the real-time assessment of the patient’s current physiologic conditions. Numerous tools are available to assist intensivists in the accurate assessment of pathophysiology and manage-ment of incipient organ failure, offering a window of opportunity for diagnosing and treating underlying disease(s) in a stabilized patient. Indeed, the use of invasive interventions such as mechanical ventilation and renal replacement therapy is commonplace in the intensive care unit


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InternalMed_Harrison. underlying disease(s) in a stabilized patient. Indeed, the use of invasive interventions such as mechanical ventilation and renal replacement therapy is commonplace in the intensive care unit (ICU). An appreciation of the risks and benefits of such aggressive and often invasive interventions is vital to ensure an optimal outcome. Nonetheless, intensivists must recognize when a patient’s chances for recovery are remote or nonexistent and must counsel and comfort dying patients and their significant others. Critical care physicians often must redirect the goals of care from resuscitation and cure to comfort when the resolution of an underlying illness is not possible. ASSESSMENT OF ILLNESS SEVERITY 321 SEC TIon 1 RESPIRAToRy CRITICAl CARE


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InternalMed_Harrison. Approach to the Patient with Critical Illness


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InternalMed_Harrison. In the ICU, illnesses are frequently categorized by degree of severity. Numerous severity-of-illness (SOI) scoring systems have been developed and validated over the past three decades. Although these scoring systems have been validated as tools to assess populations of critically ill patients, their utility in predicting individual patient outcomes is not clear. SOI scoring systems are important for defining populations of critically ill patients. Such systematic scoring allows effective comparison of groups of patients enrolled in clinical trials. In verifying a purported benefit of therapy, investigators must be confident that different groups involved in a clinical trial have similar illness severities. SOI scores are also useful in guiding hospital administrative policies, directing the allocation of resources such as nursing and ancillary care and assisting in assessments of quality of ICU care over time. Scoring system validations are based on the premise that age, chronic


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InternalMed_Harrison. the allocation of resources such as nursing and ancillary care and assisting in assessments of quality of ICU care over time. Scoring system validations are based on the premise that age, chronic medical illnesses, and derangements from normal physiology are associated with increased mortality rates. All existing SOI scoring systems are derived from patients who have already been admitted to the ICU.


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InternalMed_Harrison. SOI scoring systems cannot be used to predict survival in individual patients. No established scoring systems that purport to direct clinicians’ decision-making regarding criteria for admission to an ICU are available, although such models are being developed. Thus the use of SOI scoring systems to direct therapy and clinical decision-making cannot be recommended at present. Instead, these tools should be used as a source of important data to complement clinical bedside decision-making. The most commonly utilized scoring systems are the APACHE (Acute Physiology and Chronic Health Evaluation) and the SAPS (Simplified Acute Physiology Score) systems.


InternalMed_Harrison

InternalMed_Harrison. The most commonly utilized scoring systems are the APACHE (Acute Physiology and Chronic Health Evaluation) and the SAPS (Simplified Acute Physiology Score) systems. The APACHE II system is the most commonly used SOI scoring system in North America. Age, type of ICU admission (after elective surgery vs. nonsurgical or after emergency surgery), chronic health problems, and 12 physiologic variables (the worst values for each in the first 24 h after ICU admission) are used to derive a score. The predicted hospital mortality rate is derived from a formula that takes into account the APACHE II score, the need for emergency surgery, and a weighted, disease-specific diagnostic category (Table 321–1). The relationship between APACHE II score and mortality risk is illustrated in Fig. 321-1. Updated versions of the APACHE scoring system (APACHE III and APACHE IV) have been published.


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InternalMed_Harrison. The SAPS II score, used more frequently in Europe than in the United States, was derived in a manner similar to the APACHE score. This score is not disease specific but rather incorporates three underlying disease variables: AIDS, metastatic cancer, and hematologic malignancy. SAPS 3, which utilizes a 1-h rather than a 24-h window for measuring physiologic derangement scores, was developed in 2005. See also Chap. 324.


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InternalMed_Harrison. Shock, a common condition necessitating ICU admission or occurring in the course of critical care, is defined by the presence of multisystem end-organ hypoperfusion. Clinical indicators include reduced mean arterial pressure (MAP), tachycardia, tachypnea, cool skin and extremities, acute altered mental status, and oliguria. Hypotension is usually, though not always, present. The end result of multiorgan hypoperfusion is tissue hypoxia, often with accompanying lactic acidosis. Since the MAP is the product of cardiac output and systemic vascular resistance (SVR), reductions in blood pressure can be caused by decreases in cardiac output and/or SVR. Accordingly, once shock is contemplated, the initial evaluation of a hypotensive patient should include an early bedside assessment of the adequacy of cardiac output (Fig. 321-2). Clinical evidence of diminished cardiac output includes a narrow pulse pressure—a marker that correlates with stroke volume— and cool extremities with delayed


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InternalMed_Harrison. adequacy of cardiac output (Fig. 321-2). Clinical evidence of diminished cardiac output includes a narrow pulse pressure—a marker that correlates with stroke volume— and cool extremities with delayed capillary refill. Signs of increased cardiac output include a widened pulse pressure (particularly with a reduced diastolic pressure), warm extremities with bounding pulses, and rapid capillary refill. If a hypotensive patient has clinical signs of increased cardiac output, it can be inferred that the reduced blood pressure is from decreased SVR.


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InternalMed_Harrison. In hypotensive patients with signs of reduced cardiac output, an assessment of intravascular volume status is appropriate. A hypotensive patient with decreased intravascular volume status may have a history suggesting hemorrhage or other volume losses (e.g., vomiting, diarrhea, polyuria). Although evidence of a reduced jugular venous pressure (JVP) is often sought, static measures of right atrial pressure do not predict fluid responsiveness reliably; the change in right atrial pressure as a function of spontaneous respiration is a better predictor of fluid responsiveness (Fig. 321-3). Patients with fluid-responsive (i.e., hypovolemic) shock also may manifest large changes in pulse pressure as a function of respiration during mechanical ventilation (Fig. 321-4). A hypotensive patient with increased intravascular volume and cardiac dysfunction may have S3 and/or S4 gallops on examination, increased JVP, extremity edema, and crackles on lung auscultation. The chest x-ray may show


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InternalMed_Harrison. with increased intravascular volume and cardiac dysfunction may have S3 and/or S4 gallops on examination, increased JVP, extremity edema, and crackles on lung auscultation. The chest x-ray may show cardiomegaly, widening of the vascular pedicle, Kerley B lines, and pulmonary edema. Chest pain and electrocardiographic changes consistent with ischemia may be noted (Chap. 326).


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InternalMed_Harrison. In hypotensive patients with clinical evidence of increased cardiac output, a search for causes of decreased SVR is appropriate. The If patient is admitted after elective surgery


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InternalMed_Harrison. If patient is admitted after elective surgery If patient is admitted after emergency surgery or for reason other than after elective surgery aThe APACHE II score is the sum of the acute physiology score (vital signs, oxygenation, laboratory values), the Glasgow coma score, age, and chronic health points. The worst values during the first 24 h in the ICU should be used. bGlasgow coma score (GCS) = eye-opening score + verbal (intubated or nonintubated) score + motor score. cFor GCS component of acute physiology score, subtract GCS from 15 to obtain points assigned. dHepatic: cirrhosis with portal hypertension or encephalopathy; cardiovascular: class IV angina (at rest or with minimal self-care activities); pulmonary: chronic hypoxemia or hypercapnia, polycythemia, ventilator dependence; renal: chronic peritoneal or hemodialysis; immune: immunocompromised host.


