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InternalMed_Harrison. In severe ARDS, sedation alone can be inadequate for the patient-ventilator synchrony required for lung-protective ventilation. This clinical problem was recently addressed in a multicenter, randomized, placebo-controlled trial of early neuromuscular blockade (with cisatracurium besylate) for 48 h. In severe ARDS, early neuromuscular blockade increased the rate of survival and ventilator-free days without increasing ICU-acquired paresis. These promising findings support the early administration of neuromuscular blockade if needed to facilitate mechanical ventilation in severe ARDS; however, these results must be replicated prior to their widespread application in clinical practice. Many attempts have been made to treat both early and late ARDS with glucocorticoids, with the goal of reducing potentially deleterious pulmonary inflammation. Few studies have shown any benefit. Current evidence does not support the use of high-dose glucocorticoids in the care of ARDS patients.


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InternalMed_Harrison. Clinical trials of surfactant replacement and multiple other medical therapies have proved disappointing. Inhaled nitric oxide and inhaled epoprostenol sodium can transiently improve oxygenation but do not improve survival or decrease time on mechanical ventilation. Many clinical trials have been undertaken to improve the outcome of patients with ARDS; most have been unsuccessful in modifying the natural history. While results of large clinical trials must be judiciously applied to individual patients, evidence-based recommendations are summarized in Table 322-3, and an algorithm for the initial therapeutic goals and limits in ARDS management is provided in Fig. 322-5.


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InternalMed_Harrison. PROGNOSIS Mortality Recent mortality estimates for ARDS range from 26% to 44%. There is substantial variability, but a trend toward improved ARDS outcomes appears evident. Of interest, mortality in ARDS is largely attributable to nonpulmonary causes, with sepsis and nonpulmonary organ failure accounting for >80% of deaths. Thus, improvement in survival is aKey: A, recommended therapy based on strong clinical evidence from randomized clinical trials; B, recommended therapy based on supportive but limited clinical data; C, recommended only as alternative therapy on the basis of indeterminate evidence; D, not recommended on the basis of clinical evidence against efficacy of therapy. Abbreviations: ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; NO, nitric oxide; NSAIDs, nonsteroidal anti-inflammatory drugs; PEEP, positive end-expiratory pressure; PGE1, prostaglandin E1.


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InternalMed_Harrison. likely secondary to advances in the care of septic/infected patients and those with multiple organ failure (Chap. 321). The major risk factors for ARDS mortality are nonpulmonary. Advanced age is an important risk factor. Patients >75 years of age have a substantially higher mortality risk (~60%) than those <45 (~20%). Moreover, patients >60 years of age with ARDS and sepsis have a threefold higher mortality risk than those <60. Other risk factors include preexisting organ dysfunction from chronic medical illness—in particular, chronic liver disease, cirrhosis, chronic alcohol abuse, chronic immunosuppression, sepsis, chronic renal disease, failure of any nonpulmonary organ, and increased APACHE III scores (Chap. 321). Patients with ARDS arising from direct lung injury (including pneumonia, pulmonary contusion, and aspiration; FIO2 ˜ 0.6 PEEP ˜ 10 cmH2O SpO2 88 – 95% pH ° 7.30 RR ˜ 35 bpm FIGURE 322-5 Algorithm for the initial management of ARDS.


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InternalMed_Harrison. FIO2 ˜ 0.6 PEEP ˜ 10 cmH2O SpO2 88 – 95% pH ° 7.30 RR ˜ 35 bpm FIGURE 322-5 Algorithm for the initial management of ARDS. Clinical trials have provided evidence-based therapeutic goals for a stepwise approach to the early mechanical ventilation, oxygenation, and correction of acidosis and diuresis of critically ill patients with ARDS. FIO2, inspired O2 percentage; MAP, mean arterial pressure; PBW, predicted body weight; PEEP, positive end expiratory pressure; RR, respiratory rate; SpO2, arterial oxyhemoglobin saturation measured by pulse oximetry.


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InternalMed_Harrison. mechanical ventilatory Support Bartolome R. Celli MECHANICAL VENTILATORY SUPPORT Mechanical ventilation is used to assist or replace spontaneous breath-ing. It is implemented with special devices that can support ventilatory 323 1740 Table 322-1) are nearly twice as likely to die as those with indirect causes of lung injury, while surgical and trauma patients with ARDS— especially those without direct lung injury—have a higher survival rate than other ARDS patients. An early (within 24 h of presentation) elevation in pulmonary dead space (>0.60) and severe arterial hypoxemia (Pao2/Fio2, <100 mmHg) predict increased mortality risk from ARDS; however, there is surprisingly little additional value in predicting ARDS mortality from other measures of the severity of lung injury, including the level of PEEP (≥10 cm H2O), respiratory system compliance (≤40 mL/cm H2O), the extent of alveolar infiltrates on chest radiography, and the corrected expired volume per minute (≥10 L/min).


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InternalMed_Harrison. Functional Recovery in ARDS Survivors While it is common for patients with ARDS to experience prolonged respiratory failure and remain dependent on mechanical ventilation for survival, it is a testament to the resolving powers of the lung that the majority of patients recover nearly normal lung function. Patients usually recover maximal lung function within 6 months. One year after endotracheal extubation, more than one-third of ARDS survivors have normal spirometry values and diffusion capacity. Most of the remaining patients have only mild abnormalities in pulmonary function. Unlike mortality risk, recovery of lung function is strongly associated with the extent of lung injury in early ARDS. Low static respiratory compliance, high levels of required PEEP, longer durations of mechanical ventilation, and high lung injury scores are all associated with less recovery of pulmonary function. Of note, when physical function is assessed 5 years after ARDS, exercise limitation and decreased


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InternalMed_Harrison. ventilation, and high lung injury scores are all associated with less recovery of pulmonary function. Of note, when physical function is assessed 5 years after ARDS, exercise limitation and decreased physical quality of life are often documented despite normal or nearly normal pulmonary function. When caring for ARDS survivors, it is important to be aware of the potential for a substantial burden of psychological problems in patients and family caregivers, including significant rates of depression and posttraumatic stress disorder.


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InternalMed_Harrison. ARDS Support Center for patient-oriented education: www.ards.org NHLBI ARDS Clinical Trials information: www.ardsnet.org ARDS Foundation: www.ardsusa.org The authors acknowledge the contribution to this chapter by the previous author, Dr. Steven D. Shapiro.


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InternalMed_Harrison. The authors acknowledge the contribution to this chapter by the previous author, Dr. Steven D. Shapiro. function and improve oxygenation through the application of highoxygen-content gas and positive pressure. The primary indication for initiation of mechanical ventilation is respiratory failure, of which there are two basic types: (1) hypoxemic, which is present when arterial O2 saturation (Sao2) <90% occurs despite an increased inspired O2 fraction and usually results from ventilation-perfusion mismatch or shunt; and (2) hypercarbic, which is characterized by elevated arterial carbon dioxide partial pressure (PCO2) values (usually >50 mmHg) resulting from conditions that decrease minute ventilation or increase physiologic dead space such that alveolar ventilation is inadequate to meet metabolic demands. When respiratory failure is chronic, neither of the two types is obligatorily treated with mechanical ventilation, but when it is acute, mechanical ventilation may be lifesaving.


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InternalMed_Harrison. The most common reasons for instituting mechanical ventilation are acute respiratory failure with hypoxemia (acute respiratory distress syndrome, heart failure with pulmonary edema, pneumonia, sepsis, complications of surgery and trauma), which accounts for ~65% of all ventilated cases, and hypercarbic ventilatory failure—e.g., due to coma (15%), exacerbations of chronic obstructive pulmonary disease (COPD; 13%), and neuromuscular diseases (5%). The primary objectives of mechanical ventilation are to decrease the work of breathing, thus avoiding respiratory muscle fatigue, and to reverse life-threatening hypoxemia and progressive respiratory acidosis.


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InternalMed_Harrison. In some cases, mechanical ventilation is used as an adjunct to other forms of therapy. For example, it is used to reduce cerebral blood flow in patients with increased intracranial pressure. Mechanical ventilation also is used frequently in conjunction with endotracheal intubation for airway protection to prevent aspiration of gastric contents in otherwise unstable patients during gastric lavage for suspected drug overdose or during gastrointestinal endoscopy. In critically ill patients, intubation and mechanical ventilation may be indicated before the performance of essential diagnostic or therapeutic studies if it appears that respiratory failure may occur during those maneuvers. There are two basic methods of mechanical ventilation: noninvasive ventilation (NIV) and invasive (or conventional mechanical) ventilation (MV).


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InternalMed_Harrison. Noninvasive Ventilation NIV has gained acceptance because it is effective in certain conditions, such as acute or chronic respiratory failure, and is associated with fewer complications—namely, pneumonia and tracheolaryngeal trauma. NIV usually is provided with a tight-fitting face mask or nasal mask similar to the masks traditionally used for treatment of sleep apnea. NIV has proved highly effective in patients with respiratory failure arising from acute exacerbations of chronic obstructive pulmonary disease. It is most frequently implemented as bilevel positive airway pressure ventilation or pressure-support ventilation. Both modes, which apply a preset positive pressure during inspiration and a lower pressure during expiration at the mask, are well tolerated by a conscious patient and optimize patient-ventilator synchrony. The major limitation to the widespread application of NIV has been patient intolerance: the tight-fitting mask required for NIV can cause both physical and


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InternalMed_Harrison. and optimize patient-ventilator synchrony. The major limitation to the widespread application of NIV has been patient intolerance: the tight-fitting mask required for NIV can cause both physical and psychological discomfort. In addition, NIV has had limited success in patients with acute hypoxemic respiratory failure, for whom endotracheal intubation and conventional MV remain the ventilatory method of choice.


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InternalMed_Harrison. The most important group of patients who benefit from a trial of NIV are those with exacerbations of COPD and respiratory acidosis (pH <7.35). Experience from several randomized trials has shown that, in patients with ventilatory failure characterized by blood pH levels between 7.25 and 7.35, NIV is associated with low failure rates (15–20%) and good outcomes (as judged by intubation rate, length of stay in intensive care, and—in some series—mortality rates). In more severely ill patients with a blood pH <7.25, the rate of NIV failure is inversely related to the severity of respiratory acidosis, with higher failure rates as the pH decreases. In patients with milder acidosis (pH >7.35), NIV is not better than conventional treatment that includes controlled oxygen delivery and pharmacotherapy for exacerbations of COPD (systemic glucocorticoids, bronchodilators, and, if needed, antibiotics).


