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Common ICU Conditions or supraglottic device or laryngeal mask airway can aid oxygena- IEY POIIIS tion and ventilation when immediate intubation is not feasible e The most common cause of hypoxemic respiratory fail- and may be used until the airway can be secured. ure in the ICU is shunt, which occurs when perfused Respiratory failure can result from obstruction or com- areas ofthe lung are not ventilated, whether because of pression of the upper airways. Patients with partial airway alveolar collapse (atelectasis) or alveolar filling with blood, obstruction may have tachypnea, stridor, increased respira- protein, or water. tory effort, or an upright (tripod) posture with the use of accessory muscles. Absent air movement, inability to talk, or . Management of hypoxemic respiratory failure centers cyanosis suggests complete obstruction, which is a medical on administration of supplemental oxygen and measures emergency. Inspiratory stridor suggests obstruction at or to open alveoli that are fluid-filled or collapsed. above the vocal cords, whereas expiratory stridor and wheez ing suggest an intrathoracic process. Pulse oximetry in the Acute lnhalational lnjuries setting ofpartial upper airway obstruction and stridor is usu- Pulmonary complications are a leading cause of morbidity and ally normal. In patients with respiratory distress or for whom mortality in burn patients or those who experience significant the risk for respiratory deterioration is high, early intubation smoke exposure from fires. Direct thermal injury resulting is indicated. from smoke inhalation is usually limited to the upper airways. However, steam inhalation causes direct thermal injury f,lY P0rrI throughout the tracheobronchial tree because of its ability to o In patients who cannot maintain a patent airway or carry heat more efficiently than dry. hot gas. After smoke protect their airway against aspiration, a secure airway inhalation, one third of patients develop airway edema or should be established by inserting a cuffed endotracheal mucosal sloughing from epithelial necrosis. Chest physiother or tracheostomy tube. apy and serial bronchoscopy are frequently necessary to facili tate continued airway clearance. Injury to the distal tracheo bronchial tree and Iung parenchyma is caused by chemicals in Hypoxemic Respiratory Failure smoke that generate a combination of bronchoconstriction, Hypoxemic respiratory failure is caused by inadequate pulmonary edema, V/Q mismatch, and bronchial cast lorma oxygenation of hemoglobin. The most common cause of tion. Treatment is supportive. hypoxemic respiratory failure is shunt, which is an extreme Secondary infections after inhalational injury are com ventilation/perfusion (V/Q) mismatch (V/Q = 0), which occurs mon and are a major cause of morbidity and mortality. when perfused areas ofthe lung are not ventilated. There are Pneumonia is the most common complication after smoke two main causes: alveolar collapse (atelectasis) and alveolar inhalation, especially from Staphylococcus and Pseudomonos filling with blood, cells, protein, or water. The key feature of species. Toxicity from carbon monoxide (CO) and hydrogen the shunt is an increased alveolar-arterial oxygen gradient not cyanide (HCN) are common after smoke inhalation and should responsive to oxygen supplementation, derived by subtracting be suspected in all patients with smoke exposure. Management the measured arterial Po, from the calculated alveolar Po, from ofthese toxicities is discussed in the section on Specific Critical the alveolar gas equation: Care Topics. Alveolar Po2 = (Fro2 x [P,t. - 47]) - (1.25 x Pcnr) Inhalational injuries related to chemical vapors are Fro, is the fraction of inspired orygen (O.Zt in ambient uncommon. War, industry farming, and exposure to home air), Pr,, is the atmospheric pressure (z60 mm Hg at sea level), cleaning or pesticide agents constitute most chemical inhala- and 47 represents the partial pressure of water in mm Hg at tion injuries. Water-soluble agents usually affect mucosal 37"c (98.6'F). structures of the upper airway and have rapid onset of symp Features of acute hypoxemic respiratory failure include toms. Water-insoluble agents affect deeper structures includ recent onset of increased work of breathing, tachypnea, and ing lung parenchyma and distal airways, and symptoms are anxiety. Cyanosis of the lips or fingers may be present when often delayed. Edema, bronchospasm, asphyxiation, and direct oxygenation of hemoglobin is severely compromised often systemic toxicity are common. Key features of inhalational below 80'7,. Auscultation of crackles, wheezing, egophony, or agents are listed in Table 53. Treatment is supportive. In rhonchi may suggest underlying etiologies. Clubbing suggests patients with cholinesterase inhibitor exposure (typically chronic diseases. Findings on chest imaging may be helpful to organophosphate pesticides), high-dose atropine is adminis identify the cause of acute respiratory failure. tered until bronchorrhea and bronchospasm are controlled. Treatment of hypoxemic respiratory failure includes E cigarette or vaping-associated lung injury (EVALI) rep- administration of supplemental oxygen, mechanical venti resents another type of inhalational injury. Vitamin E acetate, Iation (with positive end-expiratory pressure, or PEEP) to used to thicken illicit vaping products, is linked to toxicity. open alveoli, and in severe cases, extracorporeal mem Clinical suspicion for EVALI should be high in patients who brane oxygenation (ECMO). Disease specific management is use e cigarettes or vaping devices, have hypoxemia, and report discussed here. respiratory symptoms (cough, dyspnea) or gastrointestinal

or supraglottic device or laryngeal mask airway can aid oxygena- IEY POIIIS tion and ventilation when immediate intubation is not feasible e The most common cause of hypoxemic respiratory fail- and may be used until the airway can be secured. ure in the ICU is shunt, which occurs when perfused Respiratory failure can result from obstruction or com- areas ofthe lung are not ventilated, whether because of pression of the upper airways. Patients with partial airway alveolar collapse (atelectasis) or alveolar filling with blood, obstruction may have tachypnea, stridor, increased respira- protein, or water. tory effort, or an upright (tripod) posture with the use of accessory muscles. Absent air movement, inability to talk, or . Management of hypoxemic respiratory failure centers cyanosis suggests complete obstruction, which is a medical on administration of supplemental oxygen and measures emergency. Inspiratory stridor suggests obstruction at or to open alveoli that are fluid-filled or collapsed. above the vocal cords, whereas expiratory stridor and wheez ing suggest an intrathoracic process. Pulse oximetry in the Acute lnhalational lnjuries setting ofpartial upper airway obstruction and stridor is usu- Pulmonary complications are a leading cause of morbidity and ally normal. In patients with respiratory distress or for whom mortality in burn patients or those who experience significant the risk for respiratory deterioration is high, early intubation smoke exposure from fires. Direct thermal injury resulting is indicated. from smoke inhalation is usually limited to the upper airways. However, steam inhalation causes direct thermal injury f,lY P0rrI throughout the tracheobronchial tree because of its ability to o In patients who cannot maintain a patent airway or carry heat more efficiently than dry. hot gas. After smoke protect their airway against aspiration, a secure airway inhalation, one third of patients develop airway edema or should be established by inserting a cuffed endotracheal mucosal sloughing from epithelial necrosis. Chest physiother or tracheostomy tube. apy and serial bronchoscopy are frequently necessary to facili tate continued airway clearance. Injury to the distal tracheo bronchial tree and Iung parenchyma is caused by chemicals in Hypoxemic Respiratory Failure smoke that generate a combination of bronchoconstriction, Hypoxemic respiratory failure is caused by inadequate pulmonary edema, V/Q mismatch, and bronchial cast lorma oxygenation of hemoglobin. The most common cause of tion. Treatment is supportive. hypoxemic respiratory failure is shunt, which is an extreme Secondary infections after inhalational injury are com ventilation/perfusion (V/Q) mismatch (V/Q = 0), which occurs mon and are a major cause of morbidity and mortality. when perfused areas ofthe lung are not ventilated. There are Pneumonia is the most common complication after smoke two main causes: alveolar collapse (atelectasis) and alveolar inhalation, especially from Staphylococcus and Pseudomonos filling with blood, cells, protein, or water. The key feature of species. Toxicity from carbon monoxide (CO) and hydrogen the shunt is an increased alveolar-arterial oxygen gradient not cyanide (HCN) are common after smoke inhalation and should responsive to oxygen supplementation, derived by subtracting be suspected in all patients with smoke exposure. Management the measured arterial Po, from the calculated alveolar Po, from ofthese toxicities is discussed in the section on Specific Critical the alveolar gas equation: Care Topics. Alveolar Po2 = (Fro2 x [P,t. - 47]) - (1.25 x Pcnr) Inhalational injuries related to chemical vapors are Fro, is the fraction of inspired orygen (O.Zt in ambient uncommon. War, industry farming, and exposure to home air), Pr,, is the atmospheric pressure (z60 mm Hg at sea level), cleaning or pesticide agents constitute most chemical inhala- and 47 represents the partial pressure of water in mm Hg at tion injuries. Water-soluble agents usually affect mucosal 37"c (98.6'F). structures of the upper airway and have rapid onset of symp Features of acute hypoxemic respiratory failure include toms. Water-insoluble agents affect deeper structures includ recent onset of increased work of breathing, tachypnea, and ing lung parenchyma and distal airways, and symptoms are anxiety. Cyanosis of the lips or fingers may be present when often delayed. Edema, bronchospasm, asphyxiation, and direct oxygenation of hemoglobin is severely compromised often systemic toxicity are common. Key features of inhalational below 80'7,. Auscultation of crackles, wheezing, egophony, or agents are listed in Table 53. Treatment is supportive. In rhonchi may suggest underlying etiologies. Clubbing suggests patients with cholinesterase inhibitor exposure (typically chronic diseases. Findings on chest imaging may be helpful to organophosphate pesticides), high-dose atropine is adminis identify the cause of acute respiratory failure. tered until bronchorrhea and bronchospasm are controlled. Treatment of hypoxemic respiratory failure includes E cigarette or vaping-associated lung injury (EVALI) rep- administration of supplemental oxygen, mechanical venti resents another type of inhalational injury. Vitamin E acetate, Iation (with positive end-expiratory pressure, or PEEP) to used to thicken illicit vaping products, is linked to toxicity. open alveoli, and in severe cases, extracorporeal mem Clinical suspicion for EVALI should be high in patients who brane oxygenation (ECMO). Disease specific management is use e cigarettes or vaping devices, have hypoxemia, and report discussed here. respiratory symptoms (cough, dyspnea) or gastrointestinal 68

Common ICU Conditions TABLE 53. Key Features of lnhaled Agents TABLE 54. Common Causes of Acute Respiratory Distress Syndrome Agent Characteristics Clinical Features After Exposure Direct Pulmonary lnjury Ammonia Colorless; Cough, upper Aspiration of gastric contents ammonia odor airway burns, Fat embolism pulmonary edema, asphyxiation in Near drowning poorly vented areas Pneumonia (including viral causes such as COVID-19) Chlorine Yellow-green; Upper airway chlorine odor irritation and burns, Smoke or chemical inhalation bronchospasm, Thoracic trauma/thoracic contusion pulmonary edema lndirect Pulmonary lnjury Phosgene Colorless; Systemic toxicity, musty odor like including elevated Disseminated intravascular coagulation fresh-cut grass methemoglobin Nonthoracic trauma level, cyanosis, and metabolic acidosis; Pancreatitis pulmonary edema Pulmonary reperfusion injury (after lung transplantation) Mustard gas Yellow-brown Upper airways Sepsis/septic shock vapor; odor like burns and garlic or onions obstruction can Transfusion of blood products

TABLE 53. Key Features of lnhaled Agents TABLE 54. Common Causes of Acute Respiratory Distress Syndrome Agent Characteristics Clinical Features After Exposure Direct Pulmonary lnjury Ammonia Colorless; Cough, upper Aspiration of gastric contents ammonia odor airway burns, Fat embolism pulmonary edema, asphyxiation in Near drowning poorly vented areas Pneumonia (including viral causes such as COVID-19) Chlorine Yellow-green; Upper airway chlorine odor irritation and burns, Smoke or chemical inhalation bronchospasm, Thoracic trauma/thoracic contusion pulmonary edema lndirect Pulmonary lnjury Phosgene Colorless; Systemic toxicity, musty odor like including elevated Disseminated intravascular coagulation fresh-cut grass methemoglobin Nonthoracic trauma level, cyanosis, and metabolic acidosis; Pancreatitis pulmonary edema Pulmonary reperfusion injury (after lung transplantation) Mustard gas Yellow-brown Upper airways Sepsis/septic shock vapor; odor like burns and garlic or onions obstruction can Transfusion of blood products Organophosphates Colorless; fruity Systemic toxicity Ventilatory Management and other odor causing cholinesterase acetylcholine Most patients with ARDS are managed with invasive mechani- inhibitors toxicity (rhinorrhea, cal ventilation. PEEP and low tidal volume ventilation are the bronchorrhea, cornerstones of ARDS management, as they are associated diarrhea, bronchospasm, with improved patient outcomes. In ARDS, the lung injury is bradycardia, flaccid not homogenous-it is characterized by areas of noncompliant paralysis, apnea) lung adjacent to lung with more normal compliance. The compliant lung is susceptible to overdistention and injury by tidal volume (volutrauma). Based on evidence showing an 11% symptoms (abdominal pain, vomiting, diarrhea). Patients may absolute reduction in reduction in mortality, guidelines rec- also have constitutional symptoms (fever, chills). Reported ommend a tidal volume of 4 to B mllkg of predicted body cases of EVALI have declined sharply since their peak in weight and a plateau pressure less than 30 cm HrO. September 2019. CDC guidelines on diagnosis and treatment PEEP prevents lung injury associated with repeated open- of EVALI are available at https : //www. cdc. gov/tobacco /basic ing and closing of distal airways and alveoli (atelectrauma). It information/e-cigarettes/severe lung-disease/healthcare- improves homogeneity of the lung parenchyma by reducing providers /index. html.