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InternalMed_Harrison. Abbreviations: (A − a) DO2, alveolar-arterial oxygen difference; FIO2, fraction of inspired oxygen; PaO2, partial pressure of oxygen; WBC, white blood cell count. Mortality rate, % FIGURE 321-1 APACHE II survival curve. Blue, nonoperative; green, (See also Chap. 323) During the initial resuscitation of patients in postoperative. shock, principles of advanced cardiac life support should be followed. most common cause of high-cardiac-output hypotension is sepsis (Chap. 325). Other causes include liver failure, severe pancreatitis, burns and other trauma that elicit the systemic inflammatory response syndrome (SIRS), anaphylaxis, thyrotoxicosis, and peripheral arteriovenous shunts. In summary, the most common categories of shock are hypovolemic, cardiogenic, and high-cardiac-output with decreased SVR (highoutput hypotension). Certainly more than one category can occur simultaneously (e.g., hypovolemic and septic shock).


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InternalMed_Harrison. The initial assessment of a patient in shock should take only a few minutes. It is important that aggressive resuscitation is instituted on the basis of the initial assessment, particularly since early resuscitation from septic and cardiogenic shock may improve survival (see below). If the initial bedside assessment yields equivocal or confounding data, more objective assessments such as echocardiography and/or invasive vascular monitoring may be useful. The goal of early resuscitation is to reestablish adequate tissue perfusion and thus to prevent or minimize 5-9 15-19 25-29 35+ end-organ injury. APACHE II Score


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InternalMed_Harrison. Inotropes, afterload reduction Heart is “full” (cardiogenic shock) Evaluate for myocardial ischemia Cold, clammy extremities Warm, bounding extremities High cardiac output No improvement What does not fit? Adrenal crisis, right heart syndrome, pericardial disease Consider echocardiogram, invasive vascular monitoring Consider echocardiogram, invasive vascular monitoring Septic shock, liver failure Low cardiac output JVP, crackles JVP, orthostasis Intravenous fluids Antibiotics, EGDT May convert to SHOCK Heart is “empty” (hypovolemic shock) FIGURE 321-2 Approach to the patient in shock. EGDT, early goal-directed therapy; JVP, jugular venous pulse.


InternalMed_Harrison

InternalMed_Harrison. As such patients may be obtunded and unable to protect the airway, an early assessment of the airway is mandatory. Early intubation and mechanical ventilation often are required. Reasons for the institution of endotracheal intubation and mechanical ventilation include acute hypoxemic respiratory failure and ventilatory failure, which frequently accompany shock. Acute hypoxemic respiratory failure may occur in patients with cardiogenic shock and pulmonary edema (Chap. 326) as well as in those who are in septic shock with pneumonia or acute respiratory distress syndrome (ARDS) (Chaps. 322 and 325). Ventilatory failure often occurs as a consequence of an increased load on the respiratory system in the form of acute metabolic (often lactic) acidosis or decreased lung compliance due to pulmonary edema. Inadequate perfusion to respiratory muscles in the setting of shock may be another reason for early intubation and mechanical ventilation. Normally, the respiratory muscles receive a very


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InternalMed_Harrison. edema. Inadequate perfusion to respiratory muscles in the setting of shock may be another reason for early intubation and mechanical ventilation. Normally, the respiratory muscles receive a very small percentage of the cardiac output. However, in patients who are in shock with respiratory distress, the percentage of cardiac output dedicated to respiratory muscles may increase by tenfold or more. Lactic acid production from inefficient respiratory muscle activity presents an additional ventilatory load.


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InternalMed_Harrison. Mechanical ventilation may relieve the work of breathing and 1731 allow redistribution of a limited cardiac output to other vital organs. Patients demonstrate respiratory distress by an inability to speak full sentences, accessory use of respiratory muscles, paradoxical abdominal muscle activity, extreme tachypnea (>40 breaths/min), and decreasing respiratory rate despite an increasing drive to breathe. When patients with shock are treated with mechanical ventilation, a major goal is for the ventilator to assume all or the majority of the work of breathing, facilitating a state of minimal respiratory muscle work. With the institution of mechanical ventilation for shock, further declines in MAP are frequently seen. The reasons include impeded venous return from positive-pressure ventilation, reduced endogenous catecholamine secretion once the stress associated with respiratory failure abates, and the actions of drugs used to facilitate endotracheal intubation (e.g., propofol, opiates).


InternalMed_Harrison

InternalMed_Harrison. reduced endogenous catecholamine secretion once the stress associated with respiratory failure abates, and the actions of drugs used to facilitate endotracheal intubation (e.g., propofol, opiates). Accordingly, hypotension should be anticipated during endotracheal intubation. Because many of these patients may be fluid responsive, IV volume administration should be considered. Figure 321-2 summarizes the diagnosis and treatment of different types of shock For further discussion of individual forms of shock, see Chaps. 324, 325, and 326.


InternalMed_Harrison

InternalMed_Harrison. Respiratory failure is one of the most common reasons for ICU admission. In some ICUs, ≥75% of patients require mechanical ventilation during their stay. Respiratory failure can be categorized mechanistically on the basis of pathophysiologic derangements in respiratory function. TYPE I: ACUTE HYPOXEMIC RESPIRATORY FAILURE


InternalMed_Harrison

InternalMed_Harrison. This type of respiratory failure occurs with alveolar flooding and subsequent intrapulmonary shunt physiology. Alveolar flooding may be a consequence of pulmonary edema, pneumonia, or alveolar hemorrhage. Pulmonary edema can be further categorized as occurring due to elevated pulmonary microvascular pressures, as seen in heart failure and intravascular volume overload or ARDS (“low-pressure pulmonary edema,” Chap. 322). This syndrome is defined by acute onset (≤1 week) of bilateral opacities on chest imaging that are not fully explained by cardiac failure or fluid overload and of shunt physiology requiring positive end-expiratory pressure (PEEP). Type I respiratory failure occurs in clinical settings such as sepsis, gastric aspiration, pneumonia, near-drowning, multiple blood transfusions, and pancreatitis. The mortality rate among patients with ARDS was traditionally very high (50–70%), although changes in patient care have led to mortality rates closer to 30% (see below).


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InternalMed_Harrison. For many years, physicians have suspected that mechanical ventilation of patients with ARDS may propagate lung injury. Cyclical collapse and reopening of alveoli may be partly responsible for this adverse effect. As seen in Fig. 321-5, the pressure-volume relationship of the lung in ARDS is not linear. Alveoli may collapse at very low lung volumes. Animal studies have suggested that stretching and overdistention of injured alveoli during mechanical ventilation can further injure the lung. Concern over this alveolar overdistention, termed ventilator-induced “volutrauma,” led to a multicenter, randomized, prospective trial comparing traditional ventilator strategies for ARDS (large tidal volume: 12 mL/kg of ideal body weight) with a low tidal volume (6 mL/kg of ideal body weight). This study showed a dramatic reduction in mortality rate in the low-tidal-volume group from that in the high-tidalvolume group (31% versus 39.8%). In addition, a “fluid-conservative” management strategy


InternalMed_Harrison

InternalMed_Harrison. study showed a dramatic reduction in mortality rate in the low-tidal-volume group from that in the high-tidalvolume group (31% versus 39.8%). In addition, a “fluid-conservative” management strategy (maintaining a low central venous pressure [CVP] or pulmonary capillary wedge pressure


InternalMed_Harrison

InternalMed_Harrison. Approach to the Patient with Critical Illness This form of respiratory failure results from lung atelectasis. Because atelectasis occurs so commonly in the perioperative period, this form is also called periop erative respiratory failure. After general anesthesia, decreases in functional residual capacity lead to collapse of depen dent lung units. Such atelectasis can be treated by frequent changes in position, FIGURE 321-4 Pulse pressure change during mechanical ventilation in a patient with shock chest physiotherapy, upright positioning, whose cardiac output will increase in response to intravenous fluid administration. The pulse pres- and control of incisional and/or abdomi nal pain. Noninvasive positive-pressure with septic shock.