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InternalMed_Harrison. Despite its benign outcomes, NIV is not useful in the majority of cases of respiratory failure and is contraindicated in patients with the conditions listed in Table 323-1. NIV can delay lifesaving ventilatory support in those cases and, in fact, can actually result in aspiration or hypoventilation. Once NIV is initiated, patients should be monitored; a reduction in respiratory frequency and a decrease in the use of accessory muscles (scalene, sternomastoid, and intercostals) are good clinical indicators of adequate therapeutic benefit. Arterial blood gases should be determined at least within hours of the initiation of therapy to ensure that NIV is having the desired effect. Lack of benefit within High-risk aspiration and/or inability to protect airways Inability to clear secretions that time frame should alert the physician to the possible need for conventional MV.


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InternalMed_Harrison. Conventional Mechanical Ventilation Conventional MV is implemented once a cuffed tube is inserted into the trachea to allow conditioned gas (warmed, oxygenated, and humidified) to be delivered to the airways and lungs at pressures above atmospheric pressure. Care should be taken during intubation to avoid brain-damaging hypoxia. In most cases, the administration of mild sedation may facilitate the procedure. Opiates and benzodiazepines are good choices but can have a deleterious effect on hemodynamics in patients with depressed cardiac function or low systemic vascular resistance. Morphine can promote histamine release from tissue mast cells and may worsen bronchospasm in patients with asthma; fentanyl, sufentanil, and alfentanil are acceptable alternatives. Ketamine may increase systemic arterial pressure and has been associated with hallucinatory responses. The shorter-acting agents etomidate and propofol have been used for both induction and maintenance of anesthesia in ventilated


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InternalMed_Harrison. arterial pressure and has been associated with hallucinatory responses. The shorter-acting agents etomidate and propofol have been used for both induction and maintenance of anesthesia in ventilated patients because they have fewer adverse hemodynamic effects, but both are significantly more expensive than older agents. Great care must be taken to avoid the use of neuromuscular paralysis during intubation of patients with renal failure, tumor lysis syndrome, crush injuries, medical conditions associated with elevated serum potassium levels, and muscular dystrophy syndromes; in particular, the use of agents whose mechanism of action includes depolarization at the neuromuscular junction, such as succinylcholine chloride, must be avoided.


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InternalMed_Harrison. Once the patient has been intubated, the basic goals of MV are to optimize oxygenation while avoiding ventilator-induced lung injury due to overstretch and collapse/re-recruitment. This concept, known as the “protective ventilatory strategy” (see below and Fig. 323-1) is supported by evidence linking high airway pressures and volumes and overstretching of the lung as well as collapse/re-recruitment to poor clinical outcomes (barotrauma and volume trauma). Although normalization of pH through elimination of CO2 is desirable, the risk of lung damage associated with the large volume and high pressures needed to achieve this goal has led to the acceptance of permissive hypercapnia. This condition is well tolerated when care is taken to avoid excess acidosis by pH buffering.


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InternalMed_Harrison. Mode refers to the manner in which ventilator breaths are triggered, cycled, and limited. The trigger, either an inspiratory effort or a time-based signal, defines what the ventilator senses to initiate an assisted breath. Cycle refers to the factors that determine the end of inspiration. For example, in volume-cycled ventilation, inspiration ends when a specific tidal volume is delivered. Other types of cycling include pressure cycling and time cycling. The limiting factors are operator-specified values, such as airway pressure, that are monitored by transducers internal to the ventilator circuit throughout the respiratory cycle; if the specified values are exceeded, inspiratory flow is terminated, and the ventilator circuit is vented to atmospheric pressure or the specified pressure at the end of expiration (positive end-expiratory pressure, or PEEP). Most patients are ventilated with assist-control ventilation, B 0.8 Alveolar 0.6 0.4 0.2 A Pressure (cm of water)


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InternalMed_Harrison. B 0.8 Alveolar 0.6 0.4 0.2 A Pressure (cm of water) FIGURE 323-1 Hypothetical pressure-volume curve of the lung in a patient undergoing mechanical ventilation. Alveoli tend to close if the distending pressure falls below the lower inflection point (A), whereas they overstretch if the pressure within them is higher than that of the upper inflection point (B). Collapse and opening of ventilated alveoli are associated with poor outcomes in patients with acute respiratory failure. Protective ventilation (purple shaded area), using a lower tidal volume (6 mL/kg of ideal body weight) and maintaining positive end-expiratory pressure to prevent overstretching and collapse/opening of alveoli, has resulted in improved survival rates among patients receiving mechanical ventilatory support. intermittent mandatory ventilation, or pressure-support ventilation, with the latter two modes often used simultaneously (Table 323-2).


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InternalMed_Harrison. intermittent mandatory ventilation, or pressure-support ventilation, with the latter two modes often used simultaneously (Table 323-2). Assist-Control Ventilation (ACMV) ACMV is the most widely used mode of ventilation. In this mode, an inspiratory cycle is initiated either by the patient’s inspiratory effort or, if none is detected within a specified time window, by a timer signal within the ventilator. Every breath delivered, whether patientor timer-triggered, consists of the operator-specified tidal volume. Ventilatory rate is determined either by the patient or by the operator-specified backup rate, whichever is of higher frequency. ACMV is commonly used for initiation of mechanical ventilation because it ensures a backup minute ventilation in the absence of an intact respiratory drive and allows for synchronization of the ventilator cycle with the patient’s inspiratory effort.


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InternalMed_Harrison. Problems can arise when ACMV is used in patients with tachypnea due to nonrespiratory or nonmetabolic factors, such as anxiety, pain, and airway irritation. Respiratory alkalemia may develop and trigger myoclonus or seizures. Dynamic hyperinflation leading to increased intrathoracic pressures (so-called auto-PEEP) may occur if the patient’s respiratory mechanics are such that inadequate time is available for complete exhalation between inspiratory cycles. Auto-PEEP can limit venous return, decrease cardiac output, and increase airway pressures, predisposing to barotrauma.


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InternalMed_Harrison. Intermittent Mandatory Ventilation (IMV) With this mode, the operator sets the number of mandatory breaths of fixed volume to be delivered by the ventilator; between those breaths, the patient can breathe spontaneously. In the most frequently used synchronized mode (SIMV), mandatory breaths are delivered in synchrony with the patient’s inspiratory efforts at a frequency determined by the operator. If the patient fails to initiate a breath, the ventilator delivers a fixed-tidal-volume breath and resets the internal timer for the next inspiratory cycle. SIMV differs from ACMV in that only a preset number of breaths are ventilator-assisted. SIMV allows patients with an intact respiratory drive to exercise inspiratory muscles between assisted breaths; thus it is useful for both supporting and weaning intubated patients. SIMV may be difficult to Peak, mean, and plateau airway pressures VE ABG I/E ratio Peak, mean, and plateau airway pressures VE ABG I/E ratio


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InternalMed_Harrison. Peak, mean, and plateau airway pressures VE ABG I/E ratio Peak, mean, and plateau airway pressures VE ABG I/E ratio Mask interface may cause discomfort and facial bruising Leaks are common Hypoventilation Abbreviations: ABG, arterial blood gases; FIO2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure; I/E, inspiratory to expiratory time ratio; VE, minute ventilation. use in patients with tachypnea because they may attempt to exhale during the ventilator-programmed inspiratory cycle. Consequently, the airway pressure may exceed the inspiratory pressure limit, the ventilator-assisted breath will be aborted, and minute volume may drop below that programmed by the operator. In this setting, if the tachypnea represents a response to respiratory or metabolic acidosis, a change in ACMV will increase minute ventilation and help normalize the pH while the underlying process is further evaluated and treated.


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InternalMed_Harrison. Pressure-Support Ventilation (PSV) This form of ventilation is patient-triggered, flow-cycled, and pressure-limited. It provides graded assistance and differs from the other two modes in that the operator sets the pressure level (rather than the volume) to augment every spontaneous respiratory effort. The level of pressure is adjusted by observing the patient’s respiratory frequency. During PSV, the inspiration is terminated when inspiratory airflow falls below a certain level; in most ventilators, this flow rate cannot be adjusted by the operator. With PSV, patients receive ventilator assistance only when the ventilator detects an inspiratory effort. PSV is often used in combination with SIMV to ensure volume-cycled backup for patients whose respiratory drive is depressed. PSV is well tolerated by most patients who are being weaned from MV; PSV parameters can be set to provide full ventilatory support and can be withdrawn to load the respiratory muscles gradually.


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InternalMed_Harrison. Other Modes of Ventilation There are other modes of ventilation, each with its own acronym and each with specific modifications of the manner and duration in which pressure is applied to the airway and lungs and of the interaction between the mechanical assistance provided by the ventilator and the patient’s respiratory effort. Although their use in acute respiratory failure is limited, the following modes have been used with varying levels of enthusiasm and adoption.


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InternalMed_Harrison. Pressure-control ventilation (Pcv) This form of ventilation is time-triggered, time-cycled, and pressure-limited. A specified pressure is imposed at the airway opening throughout inspiration. Since the inspiratory pressure is specified by the operator, tidal volume and inspiratory flow rate are dependent, rather than independent, variables and are not operator-specified. PCV is the preferred mode of ventilation for patients in whom it is desirable to regulate peak airway pressures, such as those with preexisting barotrauma, and for post– thoracic surgery patients, in whom the shear forces across a fresh suture line should be limited. When PCV is used, minute ventilation is altered through changes in rate or in the pressure-control value, with consequent changes in tidal volume.


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InternalMed_Harrison. inverse-ratio ventilation (irv) This mode is a variant of PCV that incorporates the use of a prolonged inspiratory time with the appropriate shortening of the expiratory time. IRV has been used in patients with severe hypoxemic respiratory failure. This approach increases mean distending pressures without increasing peak airway pressures. It is thought to work in conjunction with PEEP to open collapsed alveoli and improve oxygenation. However, no clinical-trial data have shown that IRV improves outcomes.


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InternalMed_Harrison. continuous Positive airway Pressure (cPaP) CPAP is not a true support mode of ventilation because all ventilation occurs through the patient’s spontaneous efforts. The ventilator provides fresh gas to the breathing circuit with each inspiration and sets the circuit to a constant, operator-specified pressure. CPAP is used to assess extubation potential in patients who have been effectively weaned and who require little ventilatory support and in patients with intact respiratory system function who require an endotracheal tube for airway protection.