Organophosphates Colorless; fruity Systemic toxicity Ventilatory Management and other odor causing cholinesterase acetylcholine Most patients with ARDS are managed with invasive mechani- inhibitors toxicity (rhinorrhea, cal ventilation. PEEP and low tidal volume ventilation are the bronchorrhea, cornerstones of ARDS management, as they are associated diarrhea, bronchospasm, with improved patient outcomes. In ARDS, the lung injury is bradycardia, flaccid not homogenous-it is characterized by areas of noncompliant paralysis, apnea) lung adjacent to lung with more normal compliance. The compliant lung is susceptible to overdistention and injury by tidal volume (volutrauma). Based on evidence showing an 11% symptoms (abdominal pain, vomiting, diarrhea). Patients may absolute reduction in reduction in mortality, guidelines rec- also have constitutional symptoms (fever, chills). Reported ommend a tidal volume of 4 to B mllkg of predicted body cases of EVALI have declined sharply since their peak in weight and a plateau pressure less than 30 cm HrO. September 2019. CDC guidelines on diagnosis and treatment PEEP prevents lung injury associated with repeated open- of EVALI are available at https : //www. cdc. gov/tobacco /basic ing and closing of distal airways and alveoli (atelectrauma). It information/e-cigarettes/severe lung-disease/healthcare- improves homogeneity of the lung parenchyma by reducing providers /index. html. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) is a syndrome characterized by acute hypoxemia and diffuse lung injury as a result of an inciting insult. The most common causes are sepsis and pneumonia, but there are other causes of ARDS (Table s+). In ARDS, disruption of surfactant, vascular endothelial injury and alveolar epithelial injury lead to fluid and protein extravasation into interstitial and alveolar spaces and alveolar collapse, V/Q mismatch, and decreased lung compliance. Histologr shows diffuse alveolar damage (Figure 26). ARDS has no specific diagnostic test. The most recent ARDS diagnostic consensus is summarized in the 2012 Berlin Definition of ARDS (Table 55). Patients with ARDS are at high fIGURE 26. Diffuse alveolar damage. l = interstitial edema (thickened cellular risk for mortality, which increases with ARDS severity. space between airspace and vasculature); 2 = hyaline membranes (proteinaceous Importantly, mortality is usually the result of underlying dis alveolar exudates that accumulate along the alveolar surfaces and impair gas ease, secondary infection, or multiorgan dysfunction rather exchange); 3 = denuded epithelium (usually numerous type 1 alveolar cells have than refractory respiratory failure. undergone apoptosis and been replaced by hyaline membrane or fibrosis).

Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) is a syndrome characterized by acute hypoxemia and diffuse lung injury as a result of an inciting insult. The most common causes are sepsis and pneumonia, but there are other causes of ARDS (Table s+). In ARDS, disruption of surfactant, vascular endothelial injury and alveolar epithelial injury lead to fluid and protein extravasation into interstitial and alveolar spaces and alveolar collapse, V/Q mismatch, and decreased lung compliance. Histologr shows diffuse alveolar damage (Figure 26). ARDS has no specific diagnostic test. The most recent ARDS diagnostic consensus is summarized in the 2012 Berlin Definition of ARDS (Table 55). Patients with ARDS are at high fIGURE 26. Diffuse alveolar damage. l = interstitial edema (thickened cellular risk for mortality, which increases with ARDS severity. space between airspace and vasculature); 2 = hyaline membranes (proteinaceous Importantly, mortality is usually the result of underlying dis alveolar exudates that accumulate along the alveolar surfaces and impair gas ease, secondary infection, or multiorgan dysfunction rather exchange); 3 = denuded epithelium (usually numerous type 1 alveolar cells have than refractory respiratory failure. undergone apoptosis and been replaced by hyaline membrane or fibrosis). 69

Common ICU Conditions TABLE 5 5. 2012 Berlin Definition of Acute Respiratory XEY POIilT Distress Syndrome o Treating patients with severe acute respiratory distress The following criteria must be met: syndrome using early prone positioning and low tidal Onset within 1 week of known ARDS insult (most cases occur volume ventilation has demonstrated clinically important within 72 hours) mortality benefit. Bilateral opacities on chest imaging consistent with pulmonary edema Nonventilatory Management Respiratory failure not related to cardiac failure or volume overload Although mortality in ARDS has decreased, the morbidity asso ciated u,ith ARDS is recognized as a major factor in survivors' Arterial Po2lFlo2 <300 on at least 5 cm H2O PEEP from noninvasive or invasive mechanical ventilator well being. Many interventions will have lasting effects beyond hospital discharge. Sedation and analgesia guidelines (discussed Once criteria for diagnosis are met, severity of ARDS is based on the following criteria: in the Principles of Critical Care section) are designed to limit Mild = arterial Po2lFro2 >200 to <300 the complications of sedative and opioid medications. Volume overload is recognized as a source of morbidity. Moderate = arterialPo2/Fto2100 to 200 The Fluids and Catheters Treatment Trial compared conserva Severe = arterial Po2lFto2 <1 00 tive with liberal fluid strategies in patients with ARDS. ARDS = acute respiratory distress syndrome; PEEP = positive end-expiratory pressure. Although mortality did not differ betueen groups. patients lnformation from Ranieri VM, Rubenfeld GD, Thompson Bl et al; ARDS Definition who were treated with conservative fluid management showed Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526 2533. IPMlDr 22797 452) doi:10.1O01 /jama.2012.5669 improved oxygenation and decreased time on the ventilator and in the ICU. Patients who are hemodynamically stable and do not have end organ hypoperfusion should receive differences in regional lung compliance and improves V/Q protocol directed diuretics and management to minimize mismatch by maintaining alveolar recmitment. There is no fluid administration. definitive level of optimal PEEP for the ventilation of patients Paralytic agents in ARDS are used to increase oxygenation with ARDS. The favored method of selecting PEEP is to use a and decrease ventilator-induced lung injury. Although initial PEEP-FIo, table, where PEEP is matched to the needed Fro, trials indicated a mortality benefit, the more recent to maintain a target saturation of 887, to 957,. Guidelines rec Reevaluation of Systemic Early Neuromuscular Blockade trial ommend using higher PEEP in patients with moderate to showed that among patients with moderate to severe ARDS severe ARDS. However, a recent trial comparing higher PEEP who were treated with a strates/ of high PEEP, there was no and recruitment maneuvers to a lower PEEP strategz in mod significant difference in 90 day mortality between patients erate to severe ARDS showed an increase in mortality with who receiving cisatracurium infusion and those treated with higher PEEP. lighter sedation targets. There was a non-statistically signifi- Prone positioning reduces compression of portions of the cant increase in subsequent ICU acquired weakness in para- lung behind the cardiac and mediastinal structures and lyzed patients. improves V/Q matching in patients with ARDS. A large ran- Sedation strategies have an effect on outcomes. The current domized trial demonstrated improved mortality in patients recommendation is to lighten sedation as soon as it is safe, to with an arterial Por/Fro, ratio less than 150 who were treated allowpatient interaction. A multicentet randomized trial among with early-onset (less than 48 hours) prone positioning and ventilated ICU patients showed no difference in 90-day mortality low tidal volume ventilation. Prone positioning for at least 12 between those assigned to no sedation and those assigned to to 16 hours a day should be considered for patients with severe light sedation with daily interruption. The study highlighted the ARDS (Por/FIo2, less than 150; Fror, at least 60). importance of daily awakening, reassessment of the sedation Two large trials have evaluated the role of ECMO in the strategies, and minimizing mind altering medications. management of ARDS; both trials demonstrated feasibility and Other therapies, including nutritional modifi cations, glu trends toward decreased mortality. At this time, ECMO is part cocorticoid administration, vitamin C, macrolide antibiotics. of the therapeutic options for patients with severe refractory inhaled nitric oxide, prostacyclin analogues, and stem cells or respiratory failure resulting from ARDS. Early evaluation is granulocyte-macrophage colony stimulating factol have con recommended in patients with severe ARDS. flicting or limited evidence and are not recommended in the Other methods to optimize ventilator management in management of ARDS. ARDS have been suggested, including recruitment maneu vers, inverse ratio ventilation, airway pressure release ventila Heaft Failure tion, esophageal pressure, and driving pressure guided Acute cardiogenic pulmonary edema often presents with titration of PEEP, as well as high-frequency oscillatory venti- hypoxemic respiratory failure. In patients who present with lation. None of these methods has demonstrated a mortality acute respiratory failure, but no clear trigger for ARDS, it is benefit in ARDS. important to evaluate for cardiogenic causes, which include

TABLE 5 5. 2012 Berlin Definition of Acute Respiratory XEY POIilT Distress Syndrome o Treating patients with severe acute respiratory distress The following criteria must be met: syndrome using early prone positioning and low tidal Onset within 1 week of known ARDS insult (most cases occur volume ventilation has demonstrated clinically important within 72 hours) mortality benefit. Bilateral opacities on chest imaging consistent with pulmonary edema Nonventilatory Management Respiratory failure not related to cardiac failure or volume overload Although mortality in ARDS has decreased, the morbidity asso ciated u,ith ARDS is recognized as a major factor in survivors' Arterial Po2lFlo2 <300 on at least 5 cm H2O PEEP from noninvasive or invasive mechanical ventilator well being. Many interventions will have lasting effects beyond hospital discharge. Sedation and analgesia guidelines (discussed Once criteria for diagnosis are met, severity of ARDS is based on the following criteria: in the Principles of Critical Care section) are designed to limit Mild = arterial Po2lFro2 >200 to <300 the complications of sedative and opioid medications. Volume overload is recognized as a source of morbidity. Moderate = arterialPo2/Fto2100 to 200 The Fluids and Catheters Treatment Trial compared conserva Severe = arterial Po2lFto2 <1 00 tive with liberal fluid strategies in patients with ARDS. ARDS = acute respiratory distress syndrome; PEEP = positive end-expiratory pressure. Although mortality did not differ betueen groups. patients lnformation from Ranieri VM, Rubenfeld GD, Thompson Bl et al; ARDS Definition who were treated with conservative fluid management showed Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526 2533. IPMlDr 22797 452) doi:10.1O01 /jama.2012.5669 improved oxygenation and decreased time on the ventilator and in the ICU. Patients who are hemodynamically stable and do not have end organ hypoperfusion should receive differences in regional lung compliance and improves V/Q protocol directed diuretics and management to minimize mismatch by maintaining alveolar recmitment. There is no fluid administration. definitive level of optimal PEEP for the ventilation of patients Paralytic agents in ARDS are used to increase oxygenation with ARDS. The favored method of selecting PEEP is to use a and decrease ventilator-induced lung injury. Although initial PEEP-FIo, table, where PEEP is matched to the needed Fro, trials indicated a mortality benefit, the more recent to maintain a target saturation of 887, to 957,. Guidelines rec Reevaluation of Systemic Early Neuromuscular Blockade trial ommend using higher PEEP in patients with moderate to showed that among patients with moderate to severe ARDS severe ARDS. However, a recent trial comparing higher PEEP who were treated with a strates/ of high PEEP, there was no and recruitment maneuvers to a lower PEEP strategz in mod significant difference in 90 day mortality between patients erate to severe ARDS showed an increase in mortality with who receiving cisatracurium infusion and those treated with higher PEEP. lighter sedation targets. There was a non-statistically signifi- Prone positioning reduces compression of portions of the cant increase in subsequent ICU acquired weakness in para- lung behind the cardiac and mediastinal structures and lyzed patients. improves V/Q matching in patients with ARDS. A large ran- Sedation strategies have an effect on outcomes. The current domized trial demonstrated improved mortality in patients recommendation is to lighten sedation as soon as it is safe, to with an arterial Por/Fro, ratio less than 150 who were treated allowpatient interaction. A multicentet randomized trial among with early-onset (less than 48 hours) prone positioning and ventilated ICU patients showed no difference in 90-day mortality low tidal volume ventilation. Prone positioning for at least 12 between those assigned to no sedation and those assigned to to 16 hours a day should be considered for patients with severe light sedation with daily interruption. The study highlighted the ARDS (Por/FIo2, less than 150; Fror, at least 60). importance of daily awakening, reassessment of the sedation Two large trials have evaluated the role of ECMO in the strategies, and minimizing mind altering medications. management of ARDS; both trials demonstrated feasibility and Other therapies, including nutritional modifi cations, glu trends toward decreased mortality. At this time, ECMO is part cocorticoid administration, vitamin C, macrolide antibiotics. of the therapeutic options for patients with severe refractory inhaled nitric oxide, prostacyclin analogues, and stem cells or respiratory failure resulting from ARDS. Early evaluation is granulocyte-macrophage colony stimulating factol have con recommended in patients with severe ARDS. flicting or limited evidence and are not recommended in the Other methods to optimize ventilator management in management of ARDS. ARDS have been suggested, including recruitment maneu vers, inverse ratio ventilation, airway pressure release ventila Heaft Failure tion, esophageal pressure, and driving pressure guided Acute cardiogenic pulmonary edema often presents with titration of PEEP, as well as high-frequency oscillatory venti- hypoxemic respiratory failure. In patients who present with lation. None of these methods has demonstrated a mortality acute respiratory failure, but no clear trigger for ARDS, it is benefit in ARDS. important to evaluate for cardiogenic causes, which include 70