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InternalMed_Harrison. This type of respiratory failure is a consequence of alveolar hypoventilation and results from the inability to eliminate carbon dioxide effectively. Mechanisms are categorized by impaired central nervous system (CNS) drive to breathe, impaired strength with failure of neuromuscular function in the respiratory system, and increased load(s) on the respiratory system. Reasons for diminished CNS drive to breathe include drug overdose, brainstem injury, sleep-disordered breathing, and severe hypothyroidism. Reduced strength can be due to impaired neuromuscular transmission (e.g., myasthenia gravis, Guillain-Barré syndrome, amyotrophic lateral sclerosis) or respiratory muscle weakness (e.g., myopathy, electrolyte derangements, fatigue).


InternalMed_Harrison

InternalMed_Harrison. The overall load on the respiratory system can be subclassified into resistive loads (e.g., bronchospasm), loads due to reduced lung compliance (e.g., alveolar edema, atelectasis, intrinsic positive end-expiratory pressure [auto-PEEP]—see below), loads due to reduced chest wall compliance (e.g., pneumothorax, pleural effusion, abdominal distention), and loads due to increased minute ventilation requirements (e.g., pulmonary embolus with increased dead-space fraction, sepsis).


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InternalMed_Harrison. The mainstays of therapy for type II respiratory failure are directed at reversing the underlying cause(s) of ventilatory failure. Noninvasive positive-pressure ventilation with a tight-fitting facial or nasal mask, with avoidance of endotracheal intubation, often stabilizes these patients. This approach has been shown to be beneficial in treating patients with exacerbations of chronic obstructive pulmonary disease; it has been tested less extensively in other kinds of respiratory failure but may be attempted nonetheless in the absence of contraindications (hemodynamic instability, inability to protect the airway, respiratory arrest). ventilation may also be used to reverse regional atelectasis.


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InternalMed_Harrison. ventilation may also be used to reverse regional atelectasis. This form results from hypoperfusion of respiratory muscles in patients in shock. Normally, respiratory muscles consume <5% of total cardiac output and oxygen delivery. Patients in shock often experience respiratory distress due to pulmonary edema (e.g., in cardiogenic shock), lactic acidosis, and anemia. In this setting, up to 40% of cardiac output may be distributed to the respiratory muscles. Intubation and mechanical ventilation can allow redistribution of the cardiac output away from the respiratory muscles and back to vital organs while the shock is treated.


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InternalMed_Harrison. (See also Chap. 323) Whereas a thorough understanding of the pathophysiology of respiratory failure is essential for optimal patient care, recognition of a patient’s readiness to be liberated from mechanical ventilation is likewise important. Several studies have shown that daily spontaneous breathing trials can identify patients who are ready for extubation. Accordingly, all intubated, mechanically ventilated patients should undergo daily screening of respiratory function. If oxygenation is stable (i.e., PaO2/FIO2 [partial pressure of oxygen/fraction of inspired oxygen] >200 and PEEP ≤5 cmH2O), cough and airway reflexes are intact, and no vasopressor agents or sedatives are being administered, the patient has passed the screening test and should undergo a spontaneous breathing trial. This trial consists of a period of breathing through the endotracheal tube without ventilator support (both continuous positive airway pressure [CPAP] of 5 cmH2O and an open T-piece breathing system can


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InternalMed_Harrison. trial consists of a period of breathing through the endotracheal tube without ventilator support (both continuous positive airway pressure [CPAP] of 5 cmH2O and an open T-piece breathing system can be used) for 30–120 min. The spontaneous breathing trial is declared a failure and stopped if any of the following occur: (1) respiratory rate >35/min for >5 min, (2) O2 saturation <90%, (3) heart rate >140/min or a 20% increase or decrease from baseline, (4) systolic blood pressure <90 mmHg or >180 mmHg, or (5) increased anxiety or diaphoresis. If, at the end of the spontaneous breathing trial, none of the above events has occurred and the ratio of the respiratory rate and tidal volume in liters (f/VT) is <105, the patient can be extubated. Such protocol-driven approaches to patient care can have an important impact on the duration of mechanical ventilation and ICU stay. In spite of such a careful approach to liberation from mechanical ventilation, up to 10% of patients develop respiratory


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InternalMed_Harrison. an important impact on the duration of mechanical ventilation and ICU stay. In spite of such a careful approach to liberation from mechanical ventilation, up to 10% of patients develop respiratory distress after extubation and may require resumption of mechanical ventilation. Many of these patients will require reintubation. The use


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InternalMed_Harrison. Volume, mL of noninvasive ventilation in patients in whom extubation fails may be associated with worse outcomes than are obtained with immediate reintubation. Mechanically ventilated patients frequently require sedatives and analgesics. Opiates are the mainstay of therapy for pain control in mechanically ventilated patients. After adequate pain control has been Pressure, cmH2O ensured, additional indications for sedation include anxiolysis; treat-


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InternalMed_Harrison. FIGURE 321-5 Pressure-volume relationship in the lungs of a ment of subjective dyspnea; psychosis; facilitation of nursing care; patient with acute respiratory distress syndrome (ARDS). At reduction of autonomic hyperactivity, which may precipitate myocarthe lower inflection point, collapsed alveoli begin to open and lung dial ischemia; and reduction of total O2 consumption (VO2). compliance changes. At the upper deflection point, alveoli become Neuromuscular blocking agents are occasionally needed to facilitate overdistended. The shape and size of alveoli are illustrated at the top mechanical ventilation in patients with profound ventilator dyssynof the figure. chrony despite optimal sedation, particularly in the setting of severe ARDS. Use of these agents may result in prolonged weakness—a myopathy known as the postparalytic syndrome. For this reason, neuromuscular blocking agents typically are used as a last resort when aggressive sedation fails to achieve patient-ventilator


InternalMed_Harrison

InternalMed_Harrison. myopathy known as the postparalytic syndrome. For this reason, neuromuscular blocking agents typically are used as a last resort when aggressive sedation fails to achieve patient-ventilator synchrony. Because neuromuscular blocking agents result in pharmacologic paralysis without altering mental status, sedative-induced amnesia is mandatory when these agents are administered.


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InternalMed_Harrison. Amnesia can be achieved reliably with benzodiazepines such as lorazepam and midazolam as well as the the IV anesthetic agent propofol. Outside the setting of pharmacologic paralysis, few data support the idea that amnesia is mandatory in all patients who require intubation and mechanical ventilation. Since many of these critically patients have impaired hepatic and renal function, sedatives and opiates may accumulate when given for prolonged periods. A nursing protocol– driven approach to sedation of mechanically ventilated patients or daily interruption of sedative infusions paired with daily spontaneous breathing trials has been shown to prevent excessive drug accumulation and shorten the duration of both mechanical ventilation and ICU stay.