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InternalMed_Harrison. Nonconventional Ventilatory Strategies Several nonconventional strategies have been evaluated for their ability to improve oxygenation and reduce mortality rates in patients with advanced hypoxemic respiratory failure. These strategies include high-frequency oscillatory ventilation (HFOV), airway pressure release ventilation (APRV), extracorporeal membrane oxygenation (ECMO), and partial liquid ventilation (PLV) using perfluorocarbons. Although case reports and small uncontrolled cohort studies have shown benefit, randomized controlled trials have failed to demonstrate consistent improvements in outcome with most of these strategies. A recent randomized trial of ECMO documented positive outcomes, but the technique remains controversial because older studies failed to document positive results. Currently, these approaches should be thought of as “salvage” techniques and considered for patients with hypoxemia refractory to conventional therapy. Prone positioning of patients with


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InternalMed_Harrison. results. Currently, these approaches should be thought of as “salvage” techniques and considered for patients with hypoxemia refractory to conventional therapy. Prone positioning of patients with refractory hypoxemia has also been explored because, in theory, lying prone should improve ventilation-perfusion matching. Several randomized trials in patients with acute lung injury did not demonstrate a survival advantage with prone positioning despite demonstration of a transient physiologic benefit. The administration of nitric oxide gas, which has bronchodilator and pulmonary vasodilator effects when delivered through the airways and improves arterial oxygenation in many patients with advanced hypoxemic respiratory failure, also failed to improve outcomes in these patients with acute lung injury.


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InternalMed_Harrison. The design of new ventilator modes reflect attempts to improve patient-ventilator synchrony—a major practical issue during MV—by allowing patients to trigger the ventilator with their own effort while also incorporating flow algorithms that terminate the cycles once certain preset criteria are reached; this approach has greatly improved patient comfort. New modes of ventilation that synchronize not only the timing but also the levels of assistance to match the patient’s effort have been developed. Proportional assist ventilation (PAV) and neurally adjusted ventilatory-assist ventilation (NAV) are two modes that are designed to deliver assisted breaths through algorithms incorporating not only pressure, volume, and time but also overall respiratory resistance as well as compliance (in the case of PAV) and neural activation of the diaphragm (in the case of NAV). Although these modes enhance patient-ventilator synchrony, their practical use in the everyday management of patients


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InternalMed_Harrison. (in the case of PAV) and neural activation of the diaphragm (in the case of NAV). Although these modes enhance patient-ventilator synchrony, their practical use in the everyday management of patients undergoing MV needs further study.


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InternalMed_Harrison. Whichever mode of MV is used in acute respiratory failure, the evidence from several important controlled trials indicates that a protective ventilation approach guided by the following principles (and summarized in Fig. 323-1) is safe and offers the best chance of a good outcome: (1) Set a target tidal volume close to 6 mL/kg of ideal body weight. (2) Prevent plateau pressure (static pressure in the airway at the end of inspiration) exceeding 30 cm H2O. (3) Use the lowest possible fraction of inspired oxygen (Fio2) to keep the Sao2 at ≥90%. (4) Adjust the PEEP to maintain alveolar patency while preventing overdistention and closure/reopening. With the application of these techniques, the mortality rate among patients with acute hypoxemic respiratory failure has decreased to ~30% from close to 50% a decade ago.


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InternalMed_Harrison. Once the patient has been stabilized with respect to gas exchange, definitive therapy for the underlying process responsible for respiratory failure is initiated. Subsequent modifications in ventilator therapy must be provided in parallel with changes in the patient’s clinical status. As improvement in respiratory function is noted, the first priority is to reduce the level of mechanical ventilatory support. Patients on full ventilatory support should be monitored frequently, with the goal of switching to a mode that allows for weaning as soon as possible. Protocols and guidelines that can be applied by paramedical personnel when physicians are not readily available have proved to be of value in shortening ventilator and intensive care unit (ICU) time, with very good outcomes. Patients whose condition continues to deteriorate after ventilatory support is initiated may require increased O2, PEEP, or one of the alternative modes of ventilation.


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InternalMed_Harrison. Patients for whom mechanical ventilation has been initiated usually require sedation and analgesia to maintain an acceptable level of comfort. Often, this treatment consists of a combination of a benzodiazepine and an opiate administered intravenously. Medications commonly used for this purpose include lorazepam, midazolam, diazepam, morphine, and fentanyl. Oversedation must be avoided in the ICU because most (but not all) studies show that daily interruption of sedation in patients with improved ventilatory status results in a shorter time on 1743 the ventilator and a shorter ICU stay.


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InternalMed_Harrison. Immobilized patients receiving mechanical ventilatory support are at risk for deep venous thrombosis and decubitus ulcers. Venous thrombosis should be prevented with the use of subcutaneous heparin and/or pneumatic compression boots. Fractionated low-molecularweight heparin appears to be equally effective for this purpose. To help prevent decubitus ulcers, frequent changes in body position and the use of soft mattress overlays and air mattresses are employed. Prophylaxis against diffuse gastrointestinal mucosal injury is indicated for patients undergoing MV. Histamine-receptor (H2-receptor) antagonists, antacids, and cytoprotective agents such as sucralfate have all been used for this purpose and appear to be effective. Nutritional support by enteral feeding through either a nasogastric or an orogastric tube should be initiated and maintained whenever possible. Delayed gastric emptying is common in critically ill patients taking sedative medications but often responds to promotility


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InternalMed_Harrison. or an orogastric tube should be initiated and maintained whenever possible. Delayed gastric emptying is common in critically ill patients taking sedative medications but often responds to promotility agents such as metoclopramide. Parenteral nutrition is an alternative to enteral nutrition in patients with severe gastrointestinal pathology who need prolonged MV.


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InternalMed_Harrison. Endotracheal intubation and mechanical ventilation have direct and indirect effects on the lung and upper airways, the cardiovascular system, and the gastrointestinal system. Pulmonary complications include barotrauma, nosocomial pneumonia, oxygen toxicity, tracheal stenosis, and deconditioning of respiratory muscles. Barotrauma and volutrauma overdistend and disrupt lung tissue; may be clinically manifest by interstitial emphysema, pneumomediastinum, subcutaneous emphysema, or pneumothorax; and can result in the liberation of cytokines from overdistended tissues, further promoting tissue injury. Clinically significant pneumothorax requires tube thoracostomy. Intubated patients are at high risk for ventilator-associated pneumonia as a result of aspiration from the upper airways through small leaks around the endotracheal tube cuff; the most common organisms responsible for this condition are Pseudomonas aeruginosa, enteric gram-negative rods, and Staphylococcus aureus. Given the high


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InternalMed_Harrison. leaks around the endotracheal tube cuff; the most common organisms responsible for this condition are Pseudomonas aeruginosa, enteric gram-negative rods, and Staphylococcus aureus. Given the high associated mortality rates, early initiation of empirical antibiotics directed against likely pathogens is recommended. Hypotension resulting from elevated intrathoracic pressures with decreased venous return is almost always responsive to intravascular volume repletion. In patients who are judged to have respiratory failure on the basis of alveolar edema but in whom the cardiac or pulmonary origin of the edema is unclear, hemodynamic monitoring with a pulmonary arterial catheter may be of value in helping to clarify the cause of the edema. Gastrointestinal effects of positive-pressure ventilation include stress ulceration and mild to moderate cholestasis.


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InternalMed_Harrison. WEANING FROM MECHANICAL VENTILATION The Decision to Wean It is important to consider discontinuation of mechanical ventilation once the underlying respiratory disease begins to reverse. Although the predictive capacities of multiple clinical and physiologic variables have been explored, the consensus from a ventilatory weaning task force cites the following conditions as indicating amenability to weaning: (1) Lung injury is stable or resolving. (2) Gas exchange is adequate, with low PEEP/Fio2 (<8 cmH2O) and Fio2(<0.5).


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InternalMed_Harrison. (3) Hemodynamic variables are stable, and the patient is no longer receiving vasopressors). (4) The patient is capable of initiating spontaneous breaths. A “wean screen” based on these variables should be done at least daily. If the patient is deemed capable of beginning to wean, the recommendation is to perform a spontaneous breathing trial (SBT), whose value is supported by several randomized trials (Fig. 323-2). The SBT involves an integrated patient assessment during spontaneous breathing with little or no ventilatory support. The SBT is usually implemented with a T-piece using 1–5 cmH2O CPAP with 5–7 cmH2O or PSV from the ventilator to offset resistance from the endotracheal tube. Once it is determined that the patient can breathe spontaneously, a decision must be made about the removal of the artificial airway, which should be undertaken only when it is concluded that the patient has the ability to protect the airway, is able to cough and clear


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InternalMed_Harrison. FIGURE 323-2 Flow chart to guide the daily approach to management of patients being considered for weaning off mechanical ventilation (MV). If attempts at extubation fail, a tracheostomy should be considered. SBT, spontaneous breathing trial.


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InternalMed_Harrison. Critical Care Medicine Approach to the Patient with Shock Ronald V. Maier Shock is the clinical syndrome that results from inadequate tissue perfusion. Irrespective of cause, the hypoperfusion-induced imbal-ance between the delivery of and requirements for oxygen and substrate leads to cellular dysfunction. The cellular injury created by the inadequate delivery of oxygen and substrates also induces the production and release of damage-associated molecular patterns (DAMPs or “danger signals”) and inflammatory mediators that further compromise perfusion through functional and structural changes within the microvasculature. This leads to a vicious cycle in which impaired perfusion is responsible for cellular injury that causes maldistribution of blood flow, further compromising cellular perfusion; the latter ultimately causes multiple organ failure (MOF) and, if the process is not interrupted, leads to death. The clinical manifestations of shock are also the result, in part, of autonomic


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InternalMed_Harrison. the latter ultimately causes multiple organ failure (MOF) and, if the process is not interrupted, leads to death. The clinical manifestations of shock are also the result, in part, of autonomic neuroendocrine responses to hypoperfusion as well as the break-down in organ function induced by severe cellular dysfunction (Fig. 324-1). When very severe and/or persistent, inadequate oxygen delivery leads to irreversible cell injury, only rapid restoration of oxygen 324 SEC TIon 2 SHoCK And CARdIAC ARREST delivery can reverse the progression of the shock state. The funda- 1744 Daily wean screen (resolving disease, adequate gas exchange, stable hemodynamics, spontaneous breathing ability) Pass Assess for extubation Fail NoYes SBT Pass Fail Continue MV Treat reversible elements Repeat daily screen Extubate Consider tracheostomy secretions, and is alert enough to follow commands. In addition, other factors must be taken into account, such as the possible difficulty of replacing the tube if that


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InternalMed_Harrison. Extubate Consider tracheostomy secretions, and is alert enough to follow commands. In addition, other factors must be taken into account, such as the possible difficulty of replacing the tube if that maneuver is required. If upper airway difficulty is suspected, an evaluation using a “cuff-leak” test (assessing the presence of air movement around a deflated endotracheal tube cuff) is supported by some internists. Despite all precautions, ~10–15% of extubated patients require reintubation. Several studies suggest that NIV can be used to obviate reintubation, particularly in patients with ventilatory failure secondary to COPD exacerbation; in this setting, earlier extubation with the use of prophylactic NIV has yielded good results. The use of NIV to facilitate weaning in respiratory failure of other etiologies is not currently indicated.