Common ICU Conditions cardiomyopathy, mitral and aortic valve disease, myocardial radiograph is the standard for diagnosis. However, a negative ischemia, and arrhyhmias (particularly atrial fibrillation with clinical examination or chest radiograph does not necessarily rapid ventricular rate). Evaluation for a cardiac cause of rule out community acquired pneumonia in symptomatic pulmonary edema should include an assessment for volume patients, especially in older adults. Therefore, the absence of overload (jugular venous distention, Sr, peripheral edema), an typical features or focal infiltrates on chest radiograph should electrocardiogram, B type natriuretic peptide, serial serum not preclude early antibiotic administration to persons with troponins, and an echocardiogram. an otherwise high probability of pneumonia. For further dis In general, acute cardiogenic pulmonary edema responds cussion of community acquired pneumonia, see MKSAP 19 promptly to therapy with diuretics and afterload reduction Infectious Disease. In patients who do not respond appropri (vasodilators or inodilators). Systematic reviews demonstrate ately to antibiotics, repeat sputum cultures should be obtained that noninvasive positive pressure ventilation (continuous and nonbacterial causes ofinfection and noninfectious causes positive airway pressure or bilevel positive airway pressure) should be considered. In addition, further evaluation with hastens the resolution of hypoxemia, improves symptoms, chest ultrasonography, chest CT, or bronchoscopy should be lowers intubation rates, and decreases mortality compared considered to evaluate for complicating f'actors such as pleural with oxygen therapy alone. efl'usion, abscess, or airway obstruction stemming from malig nancy or foreign body aspiration. KEY POII{T o In cardiogenic pulmonary edema, noninvasive positive KEY POIilT pressure ventilation (continuous positive airway pressure o A negative clinical examination or chest radiograph or bilevel positive airway pressure) hastens the resolution does not necessarily rule out community acquired of hypoxemia, improves symptoms, lowers intubation pneumonia in symptomatic patients, especially in rates, and decreases mortality compared with oxygen elderly individuals. therapy alone. Diffuse Parenchymal Lung Disease Atelectasis Acute exacerbations of diffuse parenchymal lung disease, par- Atelectasis is a common postoperative complication. Pain or ticularly idiopathic pulmonary fibrosis, can occur either as a impaired respiratory mechanics after thoracic and abdominal complication of an inciting event (infection, postprocedural, surgeries can lead patients to adopt shallow breathing patterns drug reaction) or, in many cases, for unknown reasons. The and to avoid coughing. Patients may be asymptomatic or pre- criteria for identifying acute exacerbations include previous or sent with diminished breath sounds at the lung bases, consoli concurrent diagnosis of diffuse parenchymal lung disease, dation on imaging, egophony, rhonchi, and labored breathing. acute worsening of respiratory status (less than 1 month), and Management includes pain control, encouraging mobility, and new ground glass opacities on imaging studies. The mortality secretion management. Respiratory physiotherapy (inspira- in patients with hypoxemic respiratory failure resulting from tory muscle training, deep breathing exercise, mobility pro an exacerbation of idiopathic pulmonary fibrosis exceeds 50%. grams, or percussion and vibration therapy) help prevent Most patients with hypoxemic respiratory failure caused by atelectasis. Bronchoscopy for routine airway mucous clear idiopathic pulmonary fibrosis are treated empirically with ance offers no clear benefit compared with other methods of antibiotics and high dose glucocorticoids or other immuno chest physiotherapy. It should be considered whether 24 hours suppressants, but the data are insufficient to recommend spe- ofchest physiotherapy fails to decrease the atelectasis. Ifsecre cific doses, duration, or certainty of benefit. Outcomes after tions are minimal, positive pressure air-way therapy (positive intubation and mechanical ventilation are very poor, as mor- expiratory pressure devices) to recruit collapsed alveoli may be tality can approach 100%. Therefore, many clinicians recom considered. No evidence exists for use of mucolytics such as mend that goals of care discussions be held and palliative care N-acetyt cysteine for treatment of atelectasis. strategies be determined early in the clinical course and that other therapies, such as ECMO, only be ofTered as a bridge for KEY POI lIT patients eligible for (and already listed fbr) lung transplanta- HVC r Strategies to prevent postoperative atelectasis include tion. See Diffuse Parenchymal Lung Disease section' pain control, early mobility, and secretion management XEY POIl{I with aggressive chest physiotherapy; bronchoscopy for airuray mucous clearance offers no clear beneflt compared . Because outcomes after intubation and mechanical ven with other methods of chest physiotherapy. tilation are very poor for patients with acute exacerba- tions of idiopathic pulmonary fibrosis, goals of care and palliative care strategies should be discussed early and Pneumonia other therapies, such as extracorporeal membrane oxy- Pneumonia is a common cause of respiratory failure in the ICU genation, should only be offered as a bridge for patients and is the most common cause of ARDS that develops outside eligible for lung transplantation. the hospital. In patients with an appropriate history chest

cardiomyopathy, mitral and aortic valve disease, myocardial radiograph is the standard for diagnosis. However, a negative ischemia, and arrhyhmias (particularly atrial fibrillation with clinical examination or chest radiograph does not necessarily rapid ventricular rate). Evaluation for a cardiac cause of rule out community acquired pneumonia in symptomatic pulmonary edema should include an assessment for volume patients, especially in older adults. Therefore, the absence of overload (jugular venous distention, Sr, peripheral edema), an typical features or focal infiltrates on chest radiograph should electrocardiogram, B type natriuretic peptide, serial serum not preclude early antibiotic administration to persons with troponins, and an echocardiogram. an otherwise high probability of pneumonia. For further dis In general, acute cardiogenic pulmonary edema responds cussion of community acquired pneumonia, see MKSAP 19 promptly to therapy with diuretics and afterload reduction Infectious Disease. In patients who do not respond appropri (vasodilators or inodilators). Systematic reviews demonstrate ately to antibiotics, repeat sputum cultures should be obtained that noninvasive positive pressure ventilation (continuous and nonbacterial causes ofinfection and noninfectious causes positive airway pressure or bilevel positive airway pressure) should be considered. In addition, further evaluation with hastens the resolution of hypoxemia, improves symptoms, chest ultrasonography, chest CT, or bronchoscopy should be lowers intubation rates, and decreases mortality compared considered to evaluate for complicating f'actors such as pleural with oxygen therapy alone. efl'usion, abscess, or airway obstruction stemming from malig nancy or foreign body aspiration. KEY POII{T o In cardiogenic pulmonary edema, noninvasive positive KEY POIilT pressure ventilation (continuous positive airway pressure o A negative clinical examination or chest radiograph or bilevel positive airway pressure) hastens the resolution does not necessarily rule out community acquired of hypoxemia, improves symptoms, lowers intubation pneumonia in symptomatic patients, especially in rates, and decreases mortality compared with oxygen elderly individuals. therapy alone. Diffuse Parenchymal Lung Disease Atelectasis Acute exacerbations of diffuse parenchymal lung disease, par- Atelectasis is a common postoperative complication. Pain or ticularly idiopathic pulmonary fibrosis, can occur either as a impaired respiratory mechanics after thoracic and abdominal complication of an inciting event (infection, postprocedural, surgeries can lead patients to adopt shallow breathing patterns drug reaction) or, in many cases, for unknown reasons. The and to avoid coughing. Patients may be asymptomatic or pre- criteria for identifying acute exacerbations include previous or sent with diminished breath sounds at the lung bases, consoli concurrent diagnosis of diffuse parenchymal lung disease, dation on imaging, egophony, rhonchi, and labored breathing. acute worsening of respiratory status (less than 1 month), and Management includes pain control, encouraging mobility, and new ground glass opacities on imaging studies. The mortality secretion management. Respiratory physiotherapy (inspira- in patients with hypoxemic respiratory failure resulting from tory muscle training, deep breathing exercise, mobility pro an exacerbation of idiopathic pulmonary fibrosis exceeds 50%. grams, or percussion and vibration therapy) help prevent Most patients with hypoxemic respiratory failure caused by atelectasis. Bronchoscopy for routine airway mucous clear idiopathic pulmonary fibrosis are treated empirically with ance offers no clear benefit compared with other methods of antibiotics and high dose glucocorticoids or other immuno chest physiotherapy. It should be considered whether 24 hours suppressants, but the data are insufficient to recommend spe- ofchest physiotherapy fails to decrease the atelectasis. Ifsecre cific doses, duration, or certainty of benefit. Outcomes after tions are minimal, positive pressure air-way therapy (positive intubation and mechanical ventilation are very poor, as mor- expiratory pressure devices) to recruit collapsed alveoli may be tality can approach 100%. Therefore, many clinicians recom considered. No evidence exists for use of mucolytics such as mend that goals of care discussions be held and palliative care N-acetyt cysteine for treatment of atelectasis. strategies be determined early in the clinical course and that other therapies, such as ECMO, only be ofTered as a bridge for KEY POI lIT patients eligible for (and already listed fbr) lung transplanta- HVC r Strategies to prevent postoperative atelectasis include tion. See Diffuse Parenchymal Lung Disease section' pain control, early mobility, and secretion management XEY POIl{I with aggressive chest physiotherapy; bronchoscopy for airuray mucous clearance offers no clear beneflt compared . Because outcomes after intubation and mechanical ven with other methods of chest physiotherapy. tilation are very poor for patients with acute exacerba- tions of idiopathic pulmonary fibrosis, goals of care and palliative care strategies should be discussed early and Pneumonia other therapies, such as extracorporeal membrane oxy- Pneumonia is a common cause of respiratory failure in the ICU genation, should only be offered as a bridge for patients and is the most common cause of ARDS that develops outside eligible for lung transplantation. the hospital. In patients with an appropriate history chest 71

Common ICU Conditions Pulmonary Embolism TABLE 56. Causes of Acute Hypercapnic Respiratory Pulmonary embolism (PE) causes respiratory failure primarily Failure through V/Q mismatch. After an acute PE, resistance to pul Decreased Respiratory Drive monary blood flow increases both because of thrombosis and Anesthesia because ofthe vasospasm ofadjacent pulmonary blood vessels Central apnea from inflammatory mediators. Blood flow is directed to other Obesity hypoventilation synd rome areas of normal lung, which become overperfused. If alveolar oxygen levels in the normal lung are insufficient to fully oxy Drugs (e.g., opioids, benzodiazepines, ethanol) genate blood in the overperfused vessels, hypoxemia ensues. Encephalitis Chest radiograph or chest CT scan may demonstrate periph Hypothermia eral, ground-glass, wedge shaped opacities (Hampton hump Hypothyroidism sign) signifying the presence of infarcted lung and surround Meningitis ing atelectasis. Blood flow through atelectatic lung can result Stroke in shunt and worsened hypoxemia. Pulmonary emboli can also cause strain on the right ven Decreased V1 or Increased Vo/Vt tricle (RV) if the PE causes significant pulmonary arterial Neu romuscular weakness obstruction. Cardiac output may be impaired, leading to Amyotrophic lateral sclerosis reduced mixed venous oxygen saturation, especially when Botulism metabolic demands exceed cardiac capacity. If this occurs in Critical illness myopathy conjunction with V/Q mismatch and shunt, blood cannot fully Guillain-Ba116 syndrome saturate with oxygen before leaving the alveolar capillaries. This adds to hypoxemia and subsequent respiratory failure. Myasthenia gravis Although most patients with hypoxemia after PE can be Myositis (polymyositis, dermatomycosis) managed with supplemental oxygen alone, some patients Polio require intubation and mechanical ventilation. Mechanical Spinal or phrenic nerve injury ventilation produces several physiologic effects that need to be Metabolic considered in the patient with PE and RV dysfunction. Electrolyte disorder (low magnesium, low phosphate) Increased intrathoracic pressures from mechanical ventilation can decrease venous return and RV preload. Increased alveolar Obstructive airway disease pressures can compress capillaries and increase RV afterload. Asthma exacerbation These effects can lead to further RV dysfunction and hemody Bronchiectasis flare (including cystic fibrosis) namic instability. Although there is no absolute contraindica COPD exacerbation tion to mechanical ventilation in patients with underlying PE, Restrictive physiology the possibility of rapid hemodynamic instability must be anticipated. This is usually managed with vasopressors (nor Ankylosing spondylitis

Pulmonary Embolism TABLE 56. Causes of Acute Hypercapnic Respiratory Pulmonary embolism (PE) causes respiratory failure primarily Failure through V/Q mismatch. After an acute PE, resistance to pul Decreased Respiratory Drive monary blood flow increases both because of thrombosis and Anesthesia because ofthe vasospasm ofadjacent pulmonary blood vessels Central apnea from inflammatory mediators. Blood flow is directed to other Obesity hypoventilation synd rome areas of normal lung, which become overperfused. If alveolar oxygen levels in the normal lung are insufficient to fully oxy Drugs (e.g., opioids, benzodiazepines, ethanol) genate blood in the overperfused vessels, hypoxemia ensues. Encephalitis Chest radiograph or chest CT scan may demonstrate periph Hypothermia eral, ground-glass, wedge shaped opacities (Hampton hump Hypothyroidism sign) signifying the presence of infarcted lung and surround Meningitis ing atelectasis. Blood flow through atelectatic lung can result Stroke in shunt and worsened hypoxemia. Pulmonary emboli can also cause strain on the right ven Decreased V1 or Increased Vo/Vt tricle (RV) if the PE causes significant pulmonary arterial Neu romuscular weakness obstruction. Cardiac output may be impaired, leading to Amyotrophic lateral sclerosis reduced mixed venous oxygen saturation, especially when Botulism metabolic demands exceed cardiac capacity. If this occurs in Critical illness myopathy conjunction with V/Q mismatch and shunt, blood cannot fully Guillain-Ba116 syndrome saturate with oxygen before leaving the alveolar capillaries. This adds to hypoxemia and subsequent respiratory failure. Myasthenia gravis Although most patients with hypoxemia after PE can be Myositis (polymyositis, dermatomycosis) managed with supplemental oxygen alone, some patients Polio require intubation and mechanical ventilation. Mechanical Spinal or phrenic nerve injury ventilation produces several physiologic effects that need to be Metabolic considered in the patient with PE and RV dysfunction. Electrolyte disorder (low magnesium, low phosphate) Increased intrathoracic pressures from mechanical ventilation can decrease venous return and RV preload. Increased alveolar Obstructive airway disease pressures can compress capillaries and increase RV afterload. Asthma exacerbation These effects can lead to further RV dysfunction and hemody Bronchiectasis flare (including cystic fibrosis) namic instability. Although there is no absolute contraindica COPD exacerbation tion to mechanical ventilation in patients with underlying PE, Restrictive physiology the possibility of rapid hemodynamic instability must be anticipated. This is usually managed with vasopressors (nor Ankylosing spondylitis epinephrine), oxygen, careful use of PEEP, and sometimes Multiple rib fractures (flail chest) pulmonary vasodilators (inhaled nitric oxide or epoprostenol). Thoracic cage deform ity (kyphoscoliosis) In patients with hemodynamic collapse, treatment with VD = volume of dead space; V; = tidal volume thrombolytics is associated with decreased mortality and improved clinical and echocardiographic parameters. \ Thrombolytic therapy has up to a 2'7, risk of intracranial alveolar ventilation, or both. Alveolar hypoventilation occurs hemorrhage, and this should be considered relative to the risk when the patient is unable to ventilate because of decreased for massive PE leading to hemodynamic collapse. In patients respiratory drive, decreased tidal volume (Vr), or increased with contraindications to thrombolysis, or in those in whom volume of dead space (Vp) relative to the overall tidal volume thrombolysis has failed, surgical or percutaneous catheter (Vr)/Vr) (Table s6). based embolectomy is an option il resources are available. For Clinical features of acute hypercapnic respiratory failure further discussion of PE, see MKSAP 19 Hematologz. are variable and nonspecific. Symptoms may include somno lence and myoclonic jerks in the setting of CO, narcosis. In some cases, increased work of breathing may precede Hypercapn ic (Ventilatory) Respiratory Fa il u re the development of acute hypercapnic respiratory failure. Hypercapnic, or ventilatory respiratory failure occurs when Underlying chest wall deformity. neurologic weakness. or alveolar ventilation is inadequate to clear the CO, produced by polycythemia should also prompt evaluation for hypercapnia cellular metabolism and the level of CO, increases in the in the setting of respiratory failure. blood. Hypercapnia reflects alveolar hypoventilation, an Patients presenting with hypercapnic respiratory failure increased metabolic load that is not matched by an increase in frequently have coexisting hypoxemia. In these cases,