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InternalMed_Harrison. Multiorgan system failure, which is commonly associated with critical illness, is defined by the simultaneous presence of physiologic dysfunction and/or failure of two or more organs. Typically, this syndrome occurs in the setting of severe sepsis, shock of any kind, severe inflammatory conditions such as pancreatitis, and trauma. The fact that multiorgan system failure occurs commonly in the ICU is a testament to our current ability to stabilize and support single-organ failure. The ability to support single-organ failure aggressively (e.g., by mechanical ventilation or by renal replacement therapy) has reduced rates of early mortality in critical illness. As a result, it is uncommon for critically ill patients to die in the initial stages of resuscitation. Instead, many patients succumb to critical illness later in the ICU stay, after the initial presenting problem has been stabilized.


InternalMed_Harrison

InternalMed_Harrison. Although there is debate regarding specific definitions of organ failure, several general principles governing the syndrome of multiorgan system failure apply. First, organ failure, no matter how it is defined, must persist beyond 24 h. Second, mortality risk increases with the accrual of failing organs. Third, the prognosis worsens with increased duration of organ failure. These observations remain true across various critical care settings (e.g., medical versus surgical). SIRS is a common basis for multiorgan system failure. Although infection is a common cause of SIRS, “sterile” triggers such as pancreatitis, trauma, and burns often are invoked to explain multiorgan system failure.


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InternalMed_Harrison. Because respiratory failure and circulatory failure are common in critically ill patients, monitoring of the respiratory and cardiovascular systems is undertaken frequently. Evaluation of respiratory gas exchange is routine in critical illness. The “gold standard” remains arterial blood-gas analysis, in which pH, PaO2, partial pressure of carbon dioxide (PCO2), and O2 saturation are measured directly. With arterial blood-gas analysis, the two main functions of the lung—oxygenation of arterial blood and elimination of CO2—can be assessed directly. In fact, the blood pH, which has a profound effect on the drive to breathe, can be assessed only by such sampling. Although sampling of arterial blood is generally safe, it may be painful and cannot provide continuous information. In light of these limitations, noninvasive monitoring of respiratory function is often employed.


InternalMed_Harrison

InternalMed_Harrison. The most commonly utilized noninvasive technique for monitoring respiratory function, pulse oximetry takes advantage of differences in the absorptive properties of oxygenated and deoxygenated hemoglobin. At wavelengths of 660 nm, oxyhemoglobin reflects light more effectively than does deoxyhemoglobin, whereas the reverse is true in the infrared spectrum (940 nm). A pulse oximeter passes both wavelengths of light through a perfused digit such as a finger, and the relative intensity of light transmission at these two wavelengths is recorded. From this information, the relative percentage of oxyhe-1733 moglobin is derived. Since arterial pulsations produce phasic changes in the intensity of transmitted light, the pulse oximeter is designed to detect only light of alternating intensity. This feature allows distinction of arterial and venous blood O2 saturations.


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InternalMed_Harrison. Respiratory system mechanics can be measured in patients during mechanical ventilation (Chap. 323). When volume-controlled modes of mechanical ventilation are used, accompanying airway pressures can easily be measured as long as the patient is passive. The peak airway pressure is determined by two variables: airway resistance and respiratory system compliance. At the end of inspiration, inspiratory flow can be stopped transiently. This end-inspiratory pause (plateau pressure) is a static measurement, affected only by respiratory system compliance and not by airway resistance. Therefore, during volume-controlled ventilation, the difference between the peak (airway resistance + respiratory system compliance) and plateau (respiratory system compliance only) airway pressures provides a quantitative assessment of airway resistance. Accordingly, during volume-controlled ventilation, patients with increases in airway resistance typically have increased peak airway pressures as well as


InternalMed_Harrison

InternalMed_Harrison. quantitative assessment of airway resistance. Accordingly, during volume-controlled ventilation, patients with increases in airway resistance typically have increased peak airway pressures as well as abnormally high gradients between peak and plateau airway pressures (typically >15 cmH2O) at an inspiratory flow rate of 1 L/sec. The compliance of the respiratory system is defined by the change in pressure of the respiratory system per unit change in volume.


InternalMed_Harrison

InternalMed_Harrison. The respiratory system can be divided into two components: the lungs and the chest wall. Normally, respiratory system compliance is ~100 mL/cmH2O. Pathophysiologic processes such as pleural effusions, pneumothorax, and increased abdominal girth all reduce chest wall compliance. Lung compliance may be reduced by pneumonia, pulmonary edema, interstitial lung disease, or auto-PEEP. Accordingly, patients with abnormalities in compliance of the respiratory system (lungs and/or chest wall) typically have elevated peak and plateau airway pressures but a normal gradient between these two pressures. Auto-PEEP occurs when there is insufficient time for emptying of alveoli before the next inspiratory cycle. Since the alveoli have not decompressed completely, alveolar pressure remains positive at the end of exhalation (functional residual capacity). This phenomenon results most commonly from critical narrowing of distal airways in disease processes such as asthma and COPD. Auto-PEEP with


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InternalMed_Harrison. at the end of exhalation (functional residual capacity). This phenomenon results most commonly from critical narrowing of distal airways in disease processes such as asthma and COPD. Auto-PEEP with resulting alveolar overdistention may result in diminished lung compliance, reflected by abnormally increased plateau airway pressures. Modern mechanical ventilators allow breath-to-breath display of pressure and flow, permitting detection of problems such as patient-ventilator dyssynchrony, airflow obstruction, and auto-PEEP (Fig. 321–6).


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InternalMed_Harrison. Oxygen delivery (QO2) is a function of cardiac output and the content of O2 in the arterial blood (CaO2). The CaO2 is determined by the hemoglobin concentration, the arterial hemoglobin saturation, and dissolved O2 not bound to hemoglobin. For normal adults: QO2 = 50 dL/min × (1.39 × 15 g/dL [hemoglobin concentration] × 1.0 [hemoglobin % saturation] + 0.0031 × 100 [PaO2]) = 50 dL/min (cardiac output) × 21.6 mL O2 per dL blood (CaO2) It is apparent that nearly all of the O2 delivered to tissues is bound to hemoglobin and that the dissolved O2 (PaO2) contributes very little to O2 content in arterial blood or to O2 delivery. Normally, the content of O2 in mixed venous blood (C–vO2) is 15.76 mL/dL since the mixed venous blood is 75% saturated. Therefore, the normal tissue extraction ratio for O2 is CaO2 – C–vO2/CaO2 ([21.16–15.76]/21.16) or ~25%. A pulmonary artery catheter allows measurements of O2 delivery and the O2 extraction ratio.


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InternalMed_Harrison. Information on the mixed venous O2 saturation allows assessment of global tissue perfusion. A reduced mixed venous O2 saturation may be caused by inadequate cardiac output, reduced hemoglobin concentration, and/or reduced arterial O2 saturation. An abnormally high VO2may also lead to a reduced mixed venous O2 saturation if O2 delivery is Approach to the Patient with Critical Illness 1.2 -1.2 FIGURE 321-6 Increased airway resistance with auto-PEEP. The top waveform (airway pressure vs. time) shows a large difference between the peak airway pressure (80 cmH2O) and the plateau airway pressure (20 cmH2O). The bottom waveform (flow vs. time) demonstrates airflow throughout expiration (reflected by the flow tracing on the negative portion of the abscissa) that persists up to the next inspiratory effort. not concomitantly increased. Abnormally increased VO2 in peripheral tissues may be caused by problems such as fever, agitation, shivering, and thyrotoxicosis.