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InternalMed_Harrison. Prolonged Mechanical Ventilation and Tracheostomy From 5% to 13% of patients undergoing MV will go on to require prolonged MV (>21 days). In these instances, critical care personnel must decide whether and when to perform a tracheostomy. This decision is individualized and is based on the risk and benefits of tracheostomy and prolonged intubation as well as the patient’s preferences and expected outcomes. A tracheostomy is thought to be more comfortable, to require less sedation, and to provide a more secure airway and may also reduce weaning time. However, tracheostomy carries the risk of complications, which occur in 5–40% of these procedures and include bleeding, cardiopulmonary arrest, hypoxia, structural damage, pneumothorax, pneumomediastinum, and wound infection. In patients with long-term tracheostomy, complex complications include tracheal stenosis, granulation, and erosion of the innominate artery. In general, if a patient needs MV for more than 10–14 days, a tracheostomy,


InternalMed_Harrison

InternalMed_Harrison. long-term tracheostomy, complex complications include tracheal stenosis, granulation, and erosion of the innominate artery. In general, if a patient needs MV for more than 10–14 days, a tracheostomy, planned under optimal conditions, is indicated. Whether it is completed at the bedside or as an operative procedure depends on local resources and experience. Some 5–10% of patients are deemed unable to wean in the ICU. These patients may benefit from transfer to special units where a multidisciplinary approach, including nutrition optimization, physical therapy with rehabilitation, and slower weaning methods (including SIMV with PSV), results in successful weaning rates of up to 30%. Unfortunately, close to 2% of ventilated patients may ultimately become dependent on ventilatory support to maintain life. Most of these patients remain in chronic care institutions, although some with strong social, economic, and family support may live a relatively fulfilling life with at-home ventilation.


InternalMed_Harrison

InternalMed_Harrison. mental approach to management, therefore, is to recognize overt and impending shock in a timely fashion and to intervene emergently to restore perfusion. Doing so often requires the expansion or reexpansion of intravascular blood volume. Control of any inciting pathologic process (e.g., continued hemorrhage, impairment of cardiac function, or infection) must occur simultaneously. Clinical shock is usually accompanied by hypotension (i.e., a mean arterial pressure [MAP] <60 mmHg in previously normotensive persons). Multiple classification schemes have been developed in an attempt to synthesize the seemingly dissimilar processes leading to shock. Strict adherence to a classification scheme may be difficult from a clinical standpoint because of the frequent combination of two or more causes of shock in any individual patient, but the classification shown in Table 324-1 provides a useful reference point from which to discuss and further delineate the underlying processes.


InternalMed_Harrison

InternalMed_Harrison. Normally when cardiac output falls, systemic vascular resistance rises to maintain a level of systemic pressure that is adequate for perfusion of the heart and brain at the expense of other tissues such as muscle, skin, and especially the gastrointestinal (GI) tract. Systemic vascular resistance is determined primarily by the luminal diameter of arterioles. The metabolic rates of the heart and brain are high, and their stores of energy substrate are low. These organs are critically dependent on a FIGURE 324-1 Shock-induced vicious cycle. continuous supply of oxygen and nutrients, and neither tolerates severe ischemia for more than brief periods (minutes). Autoregulation (i.e., the maintenance of blood flow over a wide range of perfusion pressures) is critical in sustaining cerebral and coronary perfusion despite significant hypotension. However, when MAP drops to ≤60 mmHg, blood flow to these organs falls, and their function deteriorates.


InternalMed_Harrison

InternalMed_Harrison. Arteriolar vascular smooth muscle has both αand β-adrenergic receptors. The α1 receptors mediate vasoconstriction, while the β2 receptors mediate vasodilation. Efferent sympathetic fibers release norepinephrine, which acts primarily on α1 receptors as one of the most fundamental compensatory responses to reduced perfusion pressure. Other constrictor substances that are increased in most forms of shock include angiotensin II, vasopressin, endothelin 1, and thromboxane A2. Both norepinephrine and epinephrine are released by the adrenal medulla, and the concentrations of these catecholamines in the bloodstream rise. Circulating vasodilators in shock include prostacyclin (prostaglandin [PG] I2), nitric oxide (NO), and, importantly, products of local metabolism such as adenosine that match flow to the tissue’s metabolic needs. The balance between these various vasoconstrictors and vasodilators influences the microcirculation and determines local perfusion.


InternalMed_Harrison

InternalMed_Harrison. Transport to cells depends on microcirculatory flow; capillary permeability; the diffusion of oxygen, carbon dioxide, nutrients, and products of metabolism through the interstitium; and the exchange of these products across cell membranes. Impairment of the micro-circulation that is central to the pathophysiologic responses in the late stages of all forms of shock results in the derangement of cellular metabolism that is ultimately responsible for organ failure. The endogenous response to mild or moderate hypovolemia is an attempt at restitution of intravascular volume through alterations in hydrostatic pressure and osmolarity. Constriction of arterioles leads to reductions in both the capillary hydrostatic pressure and the number of capillary beds perfused, thereby limiting the capillary surface area across which filtration occurs. When filtration is reduced while intravascular oncotic pressure remains constant or rises, there is net


InternalMed_Harrison

InternalMed_Harrison. ClASSIfICATIon of SHoCK reabsorption of fluid into the vascular bed, in 1745 accord with Starling’s law of capillary interstitial liquid exchange. Metabolic changes (including hyperglycemia and elevations in the products of glycolysis, lipolysis, and proteolysis) raise extracellular osmolarity, leading to an osmotic gradient that increases interstitial and intravascular volume at the expense of intracellular volume.


InternalMed_Harrison

InternalMed_Harrison. Interstitial transport of nutrients is impaired in shock, leading to a decline in intracellular high-energy phosphate stores. Mitochondrial dysfunction and uncoupling of oxidative phosphorylation are the most likely causes for decreased amounts of adenosine triphosphate (ATP). As a consequence, there is an accumulation of hydrogen ions, lactate, reactive oxygen species, and other products of anaerobic metabolism. As shock progresses, these vasodilator metabolites override vasomotor tone, causing fur ther hypotension and hypoperfusion. Dysfunction of cell membranes is thought to represent a common end-stage pathophysiologic pathway in the various forms of shock. Normal cellular transmembrane potential falls, and there is an associated increase in intracellular sodium and water, leading to cell swelling that interferes further with microvascular perfusion. In a preterminal event, homeostasis of calcium via membrane channels is lost with flooding of calcium into the cytosol and


InternalMed_Harrison

InternalMed_Harrison. to cell swelling that interferes further with microvascular perfusion. In a preterminal event, homeostasis of calcium via membrane channels is lost with flooding of calcium into the cytosol and concomitant extracellular hypocalcemia. There is also evidence for a widespread but selective apoptotic (programmed cell death) loss of cells, contributing to organ and immune failure.


InternalMed_Harrison

InternalMed_Harrison. Hypovolemia, hypotension, and hypoxia are sensed by baroreceptors and chemoreceptors that contribute to an autonomic response that attempts to restore blood volume, maintain central perfusion, and mobilize metabolic substrates. Hypotension disinhibits the vasomotor center, resulting in increased adrenergic output and reduced vagal activity. Release of norepinephrine from adrenergic neurons induces significant peripheral and splanchnic vasoconstriction, a major contributor to the maintenance of central organ perfusion, while reduced vagal activity increases the heart rate and cardiac output. Loss of vagal activity is also recognized to upregulate the innate immune inflammatory response. The effects of circulating epinephrine released by the adrenal medulla in shock are largely metabolic, causing increased glycogenolysis and gluconeogenesis and reduced pancreatic insulin release. However, epinephrine also inhibits production and release of inflammatory mediators through stimulation of


InternalMed_Harrison

InternalMed_Harrison. causing increased glycogenolysis and gluconeogenesis and reduced pancreatic insulin release. However, epinephrine also inhibits production and release of inflammatory mediators through stimulation of β-adrenergic receptors on innate immune cells.


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InternalMed_Harrison. Severe pain or other stresses cause the hypothalamic release of adrenocorticotropic hormone (ACTH). This stimulates cortisol secretion that contributes to decreased peripheral uptake of glucose and amino acids, enhances lipolysis, and increases gluconeogenesis. Increased pancreatic secretion of glucagon during stress accelerates hepatic gluconeogenesis and further elevates blood glucose concentration. These hormonal actions act synergistically to increase blood glucose for both selective tissue metabolism and the maintenance of blood volume. Many critically ill patients have recently been shown to exhibit low plasma cortisol levels and an impaired response to ACTH stimulation, which is linked to a decrease in survival. The importance of the cortisol response to stress is illustrated by the profound circulatory collapse that occurs in patients with adrenocortical insufficiency (Chap. 406).


InternalMed_Harrison

InternalMed_Harrison. Renin release is increased in response to adrenergic discharge and reduced perfusion of the juxtaglomerular apparatus in the kidney. Renin induces the formation of angiotensin I that is then converted to angiotensin II by the angiotensin converting enzyme; angiotensin II is an extremely potent vasoconstrictor and stimulator of aldosterone release by the adrenal cortex and of vasopressin by the posterior pituitary. Aldosterone contributes to the maintenance of intravascular Approach to the Patient with Shock 1746 volume by enhancing renal tubular reabsorption of sodium, resulting in the excretion of a low-volume, concentrated, sodium-free urine. Vasopressin has a direct action on vascular smooth muscle, contributing to vasoconstriction, and acts on the distal renal tubules to enhance water reabsorption.


InternalMed_Harrison

InternalMed_Harrison. Three variables—ventricular filling (preload), the resistance to ventricular ejection (afterload), and myocardial contractility—are paramount in controlling stroke volume (Chap. 265e). Cardiac output, the major determinant of tissue perfusion, is the product of stroke volume and heart rate. Hypovolemia leads to decreased ventricular preload that, in turn, reduces the stroke volume. An increase in heart rate is a useful but limited compensatory mechanism to maintain cardiac output. A shock-induced reduction in myocardial compliance is frequent, reducing ventricular end-diastolic volume and, hence, stroke volume at any given ventricular filling pressure. Restoration of intravascular volume may return stroke volume to normal but only at elevated filling pressures. Increased filling pressures stimulate release of brain natriuretic peptide (BNP) to secrete sodium and volume to relieve the pressure on the heart. Levels of BNP correlate with outcome following severe stress. In addition,


InternalMed_Harrison

InternalMed_Harrison. stimulate release of brain natriuretic peptide (BNP) to secrete sodium and volume to relieve the pressure on the heart. Levels of BNP correlate with outcome following severe stress. In addition, sepsis, ischemia, myocardial infarction (MI), severe tissue trauma, hypothermia, general anesthesia, prolonged hypotension, and acidemia may all also impair myocardial contractility and reduce the stroke volume at any given ventricular end-diastolic volume. The resistance to ventricular ejection is significantly influenced by the systemic vascular resistance, which is elevated in most forms of shock. However, resistance is decreased in the early hyperdynamic stage of septic shock or neurogenic shock (Chap. 325), thereby initially allowing the cardiac output to be maintained or elevated.