epinephrine), oxygen, careful use of PEEP, and sometimes Multiple rib fractures (flail chest) pulmonary vasodilators (inhaled nitric oxide or epoprostenol). Thoracic cage deform ity (kyphoscoliosis) In patients with hemodynamic collapse, treatment with VD = volume of dead space; V; = tidal volume thrombolytics is associated with decreased mortality and improved clinical and echocardiographic parameters. \ Thrombolytic therapy has up to a 2'7, risk of intracranial alveolar ventilation, or both. Alveolar hypoventilation occurs hemorrhage, and this should be considered relative to the risk when the patient is unable to ventilate because of decreased for massive PE leading to hemodynamic collapse. In patients respiratory drive, decreased tidal volume (Vr), or increased with contraindications to thrombolysis, or in those in whom volume of dead space (Vp) relative to the overall tidal volume thrombolysis has failed, surgical or percutaneous catheter (Vr)/Vr) (Table s6). based embolectomy is an option il resources are available. For Clinical features of acute hypercapnic respiratory failure further discussion of PE, see MKSAP 19 Hematologz. are variable and nonspecific. Symptoms may include somno lence and myoclonic jerks in the setting of CO, narcosis. In some cases, increased work of breathing may precede Hypercapn ic (Ventilatory) Respiratory Fa il u re the development of acute hypercapnic respiratory failure. Hypercapnic, or ventilatory respiratory failure occurs when Underlying chest wall deformity. neurologic weakness. or alveolar ventilation is inadequate to clear the CO, produced by polycythemia should also prompt evaluation for hypercapnia cellular metabolism and the level of CO, increases in the in the setting of respiratory failure. blood. Hypercapnia reflects alveolar hypoventilation, an Patients presenting with hypercapnic respiratory failure increased metabolic load that is not matched by an increase in frequently have coexisting hypoxemia. In these cases, 72

Common ICU Conditions TABLE 57. Features of Acute and Chronic Hypercapnia with a local poison control center is helpful to determine the most appropriate care ofthe patient. See discussion ofspecific Laboratory Acute Chronic Study Hypercapnia Hypercapnia agents in the Specific Critical Care Topics section. pH <7.35 -7.35-1.40 Arterial PCO2 >45 mm Hg (6.0 kPa) >45 mm Hg (6.0 kPa) Ob esity Hyp ou entilation Sy ndrome Obesity hypoventilation syndrome is characterized by the Bicarbonate 22-26 mEq/L >26 mEq/L concentration (22-26mmol/L) (26 mmol/L) presence ofobesity, sleep disordered breathing, and persistent lHCO3l daytime hypercapnia (arterial Pco, greater than 45 mm Hg Expected 1.0 mEq/L'f 3.5 mEq/L [5.9 kPa]). Hypercapnia stems from low tidal volumes and metabolic (1 mmol/L) [HCO3] (3.5 mmol/L) inappropriate central respiratory response. Acute hypercapnic compensation for each 10 mm Hg 1[HCO3] for each (1.3 kPa) I in arterial respiratory failure attributable to obesilz hypoventilation syn 1 0 mm Hg (1 .3 kPa)

pH <7.35 -7.35-1.40 Arterial PCO2 >45 mm Hg (6.0 kPa) >45 mm Hg (6.0 kPa) Ob esity Hyp ou entilation Sy ndrome Obesity hypoventilation syndrome is characterized by the Bicarbonate 22-26 mEq/L >26 mEq/L concentration (22-26mmol/L) (26 mmol/L) presence ofobesity, sleep disordered breathing, and persistent lHCO3l daytime hypercapnia (arterial Pco, greater than 45 mm Hg Expected 1.0 mEq/L'f 3.5 mEq/L [5.9 kPa]). Hypercapnia stems from low tidal volumes and metabolic (1 mmol/L) [HCO3] (3.5 mmol/L) inappropriate central respiratory response. Acute hypercapnic compensation for each 10 mm Hg 1[HCO3] for each (1.3 kPa) I in arterial respiratory failure attributable to obesilz hypoventilation syn 1 0 mm Hg (1 .3 kPa) Pco2 'l arterial Pco2 drome should be a diagnosis of exclusion. The 2019 guidelines from the American Thoracic Society recommend that hospi talized patients suspected of having this syndrome be started administration of supplemental oxygen may decrease hypox- on noninvasive ventilation with either bilevel positive airway emia, but it may increase hypercapnia (mechanisms include pressure or volume-targeted pressure support and continued V/Q mismatch, decreased respiratory drive, and the Haldane on this therapy until they undergo outpatient evaluation for efl'ect). This is particularly dangerous fbr patients with neuro obstructive sleep apnea. muscular diseases, as they may rapidly become more hyper Arterial blood gases should be monitored within 2 hours capnic, leading to obtundation and respiratory arrest. All of initiation of NPPV to ensure clinical improvement. If patients patients who are suspected of acute hypercapnic respiratory do not improve with adequate NPPV intubation is warranted. lailure should have arterial blood gas analysis even if hypox Respiratory stimulants such as acetazolamide, theophylline, or emia resolves with oxygen administration (Table 57). The pH a progestin have theoretical benefit to patients, but limited helps to determine the acuity and severity of respiratory fail data supporting their use in this setting. ure. In chronic hypercapnia, plJ changes are less marked because of metabolic compensation resulting in increased I(EY POIIITS serum bicarbonate levels. See MKSAP 19 Nephrologz for fur o Obesity hypoventilation syndrome is characterized by ther discussion of respiratory acidosis. the presence of obesity, sleep disordered breathing, and Management ofan elevated arterial Pco, depends on the persistent daytime hypercapnia (arterial Pco2 greater clinical situation and the resultant pH. For instance, an ele than 45 mm Hg [5.9 kPa]). vated arterial Pco, may represent the baseline in patients with o Noninvasive ventilation with bilevel positive airway COPD; however, in patients with asthma, the development of pressure or volume-targeted pressure support is the key elevated arterial Pco, may indicate imminent respiratory fail- to improving hypercapnia in hospitalized patients with ure requiring emergent intubation. obesity hlpoventilation syndrome. t( EY PO I I{I . All patients who are suspected of acute hypercapnic res- Decreased Tidal Volume and Increased Dead Space piratory failure should have arterial blood gas analysis N e uromuscular Weakness even if hypoxemia resolves with oxygen administration. The diaphragm is the main muscle responsible for inspiration and accounts for more than two thirds of the ventilatory work. Decreased Respiratory Drive The C3-C5 cervical nerve roots form the phrenic nerves, which Decreased respiratory drive leads to diminished alveolar CO, directly innervate the diaphragm. Diaphragmatic weakness is clearance and hypercapnia. Patients often present with som common in the ICU. Common causes are postsurgical phrenic nolence and difficulty protecting their airway. Noninvasive nerve injury and ICU-acquired weakness. positive pressure ventilation (NPPV) should be considered for Patients with diaphragmatic weakness develop ortho patients who can protect their airway. This improves minute pnea, shallow breathing, and paradoxical movement of the ventilation and gas exchange. If airway protection is compro chest wall and abdomen. Intercostal and abdominal wall mus mised or there is either significant respiratory acidosis (pH cles are required for coughing. Lower cervical and upper tho less than 7.25) or hemodynamic instability, intubation and racic nerve roots supply the intercostal and abdominal wall mechanical ventilation are indicated. muscles. Weak cough, difficulty managing secretions, or a change in voice may point to bulbar weakness. Drug Ouerdose Assessment of cranial nerves and respiratory muscle Sedating drugs (illicit or prescribed), anesthetics, and severe function is important in a patient with suspected neurologic alcohol intoxication can lead to depressed central respiratory disease. Specific components of pulmonary function testing drive. In addition to management as outlined earlier, contact can be helpful but are effort dependent (llable 58). Facial,

Pco2 'l arterial Pco2 drome should be a diagnosis of exclusion. The 2019 guidelines from the American Thoracic Society recommend that hospi talized patients suspected of having this syndrome be started administration of supplemental oxygen may decrease hypox- on noninvasive ventilation with either bilevel positive airway emia, but it may increase hypercapnia (mechanisms include pressure or volume-targeted pressure support and continued V/Q mismatch, decreased respiratory drive, and the Haldane on this therapy until they undergo outpatient evaluation for efl'ect). This is particularly dangerous fbr patients with neuro obstructive sleep apnea. muscular diseases, as they may rapidly become more hyper Arterial blood gases should be monitored within 2 hours capnic, leading to obtundation and respiratory arrest. All of initiation of NPPV to ensure clinical improvement. If patients patients who are suspected of acute hypercapnic respiratory do not improve with adequate NPPV intubation is warranted. lailure should have arterial blood gas analysis even if hypox Respiratory stimulants such as acetazolamide, theophylline, or emia resolves with oxygen administration (Table 57). The pH a progestin have theoretical benefit to patients, but limited helps to determine the acuity and severity of respiratory fail data supporting their use in this setting. ure. In chronic hypercapnia, plJ changes are less marked because of metabolic compensation resulting in increased I(EY POIIITS serum bicarbonate levels. See MKSAP 19 Nephrologz for fur o Obesity hypoventilation syndrome is characterized by ther discussion of respiratory acidosis. the presence of obesity, sleep disordered breathing, and Management ofan elevated arterial Pco, depends on the persistent daytime hypercapnia (arterial Pco2 greater clinical situation and the resultant pH. For instance, an ele than 45 mm Hg [5.9 kPa]). vated arterial Pco, may represent the baseline in patients with o Noninvasive ventilation with bilevel positive airway COPD; however, in patients with asthma, the development of pressure or volume-targeted pressure support is the key elevated arterial Pco, may indicate imminent respiratory fail- to improving hypercapnia in hospitalized patients with ure requiring emergent intubation. obesity hlpoventilation syndrome. t( EY PO I I{I . All patients who are suspected of acute hypercapnic res- Decreased Tidal Volume and Increased Dead Space piratory failure should have arterial blood gas analysis N e uromuscular Weakness even if hypoxemia resolves with oxygen administration. The diaphragm is the main muscle responsible for inspiration and accounts for more than two thirds of the ventilatory work. Decreased Respiratory Drive The C3-C5 cervical nerve roots form the phrenic nerves, which Decreased respiratory drive leads to diminished alveolar CO, directly innervate the diaphragm. Diaphragmatic weakness is clearance and hypercapnia. Patients often present with som common in the ICU. Common causes are postsurgical phrenic nolence and difficulty protecting their airway. Noninvasive nerve injury and ICU-acquired weakness. positive pressure ventilation (NPPV) should be considered for Patients with diaphragmatic weakness develop ortho patients who can protect their airway. This improves minute pnea, shallow breathing, and paradoxical movement of the ventilation and gas exchange. If airway protection is compro chest wall and abdomen. Intercostal and abdominal wall mus mised or there is either significant respiratory acidosis (pH cles are required for coughing. Lower cervical and upper tho less than 7.25) or hemodynamic instability, intubation and racic nerve roots supply the intercostal and abdominal wall mechanical ventilation are indicated. muscles. Weak cough, difficulty managing secretions, or a change in voice may point to bulbar weakness. Drug Ouerdose Assessment of cranial nerves and respiratory muscle Sedating drugs (illicit or prescribed), anesthetics, and severe function is important in a patient with suspected neurologic alcohol intoxication can lead to depressed central respiratory disease. Specific components of pulmonary function testing drive. In addition to management as outlined earlier, contact can be helpful but are effort dependent (llable 58). Facial, 73

Common ICU Conditions TABLE 58. Pulmonary Function Values Suggestive of scoliosis, kyphosis), which causes compromised respiratory Neuromuscular Weakness mechanics. Ascites and severe bowel distention can also Function Value compromise respiratory mechanics by exerting a significant cephalad force on the diaphragm. Extrapulmonary chest rtall FVC >20% decrement in FVC while supine compared with upright position restriction usually causes poorventilatory reserve without overt respiratory failure. However, acute insults such as infection or Maximal inspiratory Less than -60 cm H2O or 50% of predicted pressure sedating medications can precipitate hypercapnic respiratory Maximal expiratory Less than +60 cm H2O or 50% of failure. NPPV or invasive mechanical ventilation may be appro pressure predicted priate lthile the precipitating condition is managed. ln patients with thoracic cage deformity, NPPV is fiequently sufficient.