InternalMed_Harrison

InternalMed_Harrison. not concomitantly increased. Abnormally increased VO2 in peripheral tissues may be caused by problems such as fever, agitation, shivering, and thyrotoxicosis. The pulmonary artery catheter originally was designed as a tool to guide therapy for acute myocardial infarction but has been used in the ICU for evaluation and treatment of a variety of other conditions, such as ARDS, septic shock, congestive heart failure, and acute renal failure. This device has never been validated as a tool associated with reduction in morbidity and mortality rates. Indeed, despite numerous prospective studies, mortality or morbidity rate benefits associated with use of the pulmonary artery catheter have never been reported in any setting. Accordingly, it appears that routine pulmonary artery catheterization is not indicated as a means of monitoring and characterizing circulatory status in most critically ill patients.


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InternalMed_Harrison. Static measurements of circulatory parameters (e.g., CVP, PCWP) do not provide reliable information on the circulatory status of critically ill patients. In contrast, dynamic assessments measuring the impact of breathing on the circulation are more reliable predictors of responsiveness to IV fluid administration. A decrease in CVP of >1 mmHg during inspiration in a spontaneously breathing patient may predict an increase in cardiac output after IV fluid administration. Similarly, a changing pulse pressure during mechanical ventilation has been shown to predict an increase in cardiac output after IV fluid administration in patients with septic shock.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 325) Sepsis, defined as the presence of SIRS in the setting of known or suspected infection, is a significant problem in the care of critically ill patients, who often progress to severe sepsis with the failure of one or more organs. Sepsis is the leading cause of death in noncoronary ICUs in the United States, with case rates expected to increase as the population ages and a higher percentage of people are vulnerable to infection.


InternalMed_Harrison

InternalMed_Harrison. Many therapeutic interventions in the ICU are invasive and predispose patients to infectious complications. These interventions include endotracheal intubation, indwelling vascular catheters, transurethral bladder catheters, and other catheters placed into sterile body cavities (e.g., tube thoracostomy, percutaneous intraabdominal drainage catheterization). The longer such devices remain in place, the more prone to these infections patients become. For example, ventilator-associated pneumonia correlates strongly with the duration of intubation and mechanical ventilation. Therefore, an important aspect of preventive care is the timely removal of invasive devices as soon as they are no longer needed. Moreover, multidrug-resistant organisms are commonplace in the ICU.


InternalMed_Harrison

InternalMed_Harrison. Infection control is critical in the ICU. Care bundles, which include measures such as frequent hand washing, are effective but underutilized strategies. Other components of care bundles, such as protective isolation of patients colonized or infected by drug-resistant organisms, are also commonly used. Silver-coated endotracheal tubes reportedly reduce the incidence of ventilator-associated pneumonia. Studies evaluating multifaceted, evidence-based strategies to decrease catheter-related bloodstream infections have shown improved outcomes with strict adherence to measures such as hand washing, full-barrier precautions during catheter insertion, chlorhexidine skin preparation, avoidance of the femoral site, and timely catheter removal.


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InternalMed_Harrison. (See also Chap. 300) All ICU patients are at high risk for this complication because of their predilection for immobility. Therefore, all should receive some form of prophylaxis against DVT. The most commonly employed forms of prophylaxis are subcutaneous low-dose heparin injections and sequential compression devices for the lower extremities. Observational studies report an alarming incidence of DVTs despite the use of these standard prophylactic regimens. Furthermore, heparin prophylaxis may result in heparin-induced thrombocytopenia, another nosocomial complication in critically ill patients. Low-molecular-weight heparins such as enoxaparin are more effective than unfractionated heparin for DVT prophylaxis in high-risk patients (e.g., those undergoing orthopedic surgery) and are associated with a lower incidence of heparin-induced thrombocytopenia. Fondaparinux, a selective factor Xa inhibitor, is even more effective than enoxaparin in high-risk orthopedic patients.


InternalMed_Harrison

InternalMed_Harrison. Prophylaxis against stress ulcers is frequently administered in most ICUs; typically, histamine-2 antagonists or proton pump inhibitors are given. Available data suggest that high-risk patients, such as those with coagulopathy, shock, or respiratory failure requiring mechanical ventilation, benefit from such prophylactic treatment.


InternalMed_Harrison

InternalMed_Harrison. These are important issues that may be associated with respiratory failure, impaired wound healing, and dysfunctional immune response in critically ill patients. Early enteral feeding is reasonable, though no data are available to suggest that this treatment improves patient outcome per se. Certainly, enteral feeding, if possible, is preferred over parenteral nutrition, which is associated with numerous complications, including hyperglycemia, fatty liver, cholestasis, and sepsis. When parenteral feeding is necessary to supplement enteral nutrition, delaying this intervention until day 8 in the ICU results in better recovery and fewer ICU-related complications. Tight glucose control is an area of controversy in critical care. Although one study showed a significant mortality benefit when glucose levels were aggressively normalized in a large group of surgical ICU patients, more recent data for a large population of both medical and surgical ICU patients suggested that tight glucose


InternalMed_Harrison

InternalMed_Harrison. glucose levels were aggressively normalized in a large group of surgical ICU patients, more recent data for a large population of both medical and surgical ICU patients suggested that tight glucose control resulted in increased rates of mortality.


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InternalMed_Harrison. ICU-acquired weakness occurs frequently in patients who survive critical illness, particularly those with SIRS and/or sepsis. Both neuropathies and myopathies have been described, most commonly after ~1 week in the ICU. The mechanisms behind ICU-acquired weakness syndromes are poorly understood. Intensive insulin therapy may reduce polyneuropathy in critical illness. Very early physical and occupational therapy in mechanically ventilated patients reportedly results in significant improvements in functional independence at hospital discharge as well as in reduced durations of mechanical ventilation and delirium.


InternalMed_Harrison

InternalMed_Harrison. Studies have shown that most ICU patients are anemic as a result of chronic inflammation. Phlebotomy also contributes to ICU anemia. A large multicenter study involving patients in many different ICU settings challenged the conventional notion that a hemoglobin level of 100 g/L (10 g/dL) is needed in critically ill patients, with similar outcomes noted in those whose transfusion trigger was 7 g/dL. Red blood cell transfusion is associated with impairment of immune function and increased risk of infections as well as of ARDS and volume overload, all of which may explain the findings in this study. Recently, a conservative transfusion strategy enhanced survival among patients with active upper gastrointestinal hemorrhage.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 334) Acute renal failure occurs in a significant percentage of critically ill patients. The most common underlying etiology is acute tubular necrosis, usually precipitated by hypoperfusion and/or nephrotoxic agents. Currently, no pharmacologic agents are available for prevention of renal injury in critical illness. Studies have shown convincingly that low-dose dopamine is not effective in protecting the kidneys from acute injury.