InternalMed_Harrison

InternalMed_Harrison. The venous system contains nearly two-thirds of the total circulating blood volume, most in the small veins, and serves as a dynamic reservoir for autoinfusion of blood. Active venoconstriction as a consequence of α-adrenergic activity is an important compensatory mechanism for the maintenance of venous return and, therefore, of ventricular filling during shock. By contrast, venous dilation, as occurs in neurogenic shock, reduces ventricular filling and hence stroke volume and potentially cardiac output.


InternalMed_Harrison

InternalMed_Harrison. The response of the pulmonary vascular bed to shock parallels that of the systemic vascular bed, and the relative increase in pulmonary vascular resistance, particularly in septic shock, may exceed that of the systemic vascular resistance, leading to right heart failure. Shock-induced tachypnea reduces tidal volume and increases both dead space and minute ventilation. Relative hypoxia and the subsequent tachypnea induce a respiratory alkalosis. Recumbency and involuntary restriction of ventilation secondary to pain reduce functional residual capacity and may lead to atelectasis. Shock and, in particular, resuscitation-induced reactive oxygen species (oxidant radical) generation are recognized as major causes of acute lung injury and subsequent acute respiratory distress syndrome (ARDS; Chap. 322). These disorders are characterized by noncardiogenic pulmonary edema secondary to diffuse pulmonary capillary endothelial and alveolar epithelial injury, hypoxemia, and bilateral diffuse


InternalMed_Harrison

InternalMed_Harrison. Chap. 322). These disorders are characterized by noncardiogenic pulmonary edema secondary to diffuse pulmonary capillary endothelial and alveolar epithelial injury, hypoxemia, and bilateral diffuse pulmonary infiltrates. Hypoxemia results from perfusion of underventilated and nonventilated alveoli. Loss of surfactant and lung volume in combination with increased interstitial and alveolar edema reduces lung compliance. The work of breathing and the oxygen requirements of respiratory muscles increase.


InternalMed_Harrison

InternalMed_Harrison. Acute kidney injury (Chap. 334), a serious complication of shock and hypoperfusion, occurs less frequently than heretofore because of early aggressive volume repletion. Acute tubular necrosis is now more frequently seen as a result of the interactions of shock, sepsis, the administration of nephrotoxic agents (such as aminoglycosides and angiographic contrast media), and rhabdomyolysis; the latter may be particularly severe in skeletal muscle trauma. The physiologic response of the kidney to hypoperfusion is to conserve salt and water. In addition to decreased renal blood flow, increased afferent arteriolar resistance accounts for diminished glomerular filtration rate (GFR) that, together with increased aldosterone and vasopressin, is responsible for reduced urine formation. Toxic injury causes necrosis of tubular epithelium and tubular obstruction by cellular debris with back leak of filtrate. The depletion of renal ATP stores that occurs with prolonged renal hypoperfusion


InternalMed_Harrison

InternalMed_Harrison. injury causes necrosis of tubular epithelium and tubular obstruction by cellular debris with back leak of filtrate. The depletion of renal ATP stores that occurs with prolonged renal hypoperfusion contributes to subsequent impairment of renal function.


InternalMed_Harrison

InternalMed_Harrison. During shock, there is disruption of the normal cycles of carbohydrate, lipid, and protein metabolism. Through the citric acid cycle, alanine in conjunction with lactate, which is converted from pyruvate in the periphery in the presence of oxygen deprivation, enhances the hepatic production of glucose. With reduced availability of oxygen, the breakdown of glucose to pyruvate, and ultimately lactate, represents an inefficient cycling of substrate with minimal net energy production. An elevated plasma lactate/pyruvate ratio is preferable to lactate alone as a measure of anaerobic metabolism and reflects inadequate tissue perfusion. Decreased clearance of exogenous triglycerides coupled with increased hepatic lipogenesis causes a significant rise in serum triglyceride concentrations. There is increased protein catabolism as energy substrate, a negative nitrogen balance, and, if the process is prolonged, severe muscle wasting.


InternalMed_Harrison

InternalMed_Harrison. Activation of an extensive network of proinflammatory mediator pathways by the innate immune system plays a significant role in the progression of shock and contributes importantly to the development of multiple organ injury, multiple organ dysfunction (MOD), and MOF (Fig. 324-2). In those surviving the acute insult, there is a prolonged endogenous counterregulatory response to “turn off” or balance the excessive proinflammatory response. If balance is restored, the patient does well. If the response is excessive, adaptive immunity is suppressed and the patient is highly susceptible to secondary nosocomial infections, which may then drive the inflammatory response and lead to delayed MOF.


InternalMed_Harrison

InternalMed_Harrison. Multiple humoral mediators are activated during shock and tissue injury. The complement cascade, activated through both the classic and alternate pathways, generates the anaphylatoxins C3a and C5a (Chap. 372e). Direct complement fixation to injured tissues can progress to the C5-C9 attack complex, causing further cell damage. Activation of the coagulation cascade (Chap. 141) causes microvascular thrombosis, with subsequent fibrinolysis leading to repeated episodes of ischemia and reperfusion. Components of the coagulation system (e.g., thrombin) are potent proinflammatory mediators that cause expression of adhesion molecules on endothelial cells and activation of neutrophils, leading to microvascular injury. Coagulation also activates the kallikrein-kininogen cascade, contributing to hypo-tension.


InternalMed_Harrison

InternalMed_Harrison. Eicosanoids are vasoactive and immunomodulatory products of arachidonic acid metabolism that include cyclooxygenase-derived prostaglandins (PGs) and thromboxane A2, as well as lipoxygenasederived leukotrienes and lipoxins. Thromboxane A2 is a potent vasoconstrictor that contributes to the pulmonary hypertension and acute tubular necrosis of shock. PGI2 and PGE2 are potent vasodilators that enhance capillary permeability and edema formation. The cysteinyl leukotrienes LTC4 and LTD4 are pivotal mediators of the vascular sequelae of anaphylaxis, as well as of shock states resulting from sepsis or tissue injury. LTB4 is a potent neutrophil chemoattractant and secretagogue that stimulates the formation of reactive oxygen species. Platelet-activating factor, an ether-linked, arachidonyl-containing phospholipid mediator, causes pulmonary vasoconstriction, bronchoconstriction, systemic vasodilation, increased capillary permeability, and the priming of macrophages and neutrophils to produce


InternalMed_Harrison

InternalMed_Harrison. phospholipid mediator, causes pulmonary vasoconstriction, bronchoconstriction, systemic vasodilation, increased capillary permeability, and the priming of macrophages and neutrophils to produce enhanced levels of inflammatory mediators.


InternalMed_Harrison

InternalMed_Harrison. Tumor necrosis factor α (TNF-α), produced by activated macrophages, reproduces many components of the shock state, including • TNF-˜, IL-1°, IL-6, IL-12, IL-18, PGE2, TGF-° Lymphocytes • TH1˙TH2 • ˛IL-2, IL-2R, IFN-ˆ, TNF-°• ˝IL-4, IL-10, IL-5, IL-13 Coagulation/ Complement ˝C3a ˝C5a ˝Thrombin ˝D-Dimers ˛Antithrombin III (AT III) ˛Activated protein C (APC) FIGURE 324-2 A schematic of the host immunoinflammatory response to shock. IFN, interferon; IL, interleukin; PG, prostaglandin; TGF, tumor growth factor; TNF, tumor necrosis factor.


InternalMed_Harrison

InternalMed_Harrison. hypotension, lactic acidosis, and respiratory failure. Interleukin 1β (IL-1β), originally defined as “endogenous pyrogen” and produced by tissue-fixed macrophages, is critical to the inflammatory response. Both are significantly elevated immediately following trauma and shock. IL-6, also produced predominantly by the macrophage, has a slightly delayed peak response but is the best single predictor of prolonged recovery and development of MOF following shock. Chemokines such as IL-8 are potent neutrophil chemoattractants and activators that upregulate adhesion molecules on the neutrophil to enhance aggregation, adherence, and damage to the vascular endothelium. While the endothelium normally produces low levels of NO, the inflammatory response stimulates the inducible isoform of NO synthase (iNOS), which is overexpressed and produces toxic nitroxyland oxygen-derived free radicals that contribute to the hyperdynamic cardiovascular response and tissue injury in sepsis.


InternalMed_Harrison

InternalMed_Harrison. Multiple inflammatory cells, including neutrophils, macrophages, and platelets, are major contributors to inflammation-induced injury. Margination of activated neutrophils in the microcirculation is a common pathologic finding in shock, causing secondary injury due to the release of toxic oxygen radicals, lipases (primarily PLA2), and proteases. Release of high levels of reactive oxygen intermediates/species (ROI/ROS) rapidly consumes endogenous essential antioxidants and generates diffuse oxygen radical damage. Newer efforts to control ischemia/reperfusion injury include treatment with carbon monoxide, hydrogen sulfide, or other agents to reduce oxidant stress. Tissue-fixed macrophages produce virtually all major mediators of the inflammatory response and orchestrate the progression and duration of the inflammatory response. A major source of activation of the monocyte/macrophage is through the highly conserved membrane toll-like receptors (TLRs) that recognize DAMPs, such as HMGB-1,


InternalMed_Harrison

InternalMed_Harrison. of the inflammatory response. A major source of activation of the monocyte/macrophage is through the highly conserved membrane toll-like receptors (TLRs) that recognize DAMPs, such as HMGB-1, and pathogen-associated molecular patterns (PAMPs), such as endotoxins released following tissue injury, and by pathogenic microbial organisms, respectively. TLRs also appear important in the chronic inflammation seen in Crohn’s disease, ulcerative colitis, and transplant rejection. The variability in individual responses is a genetic predisposition that, in part, is due to variants in genetic sequences affecting the function and production of various inflammatory mediators.


InternalMed_Harrison

InternalMed_Harrison. Patients in shock require care in an intensive care unit (ICU). Careful and continuous assessment of the physiologic status is necessary. Arterial pressure through an indwelling line, pulse, and respiratory rate should be monitored continuously; a Foley catheter should be inserted to follow urine flow; and mental status should be assessed frequently. Sedated patients should be allowed to awaken (“drug holiday”) daily to assess their neurologic status and to shorten duration of ventilator support.