TABLE 58. Pulmonary Function Values Suggestive of scoliosis, kyphosis), which causes compromised respiratory Neuromuscular Weakness mechanics. Ascites and severe bowel distention can also Function Value compromise respiratory mechanics by exerting a significant cephalad force on the diaphragm. Extrapulmonary chest rtall FVC >20% decrement in FVC while supine compared with upright position restriction usually causes poorventilatory reserve without overt respiratory failure. However, acute insults such as infection or Maximal inspiratory Less than -60 cm H2O or 50% of predicted pressure sedating medications can precipitate hypercapnic respiratory Maximal expiratory Less than +60 cm H2O or 50% of failure. NPPV or invasive mechanical ventilation may be appro pressure predicted priate lthile the precipitating condition is managed. ln patients with thoracic cage deformity, NPPV is fiequently sufficient. bulbar, or postural weakness can affect accurate measure- Obstructiue Lung Diseases (Asthmo and COPD) ment. Pressure measurements may be falsely low in patients The physiologic hallmark of obstructive lung diseases is hyper with severe obstructive lung disease inflation. The main driver is high airway resistance resulting Guillain-Barre syndrome and myasthenic crisis are the from structural changes, inflammation, high cholinergic tone. most common causes of acute neurologic respiratory failure in and mucous plugging. When combined with a decrease in the the ICU. Patients with Guillain Barre syndrome generally pre- lung's elastic recoil (as observed in emphysema), this results in sent with ascending symmetric paralysis and areflexia occur increased total lung capacity and functional residual capacity ring during the course of 2 to 4 weeks. Dysautonomia is (lung volume at end exhalation). common and can cause hemodynamic instability or cardiac The degree of airflow obstruction and the respiration rate arrhythmias. In myasthenic crisis. the hallmark feature is mus both contribute to dynamic hyperinflation. Because of high cle fatigability. Diplopia, ptosis. dysarthria, limb weakness, and airflow resistance, air in the lungs does not have enough time weak cough are common. See MKSAP 19 Neurologr fbr lurther to exit before the next breath begins. which increases the discussion of Guillain-Barre syndrome and myasthenic crisis. functional residual capacity and limits the inspiratory capac In the 25'7, olpatients with Guillain Barre syndrome who ity. When the intrathoracic pressure remains positive at the develop respiratory tailure, intubation is necessary because end of exhalation because of this trapped volume, it is called respiratory function can take days to weeks to recover. In auto-PEEP. Dynamic hyperinflation, auto-PEEB and decreased myasthenic crisis, early NPPV may prevent the need for intu- elastic recoil of the lung all contribute to disordered lung bation; the ability to protect the airway and to cough must be mechanics, increased work of breathing, and respiratory carefully evaluated in such patients. muscle fatigue. When patients are on mechanical ventilation, Acute spinal cord injuries at or above the C5 level invari auto-PEEP may decrease venous return and contribute to ably require mechanical ventilation. ln some cases (complete hemodynamic instability. The main strategies to minimize spinal cord injury below C3 or incomplete injury above C3), auto PEEP are to prolong the expiratory time (with lower res recovery of independent respiratory function can occur. piration rate) and administer bronchodilators. However, atelectasis, aspiration pneumonia, and pulmonary At the time of a COPD exacerbation, patients may present emboli are common and can lead to recurrent acute hypercap- with signs of increased respiratory work. They may also have nic respiratory failure. NPPV and mechanical cough assist findings related to the presence ofhypercapnia, such as som devices are essential in the management and prevention of nolence. See Airways Disease section fbr more detailed infor these events. mation about the management of COPD exacerbations. I(EY POIIITS In patients with COPD, excessive oxygen can worsen o Guillain-Barrd syndrome and myasthenic crisis are the hypercapnia by three mechanisms: increasing V/Q mismatch, decreasing respiratory drive, and the Haldane effect. Oxygen most common causes of acute neurologic respiratory therapy should be titrated to BB% to 92"/,, SpOr. In patients with failure in the ICU. hypercapnic respiratory failure resulting from COPD exacer r Evaluation of maximum inspiratory and expiratory pres- bation, NPPV is preferred as the initial means to reduce Pcor; sures and positional changes in vital capacity are helpful bilevel positive airway pressure is the most commonly used in assessing neuromuscular weakness as a cause of hyper, and most effective NPPV mode for this condition. Il patients capnic respiratory failure. cannot protect their airway, are hemodynamically unstable. or do not improve on NPPV intubation and mechanical ventila- Restrictiue Chest Well Diseose tion are necessary. Restrictive disease from disorders affecting the pulmonary In patients with asthma, upright posture. inability to speak parenchyma (such as diffuse parenchymal lung disease) pri in lull sentences, diaphoresis, flaring of the nares, and use of marily leads to hypoxemia without hypercapnia. Acute hyper- accessory muscles during inspiration are signs of impending capnic respiratory failure is more common in patients with respiratory failure. Blood gases usually demonstrate respiratory extrapulmonary chest wall restriction (pectus defbrmity, alkalosis resulting from rapid, shallow breathing patterns, but

bulbar, or postural weakness can affect accurate measure- Obstructiue Lung Diseases (Asthmo and COPD) ment. Pressure measurements may be falsely low in patients The physiologic hallmark of obstructive lung diseases is hyper with severe obstructive lung disease inflation. The main driver is high airway resistance resulting Guillain-Barre syndrome and myasthenic crisis are the from structural changes, inflammation, high cholinergic tone. most common causes of acute neurologic respiratory failure in and mucous plugging. When combined with a decrease in the the ICU. Patients with Guillain Barre syndrome generally pre- lung's elastic recoil (as observed in emphysema), this results in sent with ascending symmetric paralysis and areflexia occur increased total lung capacity and functional residual capacity ring during the course of 2 to 4 weeks. Dysautonomia is (lung volume at end exhalation). common and can cause hemodynamic instability or cardiac The degree of airflow obstruction and the respiration rate arrhythmias. In myasthenic crisis. the hallmark feature is mus both contribute to dynamic hyperinflation. Because of high cle fatigability. Diplopia, ptosis. dysarthria, limb weakness, and airflow resistance, air in the lungs does not have enough time weak cough are common. See MKSAP 19 Neurologr fbr lurther to exit before the next breath begins. which increases the discussion of Guillain-Barre syndrome and myasthenic crisis. functional residual capacity and limits the inspiratory capac In the 25'7, olpatients with Guillain Barre syndrome who ity. When the intrathoracic pressure remains positive at the develop respiratory tailure, intubation is necessary because end of exhalation because of this trapped volume, it is called respiratory function can take days to weeks to recover. In auto-PEEP. Dynamic hyperinflation, auto-PEEB and decreased myasthenic crisis, early NPPV may prevent the need for intu- elastic recoil of the lung all contribute to disordered lung bation; the ability to protect the airway and to cough must be mechanics, increased work of breathing, and respiratory carefully evaluated in such patients. muscle fatigue. When patients are on mechanical ventilation, Acute spinal cord injuries at or above the C5 level invari auto-PEEP may decrease venous return and contribute to ably require mechanical ventilation. ln some cases (complete hemodynamic instability. The main strategies to minimize spinal cord injury below C3 or incomplete injury above C3), auto PEEP are to prolong the expiratory time (with lower res recovery of independent respiratory function can occur. piration rate) and administer bronchodilators. However, atelectasis, aspiration pneumonia, and pulmonary At the time of a COPD exacerbation, patients may present emboli are common and can lead to recurrent acute hypercap- with signs of increased respiratory work. They may also have nic respiratory failure. NPPV and mechanical cough assist findings related to the presence ofhypercapnia, such as som devices are essential in the management and prevention of nolence. See Airways Disease section fbr more detailed infor these events. mation about the management of COPD exacerbations. I(EY POIIITS In patients with COPD, excessive oxygen can worsen o Guillain-Barrd syndrome and myasthenic crisis are the hypercapnia by three mechanisms: increasing V/Q mismatch, decreasing respiratory drive, and the Haldane effect. Oxygen most common causes of acute neurologic respiratory therapy should be titrated to BB% to 92"/,, SpOr. In patients with failure in the ICU. hypercapnic respiratory failure resulting from COPD exacer r Evaluation of maximum inspiratory and expiratory pres- bation, NPPV is preferred as the initial means to reduce Pcor; sures and positional changes in vital capacity are helpful bilevel positive airway pressure is the most commonly used in assessing neuromuscular weakness as a cause of hyper, and most effective NPPV mode for this condition. Il patients capnic respiratory failure. cannot protect their airway, are hemodynamically unstable. or do not improve on NPPV intubation and mechanical ventila- Restrictiue Chest Well Diseose tion are necessary. Restrictive disease from disorders affecting the pulmonary In patients with asthma, upright posture. inability to speak parenchyma (such as diffuse parenchymal lung disease) pri in lull sentences, diaphoresis, flaring of the nares, and use of marily leads to hypoxemia without hypercapnia. Acute hyper- accessory muscles during inspiration are signs of impending capnic respiratory failure is more common in patients with respiratory failure. Blood gases usually demonstrate respiratory extrapulmonary chest wall restriction (pectus defbrmity, alkalosis resulting from rapid, shallow breathing patterns, but 74

Common ICU Conditions when the Pco, becomes normal or elevated, it may signal TABLE 59. Common Clinical Findings in Patients impending respiratory failure. Oxygen should be given to main With Shock tain a hemoglobin saturation of 90'1, to 95%. Altered mentation In cases of severe asthma exacerbation refractory to Capillary refilltime (>2 s) conventional management, therapies with lower levels of evi Elevated serum lactate (>3 mEq/L [3 mmol/L]) dence, such as magnesium sulfate or heliox, may be used. Other adjunctive therapies are not recommended because of' Hypotension (SBP <90 mm Hg)or >30 mm Hg drop in SBP from baseline lack of demonstrated efficacy. Antibiotics should not be administered unless there is evidence of infection. Mottled skin Little evidence supports the use of NPPV in asthma exac Tachycardia (heart rate >100/min) erbations. If used, close monitoring is required. For most Tachypnea (respiration rate >2Olmin) patients with asthma with respiratory failure, mechanical Urine output <0.5 mUkg/h ventilation and intubation are recommended. As with COPD, SBP = systolic blood pressure eflbrts should be directed at maximizing expiratory time, as this reduces auto PEEP Doing so often requires sedation or paralytics and can lower the overall minute ventilation. venous thrombosis and pleural or abdominal abnormalities. Because this may increase arterial Pcor, arterial blood gas Evidence for pulmonary artery catheters demonstrates a lack of analysis should be performed frequently in these patients. See benefit and, in some cases, increased risk to patients. Despite this, Airways Disease section for more detailed information about pulmonary artery catheters may provide diagnostic utility in management of asthma exacerbations. select patients who require assessment of cardiopulmonary pressures or cardiac output, such as those with pulmonary rEY POIIITS . Patients with hypercapnic respiratory failure and COPD exacerbation benefit from noninvasive positive pressure Evaluate for clinical signs of organ hypoperfusion

when the Pco, becomes normal or elevated, it may signal TABLE 59. Common Clinical Findings in Patients impending respiratory failure. Oxygen should be given to main With Shock tain a hemoglobin saturation of 90'1, to 95%. Altered mentation In cases of severe asthma exacerbation refractory to Capillary refilltime (>2 s) conventional management, therapies with lower levels of evi Elevated serum lactate (>3 mEq/L [3 mmol/L]) dence, such as magnesium sulfate or heliox, may be used. Other adjunctive therapies are not recommended because of' Hypotension (SBP <90 mm Hg)or >30 mm Hg drop in SBP from baseline lack of demonstrated efficacy. Antibiotics should not be administered unless there is evidence of infection. Mottled skin Little evidence supports the use of NPPV in asthma exac Tachycardia (heart rate >100/min) erbations. If used, close monitoring is required. For most Tachypnea (respiration rate >2Olmin) patients with asthma with respiratory failure, mechanical Urine output <0.5 mUkg/h ventilation and intubation are recommended. As with COPD, SBP = systolic blood pressure eflbrts should be directed at maximizing expiratory time, as this reduces auto PEEP Doing so often requires sedation or paralytics and can lower the overall minute ventilation. venous thrombosis and pleural or abdominal abnormalities. Because this may increase arterial Pcor, arterial blood gas Evidence for pulmonary artery catheters demonstrates a lack of analysis should be performed frequently in these patients. See benefit and, in some cases, increased risk to patients. Despite this, Airways Disease section for more detailed information about pulmonary artery catheters may provide diagnostic utility in management of asthma exacerbations. select patients who require assessment of cardiopulmonary pressures or cardiac output, such as those with pulmonary rEY POIIITS . Patients with hypercapnic respiratory failure and COPD exacerbation benefit from noninvasive positive pressure Evaluate for clinical signs of organ hypoperfusion ventilation, provided they can protect their airway and . Absent bowel sounds . Altered mentation are hemodynamically stable. r Cool extremities/skin mottling . In patients with asthma with respiratory failure, intu- . Decreased urine output bation and mechanical evaluation are recommended . Prolonged capillary refill rather than noninvasive positive pressure ventilation. HVC . In severe refractory asthma, anesthetics with broncho- dilator properties (aminophylline, mucolltics, and leu- kotriene receptor antagonists) are not recommended. Assess hemodynamics . SBP <90 mm Hg or MAP <70 mm Hg . Tachycardia Shock Shock occurs when systemic tissue perfusion is inadequate. ln early states of tissue hypoperfusion, aerobic metabolism is supplanted by anaerobic metabolism and tissue injury is Evaluate laboratory markers of tissue hypoperfusion reversible. As compensatory mechanisms fail, sustained organ . Lactate hypoperfusion can lead to cellular dysfunction and death. o Serum creatinine There are four primary mechanisms of shock: decreased cir- . Serum pH culating volume (hypovolemic), pump failure (cardiogenic), r Serum troponin circulatory obstruction (obstructive), and inappropriate vaso dilation (distributive)-these mechanisms may overlap. Hypotension alone should not be considered diagnostic of end organ hypoperfusion. Instead, blood pressure should be Perform initial ancillary testing considered in the context of other physical examination find . Blood, sputum, wound, or urine cultures ings that may suggest end organ hypoperfusion (Table 59). . Complete blood count A thorough examination ol the patient, laboratory results, . Electrocardiogram and ancillary studies (Figure 27) are essential to identi8ring the o Point-of-care ultrasound type of shock present (Table 6O). The use of point of care ultra (echo, lung ultrasound, vascular ultrasound) sound to aid in shock assessment is increasing. Echocardiography . Radiography studies can provide usefirl data regarding cardiac function and cardiac response to treatment. Vascular, lung, and abdominal ultra F I G U R E 2 7. Evaluation o{ shock. MAP = mean arterial pressure; SBP = systolic sonography improve procedural safety and can rapidly assess for blood pressure.