InternalMed_Harrison

InternalMed_Harrison. (See also Chaps. 34 and 328) This state is defined by (1) an acute onset of changes or fluctuations in mental status, (2) inattention, (3) disorganized thinking, and (4) an altered level of consciousness (i.e., a state other than alertness). Delirium is reported to occur in a wide range of mechanically ventilated ICU patients and can be detected by the Confusion Assessment Method (CAM)-ICU or the Intensive Care Delirium Screening Checklist. These tools are used to ask patients to answer simple questions and perform simple tasks and can be used readily at the bedside. The differential diagnosis of delirium in ICU patients is broad and includes infectious etiologies (including sepsis), medications (particularly sedatives and analgesics), drug withdrawal, metabolic/electrolyte derangements, intracranial pathology (e.g., stroke, intracranial hemorrhage), seizures, hypoxia, hypertensive crisis, shock, and vitamin deficiencies (particularly thiamine). Patients with ICU delirium have


InternalMed_Harrison

InternalMed_Harrison. intracranial pathology (e.g., stroke, intracranial hemorrhage), seizures, hypoxia, hypertensive crisis, shock, and vitamin deficiencies (particularly thiamine). Patients with ICU delirium have increases in length of hospital stay, time on mechanical ventilation, cognitive impairment at hospital discharge, and 6-month mortality rate. Interventions to reduce ICU delirium are limited. The sedative dexmedetomidine has been less strongly associated with ICU delirium than midazolam. In addition, as mentioned above, very early physical and occupational therapy in mechanically ventilated patients has been demonstrated to reduce delirium.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 330) This condition is common after cardiac arrest and often results in severe and permanent brain injury in survivors. Active cooling of patients after cardiac arrest has been shown to improve neurologic outcomes. Therefore, patients who present to the ICU after circulatory arrest from ventricular fibrillation or pulseless ventricular tachycardia should be actively cooled to achieve a core body temperature of 32–34°C.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 446) Stroke is a common cause of neurologic critical illness. Hypertension must be managed carefully, since abrupt reductions in blood pressure may be associated with further brain ischemia and injury. Acute ischemic stroke treated with tissue plasminogen activator (tPA) has an improved neurologic outcome when treatment is given within 3 h of onset of symptoms. The mortality rate is not reduced when tPA is compared with placebo, despite the improved neurologic outcome. The risk of cerebral hemorrhage is significantly higher in patients given tPA. No benefit is seen when tPA therapy is given beyond 3 h after symptom onset. Heparin has not been convincingly shown to improve outcomes in patients with acute ischemic stroke. Decompressive cra-1735 niectomy is a surgical procedure that relieves increased intracranial pressure in the setting of space-occupying brain lesions or brain swelling from stroke; available evidence suggests that this procedure may improve survival


InternalMed_Harrison

InternalMed_Harrison. that relieves increased intracranial pressure in the setting of space-occupying brain lesions or brain swelling from stroke; available evidence suggests that this procedure may improve survival among select patients (≤55 years or age), albeit at a cost of increased disability for some.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 446) Subarachnoid hemorrhage may occur secondary to aneurysm rupture and is often complicated by cerebral vasospasm, re-bleeding, and hydrocephalus. Vasospasm can be detected by either transcranial Doppler assessment or cerebral angiography; it is typically treated with the calcium channel blocker nimodipine, aggressive IV fluid administration, and therapy aimed at increasing blood pressure, typically with vasoactive drugs such as phenylephrine. The IV fluids and vasoactive drugs (hypertensive hypervolemic therapy) are used to overcome the cerebral vasospasm. Early surgical clipping or endovascular coiling of aneurysms is advocated to prevent complications related to re-bleeding. Hydrocephalus, typically heralded by a decreased level of consciousness, may require ventriculostomy drainage.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 445) Recurrent or relentless seizure activity is a medical emergency. Cessation of seizure activity is required to prevent irreversible neurologic injury. Lorazepam is the most effective benzodiazepine for treating status epilepticus and is the treatment of choice for controlling seizures acutely. Phenytoin or fosphenytoin should be given concomitantly since lorazepam has a short half-life. Other drugs, such as gabapentin, carbamazepine, and phenobarbital, should be reserved for patients with contraindications to phenytoin (e.g., allergy or pregnancy) or ongoing seizures despite phenytoin.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 330) Although deaths of critically ill patients usually are attributable to irreversible cessation of circulatory and respiratory function, a diagnosis of death also may be established by irreversible cessation of all functions of the entire brain, including the brainstem, even if circulatory and respiratory functions remain intact on artificial life support. Such a diagnosis requires demonstration of the absence of cerebral function (no response to any external stimulus) and brainstem functions (e.g., unreactive pupils, lack of ocular movement in response to head turning or ice-water irrigation of ear canals, positive apnea test [no drive to breathe]). Absence of brain function must have an established cause and be permanent without possibility of recovery; a sedative effect, hypothermia, hypoxemia, neuromuscular paralysis, and severe hypotension must be ruled out. If there is uncertainty about the cause of coma, studies of cerebral blood flow and


InternalMed_Harrison

InternalMed_Harrison. a sedative effect, hypothermia, hypoxemia, neuromuscular paralysis, and severe hypotension must be ruled out. If there is uncertainty about the cause of coma, studies of cerebral blood flow and electroencephalography should be performed.


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InternalMed_Harrison. (See also Chap. 10) Withholding or withdrawal of care occurs commonly in the ICU setting. The Task Force on Ethics of the Society of Critical Care Medicine reported that it is ethically sound to withhold or withdraw care if a patient or the patient’s surrogate makes such a request or if the physician judges that the goals of therapy are not achievable. Since all medical treatments are justified by their expected benefits, the loss of such an expectation justifies the act of withdrawing or withholding such treatment; these two actions are judged to be fundamentally similar. An underlying stipulation derived from this report is that an informed patient should have his or her wishes respected with regard to life-sustaining therapy. Implicit in this stipulation is the need to ensure that patients are thoroughly and accurately informed regarding the plausibility and expected results of various therapies.


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InternalMed_Harrison. The act of informing patients and/or surrogate decision-makers is the responsibility of the physician and other health care providers. If a patient or surrogate desires therapy deemed futile by the treating physician, the physician is not obligated ethically to provide such treatment. Rather, arrangements may be made to transfer the patient’s care to another care provider. Whether the decision to withdraw


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InternalMed_Harrison. Approach to the Patient with Critical Illness 1736 life support should be initiated by the physician or left to surrogate decision-makers alone is not clear. One study reported that slightly more than half of surrogate decision-makers preferred to receive such a recommendation, whereas the rest did not. Critical care providers should meet regularly with patients and/or surrogates to discuss prognosis when the withholding or withdrawal of care is being considered. After a consensus among caregivers has been reached, this information should be relayed to the patient and/or surrogate decision-maker. If a decision to withhold or withdraw life-sustaining care for a patient has been made, aggressive attention to analgesia and anxiolysis is needed. Syndrome 322 Bruce D. Levy, Augustine M. K. Choi


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InternalMed_Harrison. Bruce D. Levy, Augustine M. K. Choi Acute respiratory distress syndrome (ARDS) is a clinical syndrome of severe dyspnea of rapid onset, hypoxemia, and diffuse pulmonary infiltrates leading to respiratory failure. ARDS is caused by diffuse lung injury from many underlying medical and surgical disorders. The lung injury may be direct, as occurs in toxic inhalation, or indirect, as occurs in sepsis (Table 322-1). The clinical features of ARDS are listed in Table 322-2. By expert consensus, ARDS is defined by three categories based on the degrees of hypoxemia (Table 322-2). These stages of mild, moderate, and severe ARDS are associated with mortality risk and with the duration of mechanical ventilation in survivors. The annual incidence of ARDS is estimated to be as high as 60 cases/100,000 population. Approximately 10% of all intensive care unit (ICU) admissions involve patients with acute respiratory failure; ~20% of these patients meet the criteria for ARDS.


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InternalMed_Harrison. While many medical and surgical illnesses have been associated with the development of ARDS, most cases (>80%) are caused by a relatively small number of clinical disorders: severe sepsis syndrome and/or bacterial pneumonia (~40–50%), trauma, multiple transfusions, aspiration of gastric contents, and drug overdose. Among patients with trauma, the most frequently reported surgical conditions in ARDS are pulmonary contusion, multiple bone fractures, and chest wall trauma/flail chest, whereas head trauma, near-drowning, toxic inhalation, and burns are rare causes. The risks of developing ARDS are increased in patients with more than one predisposing medical or surgical condition.