InternalMed_Harrison

InternalMed_Harrison. There is ongoing debate as to the indications for using the flow-directed pulmonary artery catheter (PAC; Swan-Ganz catheter) in the ICU. A recent Cochrane analysis showed that the use of a PAC did not alter mortality, length of stay, or cost for adult ICU patients. Most patients in the ICU can be safely managed without the use of a PAC. However, in shock with significant ongoing blood loss, fluid shifts, and underlying cardiac dysfunction, a PAC may be useful. The PAC is placed percutaneously via the subclavian or jugular vein through the central venous circulation and right heart into the pulmonary artery. There are ports both proximal in the right atrium and distal in the pulmonary artery to provide access for infusions and for cardiac output measurements. Right atrial and pulmonary artery pressures (PAPs) are measured, and the pulmonary capillary wedge pressure (PCWP) serves as an approximation of the left atrial pressure. Normal hemodynamic parameters and their derivation are


InternalMed_Harrison

InternalMed_Harrison. artery pressures (PAPs) are measured, and the pulmonary capillary wedge pressure (PCWP) serves as an approximation of the left atrial pressure. Normal hemodynamic parameters and their derivation are summarized in Table 272-2 and Table 324-2.


InternalMed_Harrison

InternalMed_Harrison. Cardiac output is determined by the thermodilution technique, and high-resolution thermistors can also be used to determine right ventricular end-diastolic volume to monitor further the response of the right heart to fluid resuscitation. A PAC with an oximeter port offers the additional advantage of online monitoring of the mixed venous oxygen saturation, an important index of overall tissue perfusion. Systemic and pulmonary vascular resistances are calculated as the ratio of the pressure drop across these vascular beds to the cardiac output (Chap. 272). Determinations of oxygen content in arterial and venous blood, together with cardiac output and hemoglobin concentration, allow calculation of oxygen delivery, Approach to the Patient with Shock Cardiac index (CI) CO/BSA 2.6–4.2 (L/min)/m2 Left ventricular stroke SV(MAP – PCWP) × 60–80 g-m/beat work (LVSW) 0.0136


InternalMed_Harrison

InternalMed_Harrison. Approach to the Patient with Shock Cardiac index (CI) CO/BSA 2.6–4.2 (L/min)/m2 Left ventricular stroke SV(MAP – PCWP) × 60–80 g-m/beat work (LVSW) 0.0136 Abbreviations: BSA, body surface area; HR, heart rate; MAP, mean arterial pressure; PAPm, pulmonary artery pressure—mean; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure. oxygen consumption, and oxygen-extraction ratio (Table 324-3). The hemodynamic patterns associated with the various forms of shock are shown in Table 324-4.


InternalMed_Harrison

InternalMed_Harrison. In resuscitation from shock, it is critical to restore tissue perfusion and optimize oxygen delivery, hemodynamics, and cardiac function rapidly. A reasonable goal of therapy is to achieve a normal mixed venous oxygen-saturation and arteriovenous oxygen-extraction ratio. To enhance oxygen delivery, red cell mass, arterial oxygen saturation, and cardiac output may be augmented singly or simultaneously. An increase in oxygen delivery not accompanied by an increase in oxygen consumption implies that oxygen availability is adequate and that oxygen consumption is not flow dependent. Conversely, an elevation of oxygen consumption with increased delivery implies that the oxygen supply was inadequate. However, cautious interpretation is required due to the link among increased oxygen delivery, cardiac work, and oxygen consumption. A reduction in systemic vascular resistance accompanying an increase in cardiac output indicates that compensatory vasoconstriction is reversing due to improved


InternalMed_Harrison

InternalMed_Harrison. cardiac work, and oxygen consumption. A reduction in systemic vascular resistance accompanying an increase in cardiac output indicates that compensatory vasoconstriction is reversing due to improved tissue perfusion. The determination of stepwise expansion of blood volume on cardiac performance allows identification of the optimum preload (Starling’s law). An algorithm for the resuscitation of the patient in shock is shown in Fig. 324-3.


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InternalMed_Harrison. 1.39 mL/g of hemoglobin Plasma O2 concentration PO2 × 0.0031 Arterial O2 concentration 1.39 SaO2 + 0.0031 PaO2 20 vol% (CaO2) Venous O2 concentration 1.39 SvO2 + 0.0031 PvO2 15.5 vol% (CvO2) Arteriovenous O2 1.39 (SaO2 – SvO2) + 3.5 vol% difference (CaO2 – CvO2) 0.0031 (PaO2 – PvO2) 1.39 SaO2 × CO × 10 1.39 (SaO2 – SvO2) × CO × 10 Abbreviations: BSA, body surface area; CO, cardiac output; PO2, partial pressure of oxygen; PaO2, partial pressure of oxygen in arterial blood; PvO2, partial pressure of oxygen in venous blood; SaO2, saturation of hemoglobin with oxygen in arterial blood; SvO2, saturation of hemoglobin with oxygen in venous blood. CVP and Cardiac Systemic Vascular Venous O2 Type of Shock PCWP Output Resistance Saturation Hyperdynamic ↓↑↑↓ ↑ Hypodynamic ↓↑↓↑ ↓↑ Traumatic ↓↓↑↑↓ ↓ Neurogenic ↓↓↓ ↓ Hypoadrenal ↓↓ =↓↓ Abbreviations: CVP, central venous pressure; PCWP, pulmonary capillary wedge pressure.


InternalMed_Harrison

InternalMed_Harrison. This most common form of shock results either from the loss of red blood cell mass and plasma from hemorrhage or from the loss of plasma volume alone due to extravascular fluid sequestration or GI, urinary, and insensible losses. The signs and symptoms of nonhemorrhagic hypovolemic shock are the same as those of hemorrhagic shock, although they may have a more insidious onset. The normal physiologic response to hypovolemia is to maintain perfusion of the brain and heart while attempting to restore an effective circulating blood volume. There is an increase in sympathetic activity, hyperventilation, collapse of venous capacitance vessels, release of stress hormones, and an attempt to replace the loss of intravascular volume through the recruitment of interstitial and intracellular fluid and by reduction of urine output.


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InternalMed_Harrison. Mild hypovolemia (≤20% of the blood volume) generates mild tachycardia but relatively few external signs, especially in a supine young patient (Table 324-5). With moderate hypovolemia (~20–40% of the blood volume), the patient becomes increasingly anxious and tachycardic; although normal blood pressure may be maintained in the supine position, there may be significant postural hypotension and tachycardia. If hypovolemia is severe (≥40% of the blood volume), the classic signs of shock appear; the blood pressure declines and becomes unstable even in the supine position, and the patient develops marked tachycardia, oliguria, and agitation or confusion. Perfusion of the central nervous system is well maintained until shock becomes severe. Hence, mental obtundation is an ominous clinical sign. The transition from mild to severe hypovolemic shock can be insidious or extremely rapid. If severe shock is not reversed rapidly, especially in elderly patients and those with comorbid illnesses,


InternalMed_Harrison

InternalMed_Harrison. The transition from mild to severe hypovolemic shock can be insidious or extremely rapid. If severe shock is not reversed rapidly, especially in elderly patients and those with comorbid illnesses, death is imminent. A very narrow time frame separates the derangements found in severe shock that can be reversed with aggressive resuscitation from those of progressive decompensation and irreversible cell injury.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis Hypovolemic shock is readily diagnosed when there are signs of hemodynamic instability and the source of volume loss is obvious. The diagnosis is more difficult when the source of blood loss is occult, as into the GI tract, or when plasma volume alone is depleted. Even after acute hemorrhage, hemoglobin and hematocrit values do not change until compensatory fluid shifts have occurred or exogenous fluid is administered. Thus, an initial normal hematocrit does not disprove the presence of significant blood loss. Plasma losses cause hemoconcentration, and free water loss leads to hypernatremia. These findings should suggest the presence of hypovolemia.


InternalMed_Harrison

InternalMed_Harrison. It is essential to distinguish between hypovolemic and cardiogenic shock (Chap. 326) because, although both may respond to volume initially, definitive therapy differs significantly. Both forms are associated with a reduced cardiac output and a compensatory sympathetic mediated response characterized by tachycardia and elevated systemic vascular resistance. However, the findings in cardiogenic shock of jugular venous distention, rales, and an S3 gallop distinguish it from hypovolemic shock and signify that ongoing volume expansion is undesirable and may cause further organ dysfunction. CI <3.5; PCWP <15Administer crystalloid+/– blood PCWP >15, Hct >30 CI <3.5; 15< PCWP <20CI <3.5; PCWP >20 Administer 500 mL crystalloidboluses until preload maximal CI • Inotrope as indicated(Starling’s curve)• Consider ECHO


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InternalMed_Harrison. CI <3.5; 15< PCWP <20CI <3.5; PCWP >20 Administer 500 mL crystalloidboluses until preload maximal CI • Inotrope as indicated(Starling’s curve)• Consider ECHO FIGURE 324-3 An algorithm for the resuscitation of the patient in shock. *Monitor SvO2, SVRI, and RVEDVI as additional markers of correction for perfusion and hypovolemia. Consider age-adjusted CI. CI, cardiac index in (L/min) per m2; CVP, central venous pressure; ECHO, echocardiogram; Hct, hematocrit; HR, heart rate; PAC, pulmonary artery catheter; PCWP, pulmonary capillary wedge pressure in mmHg; RVEDVI, right ventricular end-diastolic volume index; SBP, systolic blood pressure; SvO2, saturation of hemoglobin with O2 in venous blood; SVRI, systemic vascular resistance index; VS, vital signs; W/U, workup.


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InternalMed_Harrison. Initial resuscitation requires rapid reexpansion of the circulating intravascular blood volume along with interventions to control ongoing losses. In accordance with Starling’s law (Chap. 265e), stroke volume and cardiac output rise with the increase in preload. After resuscitation, the compliance of the ventricles may remain reduced due to increased interstitial fluid in the myocardium. Therefore, elevated filling pressures are frequently required to maintain adequate ventricular performance.