ventilation, provided they can protect their airway and . Absent bowel sounds . Altered mentation are hemodynamically stable. r Cool extremities/skin mottling . In patients with asthma with respiratory failure, intu- . Decreased urine output bation and mechanical evaluation are recommended . Prolonged capillary refill rather than noninvasive positive pressure ventilation. HVC . In severe refractory asthma, anesthetics with broncho- dilator properties (aminophylline, mucolltics, and leu- kotriene receptor antagonists) are not recommended. Assess hemodynamics . SBP <90 mm Hg or MAP <70 mm Hg . Tachycardia Shock Shock occurs when systemic tissue perfusion is inadequate. ln early states of tissue hypoperfusion, aerobic metabolism is supplanted by anaerobic metabolism and tissue injury is Evaluate laboratory markers of tissue hypoperfusion reversible. As compensatory mechanisms fail, sustained organ . Lactate hypoperfusion can lead to cellular dysfunction and death. o Serum creatinine There are four primary mechanisms of shock: decreased cir- . Serum pH culating volume (hypovolemic), pump failure (cardiogenic), r Serum troponin circulatory obstruction (obstructive), and inappropriate vaso dilation (distributive)-these mechanisms may overlap. Hypotension alone should not be considered diagnostic of end organ hypoperfusion. Instead, blood pressure should be Perform initial ancillary testing considered in the context of other physical examination find . Blood, sputum, wound, or urine cultures ings that may suggest end organ hypoperfusion (Table 59). . Complete blood count A thorough examination ol the patient, laboratory results, . Electrocardiogram and ancillary studies (Figure 27) are essential to identi8ring the o Point-of-care ultrasound type of shock present (Table 6O). The use of point of care ultra (echo, lung ultrasound, vascular ultrasound) sound to aid in shock assessment is increasing. Echocardiography . Radiography studies can provide usefirl data regarding cardiac function and cardiac response to treatment. Vascular, lung, and abdominal ultra F I G U R E 2 7. Evaluation o{ shock. MAP = mean arterial pressure; SBP = systolic sonography improve procedural safety and can rapidly assess for blood pressure. 75

Common ICU Conditions TABLE 60. Selected Causes of Shock Distributive Shock Distributive In distributive shock, the blood volume is generally norrnal, but a state of "relative" hypovolemia occurs from excessive Anaphylaxis vasodilation and microvascular dysfunction. Cardiac output is Drugs (periphera I vasodilators, nitrates) often increased but still cannot maintain a pressure sufficient Sepsis fbr normal tissue perfusion. Sepsis is the most common cause Spinal injury (usually above T4 level) of distributive shock, but other disease states present similarly Hypovolemic (see Table 60). Initial treatment of distributive shock should focus on fluid resuscitation. Several studies have compared the Acute blood loss (trauma, Gl bleeding, surgery, uterine bleeding, : obstetrical, retroperitoneal bleeding, aortic rupture) effectiveness of crystalloid versus colloid administration. with Crush injury, rhabdomyolysis no clear evidence that one is better than the other. A large randomized controlled trial suggested that critically ill patients Cutaneous losses (burns, toxic epidermal necrolysis, erythroderma, excessive sweating) who were resuscitated using balanced crystalloid solution had a lower composite outcome of death, need for renal replace Drugs (diuretics, laxatives) ment therapy, or persistent kidney dysfunction compared with Gl losses (vomiting/diarrhea) patients receiving normal saline solution. Balanced crystalloid Kidney losses (diabetic ketoacidosis, hyperglycemic hyperosmolar solutions have an electrolyte composition similar to plasma syndrome, adrenal insufficiency, post-ATN osmotic diuresis) with the addition of a buffer, such as lactate (for example. Cardiogenic lactated Ringer solution). If fluid administration alone is insuf- Arrhythmia (tachycardia, bradycardia) ficient to support tissue perfusion. vasopressor support is war Heart failure ranted. The selection ofa vasopressor should be based on the Pulmonary hypertension patient's comorbidities and underlying cause of shock. Myocardial infarction IEY POI lII Valvular heart disease (critical stenosis, severe insufficiency, . Several studies have compared the effectiveness of crys- HVC valve perforation, papillary muscle or chordae rupture) talloid versus colloid administration for treatment of Ventricular septal ru distributive shock, with no clear evidence of either's Obstruaive superiority; given the relative expense of colloids, crys- I Abdominal compartment syndrome talloid administration is generally preferred and recom- Atrial myxoma mended by guidelines.

TABLE 60. Selected Causes of Shock Distributive Shock Distributive In distributive shock, the blood volume is generally norrnal, but a state of "relative" hypovolemia occurs from excessive Anaphylaxis vasodilation and microvascular dysfunction. Cardiac output is Drugs (periphera I vasodilators, nitrates) often increased but still cannot maintain a pressure sufficient Sepsis fbr normal tissue perfusion. Sepsis is the most common cause Spinal injury (usually above T4 level) of distributive shock, but other disease states present similarly Hypovolemic (see Table 60). Initial treatment of distributive shock should focus on fluid resuscitation. Several studies have compared the Acute blood loss (trauma, Gl bleeding, surgery, uterine bleeding, : obstetrical, retroperitoneal bleeding, aortic rupture) effectiveness of crystalloid versus colloid administration. with Crush injury, rhabdomyolysis no clear evidence that one is better than the other. A large randomized controlled trial suggested that critically ill patients Cutaneous losses (burns, toxic epidermal necrolysis, erythroderma, excessive sweating) who were resuscitated using balanced crystalloid solution had a lower composite outcome of death, need for renal replace Drugs (diuretics, laxatives) ment therapy, or persistent kidney dysfunction compared with Gl losses (vomiting/diarrhea) patients receiving normal saline solution. Balanced crystalloid Kidney losses (diabetic ketoacidosis, hyperglycemic hyperosmolar solutions have an electrolyte composition similar to plasma syndrome, adrenal insufficiency, post-ATN osmotic diuresis) with the addition of a buffer, such as lactate (for example. Cardiogenic lactated Ringer solution). If fluid administration alone is insuf- Arrhythmia (tachycardia, bradycardia) ficient to support tissue perfusion. vasopressor support is war Heart failure ranted. The selection ofa vasopressor should be based on the Pulmonary hypertension patient's comorbidities and underlying cause of shock. Myocardial infarction IEY POI lII Valvular heart disease (critical stenosis, severe insufficiency, . Several studies have compared the effectiveness of crys- HVC valve perforation, papillary muscle or chordae rupture) talloid versus colloid administration for treatment of Ventricular septal ru distributive shock, with no clear evidence of either's Obstruaive superiority; given the relative expense of colloids, crys- I Abdominal compartment syndrome talloid administration is generally preferred and recom- Atrial myxoma mended by guidelines. Constrictive pericarditis Hypovolemic Shock Pericardial tamponade Hypovolemic shock occurs when decreased intravascular Pulmonary embolism blood volume causes decreased preload, decreased ventricular Severe dynamic hyperinflation (e.g., excessive PEEP) filling, and diminished stroke volume. Initially, tachycardia Tension pneumothorax and peripheral vasoconstriction help to preserve perfusion of vital organs but cannot compensate in the setting of severe ATN = acute tubular necrosis; Gl = gastrointestinal; PEEP = positive end-expiratory pressure. hypovolemia. Treatment of hypovolemic shock includes aggressive volume or blood product replacement and control- ling any source of bleeding. Patients with hemorrhage initially hypertension, tamponade, or pericarditis. Other tools that pre receive intravenous fluids to maintain hemodynamic stabiliry dict response to volume replacement, such as pulse contour but ultimately may need erythrocyte transfusion to prevent analysis, pulse pressure, or stroke volume, variation can also be tissue ischemia. In stable ICU patients, hemoglobin levels considered. However, these methods are invasive and carry pro- should be maintained above 7 gldL (7O glL); however, different cedural limitations that may make them impractical or unrelia- thresholds and hemoglobin levels may trigger transfusion in ble. Treatment is directed toward correcting the root cause of the actively bleeding patients who are in shock. Higher hemo- shock state. globin values may be desirable in patients with underlying I(EY POIXTS cardiovascular disease. In patients with severe trauma result- . Treatment of a patient in shock is predicated on distin- ing in massive blood replacement requirements and coagu guishing the type ofshock present and directed toward lopathy, evidence supports early resuscitation with a 1:1:1 ratio the root cause ofthe shock state. of erythrocltes, platelets, and fresh frozen plasma.

Constrictive pericarditis Hypovolemic Shock Pericardial tamponade Hypovolemic shock occurs when decreased intravascular Pulmonary embolism blood volume causes decreased preload, decreased ventricular Severe dynamic hyperinflation (e.g., excessive PEEP) filling, and diminished stroke volume. Initially, tachycardia Tension pneumothorax and peripheral vasoconstriction help to preserve perfusion of vital organs but cannot compensate in the setting of severe ATN = acute tubular necrosis; Gl = gastrointestinal; PEEP = positive end-expiratory pressure. hypovolemia. Treatment of hypovolemic shock includes aggressive volume or blood product replacement and control- ling any source of bleeding. Patients with hemorrhage initially hypertension, tamponade, or pericarditis. Other tools that pre receive intravenous fluids to maintain hemodynamic stabiliry dict response to volume replacement, such as pulse contour but ultimately may need erythrocyte transfusion to prevent analysis, pulse pressure, or stroke volume, variation can also be tissue ischemia. In stable ICU patients, hemoglobin levels considered. However, these methods are invasive and carry pro- should be maintained above 7 gldL (7O glL); however, different cedural limitations that may make them impractical or unrelia- thresholds and hemoglobin levels may trigger transfusion in ble. Treatment is directed toward correcting the root cause of the actively bleeding patients who are in shock. Higher hemo- shock state. globin values may be desirable in patients with underlying I(EY POIXTS cardiovascular disease. In patients with severe trauma result- . Treatment of a patient in shock is predicated on distin- ing in massive blood replacement requirements and coagu guishing the type ofshock present and directed toward lopathy, evidence supports early resuscitation with a 1:1:1 ratio the root cause ofthe shock state. of erythrocltes, platelets, and fresh frozen plasma. HVC . Evidence for pulmonary artery catheters demonstrates Cardiogenic Shock a lack ofbenefit and, in some cases, increased risk to patients. Arrhythmias, myocardial dysfunction, and valvular disease can lead to decreased cardiac output and cardiogenic shock.

HVC . Evidence for pulmonary artery catheters demonstrates Cardiogenic Shock a lack ofbenefit and, in some cases, increased risk to patients. Arrhythmias, myocardial dysfunction, and valvular disease can lead to decreased cardiac output and cardiogenic shock. 76

Common ICU Conditions The most common cause of cardiogenic shock is myocardial at many levels, from subcellular mitochondrial dysfunction to infarction. Cardiogenic shock-induced tachycardia and vaso failure of entire organ systems. Loss of regulation of the body's constriction increase afterload and myocardial oxygen flnely balanced proinflammatory and antiinflammatory media- demand, often precipitating a further decrease in cardiac tors and unregulated coagulation in the microvasculature are output. Initial evaluation should include a focused physical characteristic of the syndrome. examination, laboratory testing for myocardial ischemia and Operationally, sepsis can be identified whenever infection heart failure, chest radiograph, electrocardiogram, and trans- is known or suspected and clinical criteria defining organ thoracic echocardiogram. External or transvenous pacing may dysfunction are met. The recommended criteria to assess be indicated in patients with bradyarrhythmias. Emergent organ dysfunction are included in the Sequential Organ percutaneous intervention or fibrino\tic therapy is indicated Failure Assessment (SOFA) score, which assigns a value of 0 to ifECG suggests ST-elevation myocardial infarction and labora- 4 for each ofsix organ systems assessed, respiratory coagula tory examination supports coronary ischemia. Although not tion, hepatic, cardiovascular, central nervous, and renal, with clearly supported by evidence, patients with severe cardio increasing scores for more severe dysfunction (online SOFA genic shock may beneflt from adjunctive measures as a bridge score calculators are available online: http://clincalc.com/ toward definitive therapy. These include ECMO, intraaortic IcuMortality /SOFA. aspx ; https : //wr,wv. mdcalc. com/sequen- balloon pumps, and left or right ventricular assist devices. In tial-organ-failure assessment sofa score). An initial SOFA some cases, these devices can be employed as destination score of 2 or greater or an increase in SOFA score of 2 or more therapy correlates with acute organ dysfunction and predicts hospital mortality of greater than 10%. The SOFA score should be used Obstructive Shock to assess patients in the ICU. Obstructive shock is caused by extracardiac forces that, despite Sepsis-3 guidelines recommend the use of the simplified normal cardiac function, act to impair cardiac output. quick SOFA (qSOFA) score, a clinical scoring system that Examples include tamponade, tension pneumothorax, and includes only three criteria: elevated respiration rate, altered acute PE. Although hemodynamics frequently mimic those of mentation, and hypotension (Table 61). A qSOFA score of 2 or cardiogenic shock, the clinical presentation of obstructive greater in the setting of known or suspected infection predicts shock varies depending on the cause. A patient with PE may increased mortality and should prompt evaluation for resusci- have signs ofelevated right atrial pressure, including jugular tation and consideration of ICU admission. Failure to meet two venous distention and lower extremity edema, but can have a or more qSOFA criteria should not be construed as ruling out clear pulmonary exam. A patient with tamponade may have sepsis or the need for ICU admission. Recently, the use of jugularvenous distension, pulsus paradoxus, and distant heart qSOFA to predict sepsis has come under increased scrutiny, sounds. A patient with tension pneumothorax may have given conflicting studies regarding its accuracy across different absent lung sounds on the affected side ofthe chest. History patient populations. Other scoring systems, such as the and clinical examination should guide ancillary testing and National Early Warning Score, may outperform qSOFA in pre- management. Point-of-care Iung ultrasound can help rapidly dicting in-hospital death and need for ICU admission. Because assess patients for pneumothorax, and echocardiography can there is no perfect test for identi$ring sepsis, scoring systems quickly identify features consistent with PE or pericardial should not be used as the sole indicator of disease or triage effusion. In some cases, such as constrictive or restrictive needs. pericarditis or pulmonary arterial hypertension, invasive The criteria for diagnosing septic shock includes hypo hemodynamic evaluation of cardiopulmonary pressures helps tension requiring vasopressors to maintain a mean arterial to conflrm a diagnosis. Most cases ofobstructive shock can be pressure of greater than 65 mm Hg and serum lactate level rapidly reversed if promptly identified. of greater than 2 mEq/L (2 mmol/L) despite adequate fluid