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InternalMed_Harrison. Several other clinical variables have been associated with the development of ARDS. These include older age, chronic alcohol abuse, metabolic acidosis, and severity of critical illness. Trauma patients with an Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥16 (Chap. 321) have a 2.5-fold increased risk of developing ARDS, and those with a score >20 have an incidence of ARDS that Direct Lung Injury Indirect Lung Injury Chest Absence of Left Severity: Oxygenation Onset Radiograph Atrial Hypertension Abbreviations: ARDS, acute respiratory distress syndrome; FIO2, inspired O2 percentage; PaO2, arterial partial pressure of O2; PCWP, pulmonary capillary wedge pressure. is more than threefold greater than the incidence among those with APACHE II scores ≤9. The natural history of ARDS is marked by three phases—exudative, proliferative, and fibrotic—that each have characteristic clinical and pathologic features (Fig. 322-1).


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InternalMed_Harrison. Exudative Phase In this phase (Fig. 322-2), alveolar capillary endothelial cells and type I pneumocytes (alveolar epithelial cells) are injured, with consequent loss of the normally tight alveolar barrier to fluid and macromolecules. Edema fluid that is rich in protein accumulates in the interstitial and alveolar spaces. Significant concentrations of cytokines (e.g., interleukin 1, interleukin 8, and tumor necrosis factor α) and lipid mediators (e.g., leukotriene B4) are present in the lung in this acute phase. In response to proinflammatory mediators, leukocytes (especially neutrophils) traffic into the pulmonary interstitium and alveoli. In addition, condensed plasma proteins aggregate in the air spaces with cellular debris and dysfunctional pulmonary surfactant to form hyaline membrane whorls. Pulmonary vascular injury also occurs early in ARDS, with vascular obliteration by microthrombi and fibrocellular proliferation (Fig. 322-3).


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InternalMed_Harrison. Alveolar edema predominantly involves dependent portions of the lung, with diminished aeration and atelectasis. Collapse of large sections of dependent lung markedly decreases lung compliance. Consequently, intrapulmonary shunting and hypoxemia develop and the work of breathing increases, leading to dyspnea. The pathophysiologic alterations in alveolar spaces are exacerbated by microvascular occlusion that results in reductions in pulmonary arterial blood flow to ventilated portions of the lung (and thus in increased dead space) and in pulmonary hypertension. Thus, in addition to severe hypoxemia, hypercapnia secondary to an increase in pulmonary dead space is prominent in early ARDS.


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InternalMed_Harrison. The exudative phase encompasses the first 7 days of illness after exposure to a precipitating ARDS risk factor, with the patient experiencing the onset of respiratory symptoms. Although usually presenting within 12–36 h after the initial insult, symptoms can be delayed by 5–7 days. Dyspnea develops, with a sensation of rapid shallow breathing Day: 02 7 14 21. . . FIGURE 322-1 Diagram illustrating the time course for the development and resolution of ARDS. The exudative phase is notable for early alveolar edema and neutrophil-rich leukocytic infiltration of the lungs, with subsequent formation of hyaline membranes from diffuse alveolar damage. Within 7 days, a proliferative phase ensues with prominent interstitial inflammation and early fibrotic changes. Approximately 3 weeks after the initial pulmonary injury, most patients recover. However, some patients enter the fibrotic phase, with substantial fibrosis and bullae formation.


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InternalMed_Harrison. FIGURE 322-2 A representative anteroposterior chest x-ray in the exudative phase of ARDS shows diffuse interstitial and alveolar infiltrates that can be difficult to distinguish from left ventricular failure. and an inability to get enough air. Tachypnea and increased work of 1737 breathing result frequently in respiratory fatigue and ultimately in respiratory failure. Laboratory values are generally nonspecific and are primarily indicative of underlying clinical disorders. The chest radio-graph usually reveals alveolar and interstitial opacities involving at least three-quarters of the lung fields (Fig. 322-2). While characteristic for ARDS, these radiographic findings are not specific and can be indistinguishable from cardiogenic pulmonary edema (Chap. 326). Unlike the latter, however, the chest x-ray in ARDS rarely shows cardiomegaly, pleural effusions, or pulmonary vascular redistribution. Chest CT in ARDS reveals extensive heterogeneity of lung involvement (Fig. 322-4).


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InternalMed_Harrison. Because the early features of ARDS are nonspecific, alternative diagnoses must be considered. In the differential diagnosis of ARDS, the most common disorders are cardiogenic pulmonary edema, diffuse pneumonia, and alveolar hemorrhage. Less common diagnoses to consider include acute interstitial lung diseases (e.g., acute interstitial pneumonitis; Chap. 315), acute immunologic injury (e.g., hypersensitivity pneumonitis; Chap. 310), toxin injury (e.g., radiation pneumonitis; Chap. 263), and neurogenic pulmonary edema (Chap. 47e). Proliferative Phase This phase of ARDS usually lasts from day 7 to day 21. Most patients recover rapidly and are liberated from mechanical


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InternalMed_Harrison. Proliferative Phase This phase of ARDS usually lasts from day 7 to day 21. Most patients recover rapidly and are liberated from mechanical Alveolar air space Protein-rich edema fluid Inactivated surfactant Activated neutrophil Alveolar macrophages Type I cell Type II cell Endothelial basement membrane FibroblastsNeutrophils Gap formation Procollagen Proteases IL-8 TNF-˜, IL-8 MIF IL-6, IL-8 Leukotrienes Oxidants PAF Proteases IL-8 Migrating neutrophil Fibroblasts Capillary Swollen, injured endothelial cell Platelets Interstitium Widened edematous interstitium Epithelial basement membrane Sloghing of bronchial epithelium Necrotic or apoptotic type I cell Red blood cell Intact type II cell Cellular debris Fibrin Denuded basement membrane Hyaline membrane Surfactant layer Normal alveolus Injured alveolus during the acute phase


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InternalMed_Harrison. FIGURE 322-3 The normal alveolus (left) and the injured alveolus in the acute phase of acute lung injury and the acute respiratory distress syndrome (right). In the acute phase of the syndrome (right), there is sloughing of both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and transmigrating through the interstitium into the air space, which is filled with protein-rich edema fluid. In the air space, an alveolar macrophage is secreting cytokines—i.e., interleukins 1, 6, 8, and 10 (IL-1, -6, -8, and -10) and tumor necrosis factor α (TNF-α)—that act locally to stimulate chemotaxis and activate neutrophils. Macrophages also secrete other cytokines, including IL-1, -6, and -10. IL-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other


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InternalMed_Harrison. other cytokines, including IL-1, -6, and -10. IL-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). A number of antiinflammatory mediators are also present in the alveolar milieu, including the IL-1-receptor antagonist, soluble TNF-α receptor, autoantibodies to IL-8, and cytokines such as IL-10 and IL-11 (not shown). The influx of protein-rich edema fluid into the alveolus has led to the inactivation of surfactant. MIF, macrophage inhibitory factor. (From LB Ware, MA Matthay: N Engl J Med 342:1334, 2000, with permission.)


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InternalMed_Harrison. FIGURE 322-4 A representative CT scan of the chest during the exudative phase of ARDS, in which dependent alveolar edema and atelectasis predominate. ventilation during this phase. Despite this improvement, many patients still experience dyspnea, tachypnea, and hypoxemia. Some patients develop progressive lung injury and early changes of pulmonary fibrosis during the proliferative phase. Histologically, the first signs of resolution are often evident in this phase, with the initiation of lung repair, the organization of alveolar exudates, and a shift from a neutrophilto a lymphocyte-predominant pulmonary infiltrate. As part of the reparative process, type II pneumocytes proliferate along alveolar basement membranes. These specialized epithelial cells synthesize new pulmonary surfactant and differentiate into type I pneumocytes.