InternalMed_Harrison

InternalMed_Harrison. Volume resuscitation is initiated with the rapid infusion of either isotonic saline (although care must be taken to avoid hyperchloremic acidosis from loss of bicarbonate buffering capacity and replacement with excess chloride) or a balanced salt solution such as Ringer’s lactate (being cognizant of the presence of potassium and potential renal dysfunction) through large-bore intravenous lines. Data, particularly on severe traumatic brain injury (TBI), regarding benefits of small volumes of hypertonic saline that more rapidly restore blood pressure are variable but tend to show improved survival thought to be linked to immunomodulation. No distinct benefit from the use of colloid has been demonstrated, and in trauma patients, it is associated with a higher mortality particularly in patients with TBI. The infusion of 2–3 L of salt solution over 20–30 min should restore normal hemodynamic parameters. Continued hemodynamic instability implies that shock has not been reversed and/or there


InternalMed_Harrison

InternalMed_Harrison. with TBI. The infusion of 2–3 L of salt solution over 20–30 min should restore normal hemodynamic parameters. Continued hemodynamic instability implies that shock has not been reversed and/or there are significant ongoing blood or other volume losses. Continuing acute blood loss with hemoglobin concentrations declining to ≤100 g/L (10 g/dL) should initiate blood transfusion preferably as fully cross-matched, recently banked (<14 days old) blood. Resuscitated patients are often coagulopathic due


InternalMed_Harrison

InternalMed_Harrison. Approach to the Patient with Shock Same, plus: Tachycardia Tachypnea Oliguria Postural


InternalMed_Harrison

InternalMed_Harrison. Same, plus: 1750 to deficient clotting factors in crystalloids and banked packed red blood cells (PRBCs). Early administration of component therapy during massive transfusion (fresh-frozen plasma [FFP] and platelets) approaching a 1:1 ratio of PRBC/FFP appears to improve survival. In extreme emergencies, type-specific or O-negative packed red cells may be transfused. Following severe and/or prolonged hypovolemia, inotropic support with norepinephrine, vasopressin, or dopamine may be required to maintain adequate ventricular performance but only after blood volume has been restored. Increases in peripheral vasoconstriction with inadequate resuscitation lead to tissue loss and organ failure. Once hemorrhage is controlled and the patient has stabilized, blood transfusions should not be continued unless the hemoglobin is <~7 g/dL. Studies have demonstrated an increased survival in patients treated with this restrictive blood transfusion protocol. Successful resuscitation also requires


InternalMed_Harrison

InternalMed_Harrison. unless the hemoglobin is <~7 g/dL. Studies have demonstrated an increased survival in patients treated with this restrictive blood transfusion protocol. Successful resuscitation also requires support of respiratory function. Supplemental oxygen should always be provided, and endotracheal intubation may be necessary to maintain arterial oxygenation. Following resuscitation from isolated hemorrhagic shock, end-organ damage is frequently less than following septic or traumatic shock. This may be due to the absence of massive activation of the inflammatory innate immune response and consequent nonspecific organ injury and failure.


InternalMed_Harrison

InternalMed_Harrison. Shock following trauma is, in large measure, due to hemorrhage. However, even when hemorrhage has been controlled, patients can continue to suffer loss of plasma volume into the interstitium of injured tissues. These fluid losses are compounded by injury-induced inflammatory responses, which contribute to the secondary microcirculatory injury. Proinflammatory mediators are induced by DAMPs released from injured tissue and are recognized by the highly conserved membrane receptors of the TLR family (see “Inflammatory Responses” above). These receptors on cells of the innate immune system, particularly the circulating monocyte, tissue-fixed macrophage, and dendritic cell, are potent activators of an excessive proinflammatory phenotype in response to cellular injury. This causes secondary tissue injury and maldistribution of blood flow, intensifying tissue ischemia and leading to multiple organ system failure. In addition, direct structural injury to the heart, chest, or head can also


InternalMed_Harrison

InternalMed_Harrison. tissue injury and maldistribution of blood flow, intensifying tissue ischemia and leading to multiple organ system failure. In addition, direct structural injury to the heart, chest, or head can also contribute to shock. For example, pericardial tamponade or tension pneumothorax impairs ventricular filling, whereas myocardial contusion depresses myocardial contractility.


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InternalMed_Harrison. Inability of the patient to maintain a systolic blood pressure ≥90 mmHg after trauma-induced hypovolemia is associated with a mortality rate up to ~50%. To prevent this decompensation of homeostatic mechanisms, therapy must be promptly administered. The initial management of the seriously injured patient requires attention to the “ABCs” of resuscitation: assurance of an airway (A), adequate ventilation (breathing, B), and establishment of an adequate blood volume to support the circulation (C). Control of ongoing hemorrhage requires immediate attention. Early stabilization of fractures, debridement of devitalized or contaminated tissues, and evacuation of hematomata all reduce the subsequent inflammatory response to the initial insult and minimize damaged tissue release of DAMPs and subsequent diffuse organ injury. Supplementation of depleted endogenous antioxidants also reduces subsequent organ failure and mortality. See Chap. 326.


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InternalMed_Harrison. See Chap. 326. With extrinsic compression, the heart and surrounding structures are less compliant, and therefore, normal filling pressures generate inadequate diastolic filling and stroke volume. Blood or fluid within the poorly distensible pericardial sac may cause tamponade (Chap. 288). Any cause of increased intrathoracic pressure, such as tension pneumothorax, herniation of abdominal viscera through a diaphragmatic hernia, or excessive positive-pressure ventilation to support pulmonary function, can also initiate compressive cardiogenic shock while simultaneously impeding venous return and preload. Although initially responsive to increased filling pressures produced by volume expansion, as compression increases, cardiogenic shock recurs. The window of opportunity gained by volume loading may be very brief until irreversible shock recurs. Diagnosis and intervention must occur urgently.


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InternalMed_Harrison. The diagnosis of compressive cardiogenic shock is most frequently based on clinical findings, the chest radiograph, and an echocardiogram. The diagnosis of compressive cardiac shock may be more difficult to establish in the setting of trauma when hypovolemia and cardiac compression are present simultaneously. The classic findings of pericardial tamponade include the triad of hypotension, neck vein distention, and muffled heart sounds (Chap. 288). Pulsus paradoxus (i.e., an inspiratory reduction in systolic pressure >10 mmHg) may also be noted. The diagnosis is confirmed by echocardiography, and treatment consists of immediate pericardiocentesis or the creation of an open subxiphoid pericardial window. A tension pneumothorax produces ipsilateral decreased breath sounds, tracheal deviation away from the affected thorax, and jugular venous distention. Radiographic findings include increased intrathoracic volume, depression of the diaphragm of the affected hemithorax, and shifting of the


InternalMed_Harrison

InternalMed_Harrison. away from the affected thorax, and jugular venous distention. Radiographic findings include increased intrathoracic volume, depression of the diaphragm of the affected hemithorax, and shifting of the mediastinum to the contralateral side. Chest decompression must be carried out immediately and, ideally, should occur based on clinical findings rather than awaiting a chest radiograph. Release of air and restoration of normal cardiovascular dynamics are both diagnostic and therapeutic.


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InternalMed_Harrison. See Chap. 325. Interruption of sympathetic vasomotor input after a high cervical spinal cord injury, inadvertent cephalad migration of spinal anesthesia, or devastating head injury may result in neurogenic shock. In addition to arteriolar dilation, venodilation causes pooling in the venous system, which decreases venous return and cardiac output. The extremities are often warm, in contrast to the usual sympathetic vasoconstrictioninduced coolness in hypovolemic or cardiogenic shock. Treatment involves a simultaneous approach to the relative hypovolemia and to the loss of vasomotor tone. Excessive volumes of fluid may be required to restore normal hemodynamics if given alone. Once hemorrhage has been ruled out, norepinephrine or a pure α-adrenergic agent (phenylephrine) may be necessary to augment vascular resistance and maintain an adequate MAP.


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InternalMed_Harrison. (See also Chap. 406) The normal host response to the stress of illness, operation, or trauma requires that the adrenal glands hypersecrete cortisol in excess of that normally required. Hypoadrenal shock occurs in settings in which unrecognized adrenal insufficiency complicates the host response to the stress induced by acute illness or major surgery. Adrenocortical insufficiency may occur as a consequence of the chronic administration of high doses of exogenous glucocorticoids. In addition, recent studies have shown that critical illness, including trauma and sepsis, may also induce a relative hypoadrenal state. Other, less common causes include adrenal insufficiency secondary to idiopathic atrophy, use of etomidate for intubation, tuberculosis, metastatic disease, bilateral hemorrhage, and amyloidosis. The shock produced by adrenal insufficiency is characterized by loss of homeostasis with reductions in systemic vascular resistance, hypovolemia, and reduced cardiac output. The


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InternalMed_Harrison. and amyloidosis. The shock produced by adrenal insufficiency is characterized by loss of homeostasis with reductions in systemic vascular resistance, hypovolemia, and reduced cardiac output. The diagnosis of adrenal insufficiency may be established by means of an ACTH stimulation test.


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InternalMed_Harrison. In the persistently hemodynamically unstable patient, dexamethasone sodium phosphate, 4 mg, should be given intravenously. This agent is preferred if empiric therapy is required because, unlike hydrocortisone, it does not interfere with the ACTH stimulation test. If the diagnosis of absolute or relative adrenal insufficiency is established as shown by nonresponse to corticotropin stimulation (cortisol ≤9 μg/dL change after stimulation), the patient has a reduced risk of death if treated with hydrocortisone, 100 mg every 6–8 h, and tapered as the patient achieves hemodynamic stability. Simultaneous volume resuscitation and pressor support are required. The need for simultaneous mineralocoid is unclear.


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InternalMed_Harrison. The sympathomimetic amines dobutamine, dopamine, and nor-epinephrine are widely used in the treatment of all forms of shock. Dobutamine is inotropic with simultaneous afterload reduction, thus minimizing cardiac-oxygen consumption increases as cardiac output increases. Dopamine is an inotropic and chronotropic agent that also supports vascular resistance in those whose blood pressure will not tolerate peripheral vascular dilation. Norepinephrine primarily supports blood pressure through vasoconstriction and increases myocardial oxygen consumption while placing marginally perfused tissues, such as extremities and splanchnic organs, at risk for ischemia or necrosis, but it is also inotropic without significant chronotropy. Argininevasopressin (antidiuretic hormone) is being used increasingly to increase afterload and may better protect vital organ blood flow and prevent pathologic vasodilation.


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InternalMed_Harrison. Hypothermia is a frequent adverse consequence of massive volume resuscitation (Chap. 478e). The infusion of large volumes of refrigerated blood products and room temperature crystalloid solutions can rapidly drop core temperatures if fluid is not run through warming devices. Hypothermia may depress cardiac contractility and thereby further impair cardiac output and oxygen delivery/utilization. Hypothermia, particularly temperatures <35°C (<95°F), directly impairs the coagulation pathway, sometimes causing a significant coagulopathy. Rapid rewarming to >35°C (>95°F) significantly decreases the requirement for blood products and produces an improvement in cardiac function. The most effective method for rewarming is endovascular countercurrent warmers through femoral vein cannulation. This process does not require a pump and can rewarm a patient from 30° to 35°C (86° to and tachycardia are cardinal signs of the systemic response. To date, attempts to devise precise definitions for the


InternalMed_Harrison

InternalMed_Harrison. process does not require a pump and can rewarm a patient from 30° to 35°C (86° to and tachycardia are cardinal signs of the systemic response. To date, attempts to devise precise definitions for the harmful systemic reaction to infection (“sepsis”) have not resulted in a clinically useful level of specificity, in part because the systemic responses to infection, trauma, and other major stresses can be so similar. In general, when an infectious etiology is proven or strongly suspected and the response results in hypofunction of uninfected organs, the term sepsis (or severe sepsis) should be used. Septic shock refers to sepsis accompanied by hypotension that cannot be corrected by the infusion of fluids.