The most common cause of cardiogenic shock is myocardial at many levels, from subcellular mitochondrial dysfunction to infarction. Cardiogenic shock-induced tachycardia and vaso failure of entire organ systems. Loss of regulation of the body's constriction increase afterload and myocardial oxygen flnely balanced proinflammatory and antiinflammatory media- demand, often precipitating a further decrease in cardiac tors and unregulated coagulation in the microvasculature are output. Initial evaluation should include a focused physical characteristic of the syndrome. examination, laboratory testing for myocardial ischemia and Operationally, sepsis can be identified whenever infection heart failure, chest radiograph, electrocardiogram, and trans- is known or suspected and clinical criteria defining organ thoracic echocardiogram. External or transvenous pacing may dysfunction are met. The recommended criteria to assess be indicated in patients with bradyarrhythmias. Emergent organ dysfunction are included in the Sequential Organ percutaneous intervention or fibrino\tic therapy is indicated Failure Assessment (SOFA) score, which assigns a value of 0 to ifECG suggests ST-elevation myocardial infarction and labora- 4 for each ofsix organ systems assessed, respiratory coagula tory examination supports coronary ischemia. Although not tion, hepatic, cardiovascular, central nervous, and renal, with clearly supported by evidence, patients with severe cardio increasing scores for more severe dysfunction (online SOFA genic shock may beneflt from adjunctive measures as a bridge score calculators are available online: http://clincalc.com/ toward definitive therapy. These include ECMO, intraaortic IcuMortality /SOFA. aspx ; https : //wr,wv. mdcalc. com/sequen- balloon pumps, and left or right ventricular assist devices. In tial-organ-failure assessment sofa score). An initial SOFA some cases, these devices can be employed as destination score of 2 or greater or an increase in SOFA score of 2 or more therapy correlates with acute organ dysfunction and predicts hospital mortality of greater than 10%. The SOFA score should be used Obstructive Shock to assess patients in the ICU. Obstructive shock is caused by extracardiac forces that, despite Sepsis-3 guidelines recommend the use of the simplified normal cardiac function, act to impair cardiac output. quick SOFA (qSOFA) score, a clinical scoring system that Examples include tamponade, tension pneumothorax, and includes only three criteria: elevated respiration rate, altered acute PE. Although hemodynamics frequently mimic those of mentation, and hypotension (Table 61). A qSOFA score of 2 or cardiogenic shock, the clinical presentation of obstructive greater in the setting of known or suspected infection predicts shock varies depending on the cause. A patient with PE may increased mortality and should prompt evaluation for resusci- have signs ofelevated right atrial pressure, including jugular tation and consideration of ICU admission. Failure to meet two venous distention and lower extremity edema, but can have a or more qSOFA criteria should not be construed as ruling out clear pulmonary exam. A patient with tamponade may have sepsis or the need for ICU admission. Recently, the use of jugularvenous distension, pulsus paradoxus, and distant heart qSOFA to predict sepsis has come under increased scrutiny, sounds. A patient with tension pneumothorax may have given conflicting studies regarding its accuracy across different absent lung sounds on the affected side ofthe chest. History patient populations. Other scoring systems, such as the and clinical examination should guide ancillary testing and National Early Warning Score, may outperform qSOFA in pre- management. Point-of-care Iung ultrasound can help rapidly dicting in-hospital death and need for ICU admission. Because assess patients for pneumothorax, and echocardiography can there is no perfect test for identi$ring sepsis, scoring systems quickly identify features consistent with PE or pericardial should not be used as the sole indicator of disease or triage effusion. In some cases, such as constrictive or restrictive needs. pericarditis or pulmonary arterial hypertension, invasive The criteria for diagnosing septic shock includes hypo hemodynamic evaluation of cardiopulmonary pressures helps tension requiring vasopressors to maintain a mean arterial to conflrm a diagnosis. Most cases ofobstructive shock can be pressure of greater than 65 mm Hg and serum lactate level rapidly reversed if promptly identified. of greater than 2 mEq/L (2 mmol/L) despite adequate fluid TABTE S'!. qSOFA Score Sepsis Criterion Value qSOFA Points Definition, Pathophysiology, and Respiration rate >22/min 1

The most common cause of cardiogenic shock is myocardial at many levels, from subcellular mitochondrial dysfunction to infarction. Cardiogenic shock-induced tachycardia and vaso failure of entire organ systems. Loss of regulation of the body's constriction increase afterload and myocardial oxygen flnely balanced proinflammatory and antiinflammatory media- demand, often precipitating a further decrease in cardiac tors and unregulated coagulation in the microvasculature are output. Initial evaluation should include a focused physical characteristic of the syndrome. examination, laboratory testing for myocardial ischemia and Operationally, sepsis can be identified whenever infection heart failure, chest radiograph, electrocardiogram, and trans- is known or suspected and clinical criteria defining organ thoracic echocardiogram. External or transvenous pacing may dysfunction are met. The recommended criteria to assess be indicated in patients with bradyarrhythmias. Emergent organ dysfunction are included in the Sequential Organ percutaneous intervention or fibrino\tic therapy is indicated Failure Assessment (SOFA) score, which assigns a value of 0 to ifECG suggests ST-elevation myocardial infarction and labora- 4 for each ofsix organ systems assessed, respiratory coagula tory examination supports coronary ischemia. Although not tion, hepatic, cardiovascular, central nervous, and renal, with clearly supported by evidence, patients with severe cardio increasing scores for more severe dysfunction (online SOFA genic shock may beneflt from adjunctive measures as a bridge score calculators are available online: http://clincalc.com/ toward definitive therapy. These include ECMO, intraaortic IcuMortality /SOFA. aspx ; https : //wr,wv. mdcalc. com/sequen- balloon pumps, and left or right ventricular assist devices. In tial-organ-failure assessment sofa score). An initial SOFA some cases, these devices can be employed as destination score of 2 or greater or an increase in SOFA score of 2 or more therapy correlates with acute organ dysfunction and predicts hospital mortality of greater than 10%. The SOFA score should be used Obstructive Shock to assess patients in the ICU. Obstructive shock is caused by extracardiac forces that, despite Sepsis-3 guidelines recommend the use of the simplified normal cardiac function, act to impair cardiac output. quick SOFA (qSOFA) score, a clinical scoring system that Examples include tamponade, tension pneumothorax, and includes only three criteria: elevated respiration rate, altered acute PE. Although hemodynamics frequently mimic those of mentation, and hypotension (Table 61). A qSOFA score of 2 or cardiogenic shock, the clinical presentation of obstructive greater in the setting of known or suspected infection predicts shock varies depending on the cause. A patient with PE may increased mortality and should prompt evaluation for resusci- have signs ofelevated right atrial pressure, including jugular tation and consideration of ICU admission. Failure to meet two venous distention and lower extremity edema, but can have a or more qSOFA criteria should not be construed as ruling out clear pulmonary exam. A patient with tamponade may have sepsis or the need for ICU admission. Recently, the use of jugularvenous distension, pulsus paradoxus, and distant heart qSOFA to predict sepsis has come under increased scrutiny, sounds. A patient with tension pneumothorax may have given conflicting studies regarding its accuracy across different absent lung sounds on the affected side ofthe chest. History patient populations. Other scoring systems, such as the and clinical examination should guide ancillary testing and National Early Warning Score, may outperform qSOFA in pre- management. Point-of-care Iung ultrasound can help rapidly dicting in-hospital death and need for ICU admission. Because assess patients for pneumothorax, and echocardiography can there is no perfect test for identi$ring sepsis, scoring systems quickly identify features consistent with PE or pericardial should not be used as the sole indicator of disease or triage effusion. In some cases, such as constrictive or restrictive needs. pericarditis or pulmonary arterial hypertension, invasive The criteria for diagnosing septic shock includes hypo hemodynamic evaluation of cardiopulmonary pressures helps tension requiring vasopressors to maintain a mean arterial to conflrm a diagnosis. Most cases ofobstructive shock can be pressure of greater than 65 mm Hg and serum lactate level rapidly reversed if promptly identified. of greater than 2 mEq/L (2 mmol/L) despite adequate fluid TABTE S'!. qSOFA Score Sepsis Criterion Value qSOFA Points Definition, Pathophysiology, and Respiration rate >22/min 1 Clinical Presentation of Sepsis Systolic blood <1 00 mm Hg 1

TABTE S'!. qSOFA Score Sepsis Criterion Value qSOFA Points Definition, Pathophysiology, and Respiration rate >22/min 1 Clinical Presentation of Sepsis Systolic blood <1 00 mm Hg 1 The Third International Definitions for Sepsis and Septic p ressu re Shock (Sepsis-3) define sepsis as life threatening organ dys- Mental status Altered from baseline 1 function caused by a dysregulated host response to infection. Septic shock is defined as a subset ofsepsis in which profound qSOFA Score Predicted Mortality circulatory cellular, and metabolic abnormalities are associ- U <1Y" ated with a greater risk for mortality than with sepsis alone. 1 2o/o-3o/o Infections giving rise to sepsis can include any pathogen >2 >10% and involve any organ. Infections need not be disseminated. The qSOFA = quick Sequential Organ Failure Assessment. pathophysiologz of sepsis is complex and involves dysfunction 77

Common ICU Conditions resuscitation. Patients who meet these criteria have a 40% or contractility, and decreased vascular tone. Patients may pre greater risk for in hospital mortality. sent in shock, sometimes with profound hypotension requir- ing large volume resuscitation with intravenous fluids or I(EY POII{T vasopressor therapy. . The criteria for diagnosing septic shock includes a The Surviving Sepsis Campaign guidelines recommend serum lactate level of greater than 2 mEq/L (2 mmol/L) early and aggressive fluid resuscitation. In patients with sus- despite adequate fluid resuscitation and hypotension pected sepsis. an initial bolus of 30 ml/kg of crystalloid fluid requiring vasopressors to maintain a mean arterial should be given in the first hour of presentation when hypo- pressure of greater than 65 mm Hg. tension or a lactate of at least 4 mmol/L is present. When lac- tate levels are elevated more than 2 mmol/L. they should be Epidemiology of Sepsis rechecked w'ithin 2 to 4 hours to ensure improvement. The epidemiologi of sepsis is difficult to judge accurately Although experts agree that aggressive fluid resuscitation is because of its evolving definition, challenges with clinical rec- essential, the adequacy of initial fluid resuscitation and the ognition of the syndrome, and lack of standardized reporting. need for further fluid or vasopressors requires clinical judg However, estimating its clinical and economic effects is pos ment based on patient comorbidities and the available data. sible. There are disparities in sepsis rates among different When hypotension or hypoperfusion persists, additional demographic groups. For example, sepsis is more common fluids or vasopressors may be needed. The Surviving Sepsis among Black men than other racial groups or women. Sepsis Campaign guidelines support using norepinephrine as first is also more common among older adults, with incidence line therapy in patients who require vasopressor support, as increasing with each year after the age of 65 years. Mortality it increases systemic vascular resistance without compromis- from sepsis is high. A patient who is septic has a mortality rate ing myocardial performance (stroke volume or cardiac out 4 or more times greater than for the same underlying condi put). In cases where norepinephrine alone is insufficient, tion and comorbidities without sepsis. Mortality increases by secondary agents, including epinephrine, vasopressin, or roughly 15% lbr each sepsis related organ system failure. dobutamine, may be considered. Dopamine is not recom- mended for use in septic shock except in select patients with Management of Sepsis clinically significant bradycardia, given its association with For years, sepsis guidelines have focused on early diagnosis increased tachyarrhy'thmia and death compared with norepi and timely treatment of sepsis to improve survival. Early nephrine. Phenylephrine should be usedwith caution because guidelines supported time-based metrics to be achieved in the it can lead to decreased stroke volumes despite improvement form of a sepsis "bundle." In 2016 a 3 hour and a 6-hourbun- in mean arterial pressure. The Surviving Sepsis Campaign dle were proposed on the basis of evidence that bundle based guidelines recommend it be used only as a salvage therapy or care led to significant improvements in sepsis mortality. in cases where tachyarrhlthmia prevents use of alternative However, subsequent data suggested that in-hospital mortality vasopressor agents (see Table 50). might be further improved by expediting care within the ini I(EY POIIITS tial 3-hour window. In 2018 the Surviving Sepsis Campaign issued updated guidelines that combined the previous 3 and . Early and aggressive fluid resuscitation for patients with hlpoperfusion resulting from sepsis begins with an initial 6-hour bundles into a single t hour sepsis bundle. The t hour bolus of 30 ml/kg body weight of crystalloid solution. bundle includes collection of blood cultures, measurement of serum lactate levels, administration ofbroad spectrum antibi- . Norepineptrine is recommended as the first vasopressor otics, and provision of fluid or vasopressor resuscitation in ofchoice for septic shock. patients with hypotension or signs of hypoperfusion. Weak evidence behind some elements of the t hour bundle recom Antibiotic Therapy mendations has generated considerable controversy, but the Early antibiotic therapy is crucial in treating sepsis. Broad intent of these recommendations clearly addresses the tvvo spectrum antibiotics should be given within the first hour of main pillars of sepsis management: supporting organ perfu- suspected sepsis, and the regimen should be subsequently sion and controlling the infection. adjusted on the basis ofculture results. Delay in the first dose ofantibiotic therapy or use ofinappropriate antibiotic therapy KEY POIl{T increases sepsis mortality. Although antibiotic stewardship is o The two main pillars of sepsis management are sup- ofl paramount importance, the Surviving Sepsis Campaign porting organ perfusion and function and controlling guidelines recommend choosing up-front empiric therapy the infection. that is broad enough to cover the most likely pathogens caus- ing sepsis. The most common pathogens include gram Initial Resuscitation negative, gram positive, and "mixed" bacterial pathogens. Sepsis can have serious hemodynamics effects, with decreased However, treatment consideration should not be limited to preload (resulting from capillary leak), impaired cardiac bacterial coverage if empiric viral or fungal coverage are