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InternalMed_Harrison. Fibrotic Phase While many patients with ARDS recover lung function 3–4 weeks after the initial pulmonary injury, some enter a fibrotic phase that may require long-term support on mechanical ventilators and/or supplemental oxygen. Histologically, the alveolar edema and inflammatory exudates of earlier phases are now converted to extensive alveolar-duct and interstitial fibrosis. Marked disruption of acinar architecture leads to emphysema-like changes, with large bullae. Intimal fibroproliferation in the pulmonary microcirculation causes progressive vascular occlusion and pulmonary hypertension. The physiologic consequences include an increased risk of pneumothorax, reductions in lung compliance, and increased pulmonary dead space. Patients in this late phase experience a substantial burden of excess morbidity. Lung biopsy evidence for pulmonary fibrosis in any phase of ARDS is associated with increased mortality risk.


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InternalMed_Harrison. Recent reductions in ARDS mortality rates are largely the result of general advances in the care of critically ill patients (Chap. 321). Thus, caring for these patients requires close attention to (1) the recognition and treatment of underlying medical and surgical disorders (e.g., sepsis, aspiration, trauma); (2) the minimization of procedures and their complications; (3) prophylaxis against venous thromboembolism, gastrointestinal bleeding, aspiration, excessive sedation, and central venous catheter infections; (4) prompt recognition of nosocomial infections; and (5) provision of adequate nutrition. (See also Chap. 323) Patients meeting clinical criteria for ARDS frequently become fatigued from increased work of breathing and progressive hypoxemia, requiring mechanical ventilation for support.


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InternalMed_Harrison. Ventilator-Induced Lung Injury Despite its life-saving potential, mechanical ventilation can aggravate lung injury. Experimental models have demonstrated that ventilator-induced lung injury appears to require two processes: repeated alveolar overdistention and recurrent alveolar collapse. As is clearly evident from chest CT (Fig. 322-4), ARDS is a heterogeneous disorder, principally involving dependent portions of the lung with relative sparing of other regions. Because compliance differs in affected versus more “normal” areas of the lung, attempts to fully inflate the consolidated lung may lead to overdistention of and injury to the more normal areas. Ventilator-induced injury can be demonstrated in experimental models of acute lung injury, with high-tidal-volume (VT) ventilation resulting in additional, synergistic alveolar damage.


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InternalMed_Harrison. A large-scale, randomized controlled trial sponsored by the National Institutes of Health and conducted by the ARDS Network compared low VT ventilation (6 mL/kg of predicted body weight) to conventional VT ventilation (12 mL/kg predicted body weight). The mortality rate was significantly lower in the low VT patients (31%) than in the conventional VT patients (40%). This improvement in survival represents the most substantial ARDS-mortality benefit that has been demonstrated for any therapeutic intervention to date.


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InternalMed_Harrison. Prevention of Alveolar Collapse In ARDS, the presence of alveolar and interstitial fluid and the loss of surfactant can lead to a marked reduction of lung compliance. Without an increase in end-expiratory pressure, significant alveolar collapse can occur at end-expiration, with consequent impairment of oxygenation. In most clinical settings, positive end-expiratory pressure (PEEP) is empirically set to minimize FIO2 (inspired O2 percentage) and maximize PaO2 (arterial partial pressure of O2). On most modern mechanical ventilators, it is possible to construct a static pressure–volume curve for the respiratory system. The lower inflection point on the curve represents alveolar opening (or “recruitment”). The pressure at this point, usually 12–15 mmHg in ARDS, is a theoretical “optimal PEEP” for alveolar recruitment. Titration of the PEEP to the lower inflection point on the static pressure–volume curve has been hypothesized to keep the lung open, improving oxygenation and protecting


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InternalMed_Harrison. for alveolar recruitment. Titration of the PEEP to the lower inflection point on the static pressure–volume curve has been hypothesized to keep the lung open, improving oxygenation and protecting against lung injury. Three large randomized trials have investigated the utility of PEEP-based strategies to keep the lung open. In all three trials, improvement in lung function was evident but overall mortality rates were not altered significantly. Until more data become available on the clinical utility of high PEEP, it is advisable to set PEEP to minimize FIO2 and optimize PaO2 (Chap. 323). Measurement of esophageal pressures to estimate transpulmonary pressure may help identify an optimal PEEP in some cases.


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InternalMed_Harrison. Oxygenation can also be improved by increasing mean airway pressure with inverse-ratio ventilation. In this technique, the inspiratory time (I) is lengthened so that it is longer than the expiratory time (E)— that is, I:E > 1:1. With diminished time to exhale, dynamic hyperinflation leads to increased end-expiratory pressure, similar to ventilator-prescribed PEEP. This mode of ventilation has the advantage of improving oxygenation with lower peak pressures than are required for conventional ventilation. Although inverse-ratio ventilation can improve oxygenation and can help reduce FIO2 to ≤0.60, thus avoiding possible oxygen toxicity, no benefit in ARDS mortality risk has been demonstrated. Recruitment maneuvers that transiently increase PEEP to “recruit” atelectatic lung can also increase oxygenation, but a mortality benefit has not been established.


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InternalMed_Harrison. In several randomized trials, mechanical ventilation in the prone position improved arterial oxygenation, but its effect on survival and other important clinical outcomes remains uncertain. Moreover, unless the critical-care team is experienced in “proning,” repositioning critically ill patients can be hazardous, leading to accidental endotracheal extubation, loss of central venous catheters, and orthopedic injury.


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InternalMed_Harrison. Several additional mechanical-ventilation strategies that use specialized equipment have been tested in ARDS patients; most of these approaches have had mixed or disappointing results in adults. High-frequency ventilation (HFV) entails ventilating at extremely high respiratory rates (5–20 cycles per second) and low VTs (1–2 mL/ kg). Use of partial liquid ventilation (PLV) with perfluorocarbon—an inert, high-density liquid that easily solubilizes oxygen and carbon dioxide—has yielded promising preliminary results, enhancing pulmonary function in patients with ARDS, but also has provided no survival benefit. Lung-replacement therapy with extracorporeal membrane oxygenation (ECMO), which provides a clear survival benefit in neonatal respiratory distress syndrome, may also have utility in selected adult patients with ARDS.


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InternalMed_Harrison. Data supporting the efficacy of “adjunctive” ventilator therapies (e.g., high PEEP, inverse ratio ventilation, recruitment maneuvers, prone positioning, HFV, ECMO, and PLV) remain incomplete. Accordingly, these modalities are reserved for use as rescue rather than primary therapies.


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InternalMed_Harrison. (See also Chap. 321) Increased pulmonary vascular permeability leading to interstitial and alveolar edema fluid rich in protein is a central feature of ARDS. In addition, impaired vascular integrity augments the normal increase in extravascular lung water that occurs with increasing left atrial pressure. Maintaining a low left atrial filling pressure minimizes pulmonary edema and prevents further decrements in arterial oxygenation and lung compliance; improves pulmonary mechanics; shortens ICU stay and the duration of mechanical ventilation; and is associated with a lower mortality rate in both medical and surgical ICU patients. Thus, aggressive attempts to reduce left atrial filling pressures with fluid restriction and diuretics should be an important aspect of ARDS management, limited only by hypotension and hypoperfusion of critical organs such as the kidneys.