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InternalMed_Harrison. Bacteremia Presence of bacteria in blood, as evidenced by positive blood cultures Signs of possibly harmful systemic Two or more of the following condi response tions: (1) fever (oral temperature >38°C [>100.4°F]) or hypothermia (<36°C [<96.8°F]); (2) tachypnea (>24 breaths/min); (3) tachycardia (heart rate >90 beats/min); (4) leukocytosis (>12,000/μL), leukopenia (<4000/μL), or >10% bands Sepsis (or severe sepsis) The harmful host response to infection; systemic response to proven or suspected infection plus some degree of organ hypofunction, i.e.: 1. Cardiovascular: Arterial systolic blood pressure ≤90 mmHg or mean arterial pressure ≤70 mmHg that responds to administration of IV fluid 2. Renal: Urine output <0.5 mL/kg per hour for 1 h despite adequate fluid resuscitation 3. Respiratory: PaO2/FIO2 ≤250 or, if the lung is the only dysfunctional organ, ≤200 4.


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InternalMed_Harrison. Renal: Urine output <0.5 mL/kg per hour for 1 h despite adequate fluid resuscitation 3. Respiratory: PaO2/FIO2 ≤250 or, if the lung is the only dysfunctional organ, ≤200 4. Hematologic: Platelet count <80,000/μL or 50% decrease in platelet count from highest value recorded over previous 3 days 5. Unexplained metabolic acidosis: A pH ≤7.30 or a base deficit ≥5.0 mEq/L and a plasma lactate level >1.5 times upper limit of normal for reporting lab Septic shock Sepsis with hypotension (arterial blood pressure <90 mmHg systolic, or 40 mmHg less than patient’s normal blood pressure) for at least 1 h despite adequate fluid resuscitationa Need for vasopressors to maintain systolic blood pressure ≥90 mmHg or mean arterial pressure ≥70 mmHg Refractory septic shock Septic shock that lasts for >1 h and does not respond to fluid or pressor administration aFluid resuscitation is considered adequate when the pulmonary artery wedge pressure is ≥12 mmHg or the central venous pressure is ≥8 mmHg.


InternalMed_Harrison

InternalMed_Harrison. The systemic response to any class of microorganism can be harmful. Microbial invasion of the bloodstream is not essential because local inflammation can also elicit distant organ dysfunction and hypotension. In fact, blood cultures yield bacteria or fungi in only ~20–40% of cases of severe sepsis and 40–70% of cases of septic shock. In a prevalence study of 14,414 patients in intensive care units (ICUs) from 75 countries in 2007, 51% of patients were considered infected. Respiratory infection was most common (64%). Microbiologic results were positive in 70% of individuals considered infected; of the isolates, 62% were gram-negative bacteria (Pseudomonas species and Escherichia coli were most common), 47% were gram-positive bacteria (Staphylococcus aureus was most common), and 19% were fungi (Candida species). This distribution is similar to that reported a decade earlier from eight academic centers in the United States (Table 325-2). In patients whose blood cultures are negative, the


InternalMed_Harrison

InternalMed_Harrison. (Candida species). This distribution is similar to that reported a decade earlier from eight academic centers in the United States (Table 325-2). In patients whose blood cultures are negative, the etiologic agent is often established by culture or microscopic examination of infected material from a local site; specific identification of microbial DNA or RNA in blood or tissue samples is also used. In some case series, a majority of patients with a clinical picture of severe sepsis or septic shock have had negative microbiologic data.


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InternalMed_Harrison. 95°F) in 30–60 min. Severe Sepsis and Septic Shock Robert S. Munford DEFINITIONS (Table 325-1) Animals mount both local and systemic responses to microbes that traverse their epithelial barriers and enter underlying tissues. Fever or hypothermia, leukocytosis or leukopenia, tachypnea, 325 a Enterobacteriaceae, pseudomonads, Haemophilus spp., other gram-negative bacteria. b Staphylococcus aureus, coagulase-negative staphylococci, enterococci, Streptococcus pneumoniae, other streptococci, other gram-positive bacteria. cSuch as Neisseria meningitidis, S. pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes. Source: Adapted from KE Sands et al: JAMA 278:234, 1997.


InternalMed_Harrison

InternalMed_Harrison. Severe sepsis is a contributing factor in >200,000 deaths per year in the United States. The incidence of severe sepsis and septic shock has increased over the past 30 years, and the annual number of cases is now >750,000 (~3 per 1000 population). Approximately two-thirds of the cases occur in patients with significant underlying illness. Sepsis-related incidence and mortality rates increase with age and preexisting comorbidity. The rising incidence of severe sepsis in the United States has been attributable to the aging of the population, the increasing longevity of patients with chronic diseases, and the relatively high frequency with which sepsis has occurred in patients with AIDS. The widespread use of immunosuppressive drugs, indwelling catheters, and mechanical devices has also played a role. In the aforementioned international ICU prevalence study, the case–fatality rate among infected patients (33%) greatly exceeded that among uninfected patients (15%).


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InternalMed_Harrison. Invasive bacterial infections are prominent causes of death around the world, particularly among young children. In sub-Saharan Africa, for example, careful screening for positive blood cultures found that community-acquired bacteremia accounted for at least one-fourth of deaths of children >1 year of age. Nontyphoidal Salmonella species, Streptococcus pneumoniae, Haemophilus influenzae, and E. coli were the most commonly isolated bacteria. Bacteremic children often had HIV infection or were severely malnourished.


InternalMed_Harrison

InternalMed_Harrison. Sepsis is triggered most often by bacteria or fungi that do not ordinarily cause systemic disease in immunocompetent hosts (Table 325-2). To survive within the human body, these microbes often exploit acquired deficiencies in host defenses, indwelling catheters or other foreign matter, or obstructed fluid drainage conduits. Microbial pathogens, in contrast, can circumvent innate defenses because they (1) lack molecules that can be recognized by host receptors (see below) or (2) elaborate toxins or other virulence factors. In both cases, the body can mount a vigorous inflammatory reaction that results in sepsis or septic shock yet fails to kill the invaders. The septic response may also be induced by microbial exotoxins that act as superantigens (e.g., toxic shock syndrome toxin 1; Chap. 172) as well as by many pathogenic viruses.


InternalMed_Harrison

InternalMed_Harrison. Host Mechanisms for Sensing Microbes Animals have exquisitely sensitive mechanisms for recognizing and responding to certain highly conserved microbial molecules. Recognition of the lipid A moiety of lipopolysaccharide (LPS, also called endotoxin; Chap. 145e) is the best-studied example. A host protein (LPS-binding protein) binds lipid A and transfers the LPS to CD14 on the surfaces of monocytes, macrophages, and neutrophils. LPS then is passed to MD-2, a small receptor protein that is bound to Toll-like receptor (TLR) 4 to form a molecular complex that transduces the LPS recognition signal to the interior of the cell. This signal rapidly triggers the production and release of mediators, such as tumor necrosis factor (TNF; see below), that amplify the LPS signal and transmit it to other cells and tissues. Bacterial peptidoglycan and lipopeptides elicit responses in animals that are generally similar to those induced by LPS, although they interact with different TLRs. Having numerous


InternalMed_Harrison

InternalMed_Harrison. cells and tissues. Bacterial peptidoglycan and lipopeptides elicit responses in animals that are generally similar to those induced by LPS, although they interact with different TLRs. Having numerous TLR-based receptor complexes (10 different TLRs have been identified in humans) allows animals to recognize many conserved microbial molecules; others include lipopeptides (TLR2/1, TLR2/6), flagellin (TLR5), undermethylated DNA CpG sequences (TLR9), single-stranded RNA (TLR7, 8), and double-stranded RNA (TLR3). The ability of some TLRs to serve as receptors for host ligands (e.g., hyaluronans, heparan sulfate, saturated fatty acids, high-mobility group box 1) raises the possibility that they also play a role in producing noninfectious sepsis-like states. Other host pattern-recognition proteins that are important for sensing microbes include the intracellular NOD1 and NOD2 proteins, which recognize discrete fragments of bacterial peptidoglycan; the inflammasome, which senses some pathogens


InternalMed_Harrison

InternalMed_Harrison. that are important for sensing microbes include the intracellular NOD1 and NOD2 proteins, which recognize discrete fragments of bacterial peptidoglycan; the inflammasome, which senses some pathogens and produces interleukin (IL) 1β and IL-18; early complement components (principally in the alternative pathway); mannose-binding lectin and C-reactive protein, which activate the classic complement pathway; and Dectin-1 and complement receptor 3, which sense fungal β-glucan.


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InternalMed_Harrison. A host’s ability to recognize certain microbial molecules may influence both the potency of its own defenses and the pathogenesis of severe sepsis. For example, MD-2–TLR4 best senses LPS that has a bisphosphorylated, hexaacyl lipid A moiety (i.e., one with two phosphates and six fatty acyl chains). Most of the commensal aerobic and facultatively anaerobic gram-negative bacteria that trigger severe sepsis and shock (including E. coli, Klebsiella, and Enterobacter) make this lipid A structure. When they invade human hosts, often through breaks in an epithelial barrier, they are typically confined to the sub-epithelial tissue by a localized inflammatory response. Bacteremia, if it occurs, is intermittent and low grade because these bacteria are efficiently cleared from the bloodstream by TLR4-expressing Kupffer cells and splenic macrophages. These mucosal commensals seem to induce severe sepsis most often by triggering severe local tissue inflammation rather than by circulating within


InternalMed_Harrison

InternalMed_Harrison. Kupffer cells and splenic macrophages. These mucosal commensals seem to induce severe sepsis most often by triggering severe local tissue inflammation rather than by circulating within the bloodstream. One exception is Neisseria meningitidis. Its hexaacyl LPS seems to be shielded from host recognition by its polysaccharide capsule. This protection may allow meningococci to transit undetected from the nasopharyngeal mucosa into the bloodstream, where they can infect vascular endothelial cells and release large amounts of endotoxin and DNA. Host recognition of lipid A may nonetheless influence pathogenesis, as meningococci that produce pentaacyl LPS were isolated from the blood of patients with less severe coagulopathy than was found in patients whose isolates produced hexaacyl lipid A; underacylated N. meningitidis LPS has also been found in many isolates from patients with chronic meningococcemia. In contrast, gram-negative bacteria that make lipid A with fewer than six acyl chains