resuscitation. Patients who meet these criteria have a 40% or contractility, and decreased vascular tone. Patients may pre greater risk for in hospital mortality. sent in shock, sometimes with profound hypotension requir- ing large volume resuscitation with intravenous fluids or I(EY POII{T vasopressor therapy. . The criteria for diagnosing septic shock includes a The Surviving Sepsis Campaign guidelines recommend serum lactate level of greater than 2 mEq/L (2 mmol/L) early and aggressive fluid resuscitation. In patients with sus- despite adequate fluid resuscitation and hypotension pected sepsis. an initial bolus of 30 ml/kg of crystalloid fluid requiring vasopressors to maintain a mean arterial should be given in the first hour of presentation when hypo- pressure of greater than 65 mm Hg. tension or a lactate of at least 4 mmol/L is present. When lac- tate levels are elevated more than 2 mmol/L. they should be Epidemiology of Sepsis rechecked w'ithin 2 to 4 hours to ensure improvement. The epidemiologi of sepsis is difficult to judge accurately Although experts agree that aggressive fluid resuscitation is because of its evolving definition, challenges with clinical rec- essential, the adequacy of initial fluid resuscitation and the ognition of the syndrome, and lack of standardized reporting. need for further fluid or vasopressors requires clinical judg However, estimating its clinical and economic effects is pos ment based on patient comorbidities and the available data. sible. There are disparities in sepsis rates among different When hypotension or hypoperfusion persists, additional demographic groups. For example, sepsis is more common fluids or vasopressors may be needed. The Surviving Sepsis among Black men than other racial groups or women. Sepsis Campaign guidelines support using norepinephrine as first is also more common among older adults, with incidence line therapy in patients who require vasopressor support, as increasing with each year after the age of 65 years. Mortality it increases systemic vascular resistance without compromis- from sepsis is high. A patient who is septic has a mortality rate ing myocardial performance (stroke volume or cardiac out 4 or more times greater than for the same underlying condi put). In cases where norepinephrine alone is insufficient, tion and comorbidities without sepsis. Mortality increases by secondary agents, including epinephrine, vasopressin, or roughly 15% lbr each sepsis related organ system failure. dobutamine, may be considered. Dopamine is not recom- mended for use in septic shock except in select patients with Management of Sepsis clinically significant bradycardia, given its association with For years, sepsis guidelines have focused on early diagnosis increased tachyarrhy'thmia and death compared with norepi and timely treatment of sepsis to improve survival. Early nephrine. Phenylephrine should be usedwith caution because guidelines supported time-based metrics to be achieved in the it can lead to decreased stroke volumes despite improvement form of a sepsis "bundle." In 2016 a 3 hour and a 6-hourbun- in mean arterial pressure. The Surviving Sepsis Campaign dle were proposed on the basis of evidence that bundle based guidelines recommend it be used only as a salvage therapy or care led to significant improvements in sepsis mortality. in cases where tachyarrhlthmia prevents use of alternative However, subsequent data suggested that in-hospital mortality vasopressor agents (see Table 50). might be further improved by expediting care within the ini I(EY POIIITS tial 3-hour window. In 2018 the Surviving Sepsis Campaign issued updated guidelines that combined the previous 3 and . Early and aggressive fluid resuscitation for patients with hlpoperfusion resulting from sepsis begins with an initial 6-hour bundles into a single t hour sepsis bundle. The t hour bolus of 30 ml/kg body weight of crystalloid solution. bundle includes collection of blood cultures, measurement of serum lactate levels, administration ofbroad spectrum antibi- . Norepineptrine is recommended as the first vasopressor otics, and provision of fluid or vasopressor resuscitation in ofchoice for septic shock. patients with hypotension or signs of hypoperfusion. Weak evidence behind some elements of the t hour bundle recom Antibiotic Therapy mendations has generated considerable controversy, but the Early antibiotic therapy is crucial in treating sepsis. Broad intent of these recommendations clearly addresses the tvvo spectrum antibiotics should be given within the first hour of main pillars of sepsis management: supporting organ perfu- suspected sepsis, and the regimen should be subsequently sion and controlling the infection. adjusted on the basis ofculture results. Delay in the first dose ofantibiotic therapy or use ofinappropriate antibiotic therapy KEY POIl{T increases sepsis mortality. Although antibiotic stewardship is o The two main pillars of sepsis management are sup- ofl paramount importance, the Surviving Sepsis Campaign porting organ perfusion and function and controlling guidelines recommend choosing up-front empiric therapy the infection. that is broad enough to cover the most likely pathogens caus- ing sepsis. The most common pathogens include gram Initial Resuscitation negative, gram positive, and "mixed" bacterial pathogens. Sepsis can have serious hemodynamics effects, with decreased However, treatment consideration should not be limited to preload (resulting from capillary leak), impaired cardiac bacterial coverage if empiric viral or fungal coverage are 78

Common ICU Conditions warranted. Consideration of the potential source of sepsis, KEY POII{TS local antibiotic resistance patterns, and a patient's clinical his r Prompt identification and control of any potential tory (including the presence of an indwelling catheter, neutro source of infection is essential in the management of penia, or another immunocompromised state) are important sepsis. when choosing initial therapy. In addition, recent treatment with antibiotic therapy or a recent stay in a health care facili[z o Broad-spectrum antibiotics should be given within the is associated with increased bacterial resistance and may first hour of suspected sepsis, and the regimen subse- necessitate broader empiric coverage compared with patients quently adjusted based on culture results. who do not have these risk factors. Guidelines do not provide . In cases of septic shock, combination therapy with at specific recommendations about drug therapy, but the least two antibiotics from different classes should be Surviving Sepsis Campaign guidelines do suggest that a car employed against the most likely bacterial pathogen. bapenem or extended range penicillin or p Iactamase inhibi tor may be a safe starting point in most septic patients. In cases Adjunctive Therapies of septic shock (but not sepsis without shock), combination lf possible, all patients receiving vasopressor therapy should therapy with at least two antibiotics from different classes have an arterial catheter for continuous blood pressure moni should be employed against the most likely bacterial pathogen. toring. Several large trials and meta analyses have demon In addition, when specific risks for multidrug resistance are strated that there is no benefit to using a pulmonary artery present, empiric combination therapy against resistant gram catheter to manage patients with septic shock. In many studies negative bacteria or targeted coverage of methicillin resistant of pulmonary artery catheter use, patients with sepsis and staph aureus is indicated. When available, the use of antibio septic shock demonstrated higher levels of resource use, grams specific to a community or healthcare facility is recom- higher complication rates, and in some cases higher mortality mended to guide treatment. compared with no pulmonary artery catheter. Once a specific pathogen is identified, antibiotics should The use ofglucocorlicoids in the setting ofsepsis has been be tailored appropriately to the narrowest effective regimen. suggested to achieve hemodynamic stability when it is not In many cases, culture data are either not obtained or remain achieved using intravenous fluids and vasopressor therapies. negative. In these cases, deescalation of antibiotics is gener Although there is not a clear mortality benefit, recent trials ally recommended within the first f'ew days if a patient is have showed that glucocorticoids are associated with a faster improving clinically. Antibiotic therapy should usually be time to shock recovery and fewer days with organ failure or continued for 7 to 10 days, depending on the clinical situa requirement for mechanical ventilation. Glucocorticoids have tion. Antibiotics should also continually be reassessed for no role in sepsis without shock. The Society of Critical Care efficacy and opportunities for early deescalation or discon Medicine and the European Society of Intensive Care Medicine tinuation sought. In patients with neutropenia, guidelines in 2017 recommended a maximum dose of 400 mg hydrocor- recommend that antibiotics be continued until either the full tisone daily, whereas the 2016 Surviving Sepsis Campaign planned course oftherapy concludes or the neutropenic state guidelines recommend hydrocortisone to 200 mg daily fbr resolves (neutrophils higher than 500/pL [0.5 x 10'/L]), refractory shock. An adrenocorticotropic hormone stimula whichever is later. tion test is not recommended. Prompt identification and control of potential sources ol Patients with sepsis or septic shock should receive early infection is essential in the management of sepsis. Examples oral feeding when possible and should be considered at risk include drainage ofabscesses and removal ofintravenous cath for malnutrition when in the ICU for more than 48 hours. If eters suspected ofbeing infected. One exception is necrotizing oral nutrition is not feasible, early enteral nutrition is indicated pancreatitis, for which definitive resection or drainage should to minimize infectious complications associated with delayed be delayed until the extent of necrosis is clear. enteral nutrition. In cases where both oral and enteral nutri The 2016 Surviving Sepsis Campaign guidelines suggest tion is not feasible, the optimal time and method to initiate that procalcitonin, a serum marker fbr bacterial infection, may parenteral therapy is not clear. New guidelines suggest, based be used to support shortening the duration of antibiotic ther- largely on expert opinion, that caloric and protein needs apy in patients with sepsis or as a marker to support discon- should be gradually increased to their goal over the course of 3 tinuing therapy in patients who initially were thought to have to 7 days to avoid risks associated with early refeeding syn sepsis but do not. Several recent meta analyses support these drome or overfeeding. guidelines, as they have demonstrated that algorithms that Glucose control is also important in patients with sepsis use procalcitonin as a decision support tool lead to decreased and septic shock. However, the optimal target is not entirely overall use of antibiotics. However, there remains conflicting clear. In critically ill patients in a medical ICU, tight glucose evidence surrounding key outcome measures, including mor- control (for example, glucose 80 110 mg/dl) is associated tality benefit, associated with procalcitonin testing. This has with higher rates of severe hypoglycemia (glucose less than led to wide heterogeneity among clinicians regarding whether 40 mg/dl) and sometimes death compared with rates for procalcitonin is used in clinical practice. similar patients managed with more liberal glucose targets

warranted. Consideration of the potential source of sepsis, KEY POII{TS local antibiotic resistance patterns, and a patient's clinical his r Prompt identification and control of any potential tory (including the presence of an indwelling catheter, neutro source of infection is essential in the management of penia, or another immunocompromised state) are important sepsis. when choosing initial therapy. In addition, recent treatment with antibiotic therapy or a recent stay in a health care facili[z o Broad-spectrum antibiotics should be given within the is associated with increased bacterial resistance and may first hour of suspected sepsis, and the regimen subse- necessitate broader empiric coverage compared with patients quently adjusted based on culture results. who do not have these risk factors. Guidelines do not provide . In cases of septic shock, combination therapy with at specific recommendations about drug therapy, but the least two antibiotics from different classes should be Surviving Sepsis Campaign guidelines do suggest that a car employed against the most likely bacterial pathogen. bapenem or extended range penicillin or p Iactamase inhibi tor may be a safe starting point in most septic patients. In cases Adjunctive Therapies of septic shock (but not sepsis without shock), combination lf possible, all patients receiving vasopressor therapy should therapy with at least two antibiotics from different classes have an arterial catheter for continuous blood pressure moni should be employed against the most likely bacterial pathogen. toring. Several large trials and meta analyses have demon In addition, when specific risks for multidrug resistance are strated that there is no benefit to using a pulmonary artery present, empiric combination therapy against resistant gram catheter to manage patients with septic shock. In many studies negative bacteria or targeted coverage of methicillin resistant of pulmonary artery catheter use, patients with sepsis and staph aureus is indicated. When available, the use of antibio septic shock demonstrated higher levels of resource use, grams specific to a community or healthcare facility is recom- higher complication rates, and in some cases higher mortality mended to guide treatment. compared with no pulmonary artery catheter. Once a specific pathogen is identified, antibiotics should The use ofglucocorlicoids in the setting ofsepsis has been be tailored appropriately to the narrowest effective regimen. suggested to achieve hemodynamic stability when it is not In many cases, culture data are either not obtained or remain achieved using intravenous fluids and vasopressor therapies. negative. In these cases, deescalation of antibiotics is gener Although there is not a clear mortality benefit, recent trials ally recommended within the first f'ew days if a patient is have showed that glucocorticoids are associated with a faster improving clinically. Antibiotic therapy should usually be time to shock recovery and fewer days with organ failure or continued for 7 to 10 days, depending on the clinical situa requirement for mechanical ventilation. Glucocorticoids have tion. Antibiotics should also continually be reassessed for no role in sepsis without shock. The Society of Critical Care efficacy and opportunities for early deescalation or discon Medicine and the European Society of Intensive Care Medicine tinuation sought. In patients with neutropenia, guidelines in 2017 recommended a maximum dose of 400 mg hydrocor- recommend that antibiotics be continued until either the full tisone daily, whereas the 2016 Surviving Sepsis Campaign planned course oftherapy concludes or the neutropenic state guidelines recommend hydrocortisone to 200 mg daily fbr resolves (neutrophils higher than 500/pL [0.5 x 10'/L]), refractory shock. An adrenocorticotropic hormone stimula whichever is later. tion test is not recommended. Prompt identification and control of potential sources ol Patients with sepsis or septic shock should receive early infection is essential in the management of sepsis. Examples oral feeding when possible and should be considered at risk include drainage ofabscesses and removal ofintravenous cath for malnutrition when in the ICU for more than 48 hours. If eters suspected ofbeing infected. One exception is necrotizing oral nutrition is not feasible, early enteral nutrition is indicated pancreatitis, for which definitive resection or drainage should to minimize infectious complications associated with delayed be delayed until the extent of necrosis is clear. enteral nutrition. In cases where both oral and enteral nutri The 2016 Surviving Sepsis Campaign guidelines suggest tion is not feasible, the optimal time and method to initiate that procalcitonin, a serum marker fbr bacterial infection, may parenteral therapy is not clear. New guidelines suggest, based be used to support shortening the duration of antibiotic ther- largely on expert opinion, that caloric and protein needs apy in patients with sepsis or as a marker to support discon- should be gradually increased to their goal over the course of 3 tinuing therapy in patients who initially were thought to have to 7 days to avoid risks associated with early refeeding syn sepsis but do not. Several recent meta analyses support these drome or overfeeding. guidelines, as they have demonstrated that algorithms that Glucose control is also important in patients with sepsis use procalcitonin as a decision support tool lead to decreased and septic shock. However, the optimal target is not entirely overall use of antibiotics. However, there remains conflicting clear. In critically ill patients in a medical ICU, tight glucose evidence surrounding key outcome measures, including mor- control (for example, glucose 80 110 mg/dl) is associated tality benefit, associated with procalcitonin testing. This has with higher rates of severe hypoglycemia (glucose less than led to wide heterogeneity among clinicians regarding whether 40 mg/dl) and sometimes death compared with rates for procalcitonin is used in clinical practice. similar patients managed with more liberal glucose targets 79

Specific Critical Care Topics (either 140-180 mg/dl or 180 200 mg/dl). The Surviving Sepsis Campaign Guidelines recommend targeting an upper glucose limit lower than 180 mg/dl in patients with sepsis and septic shock. xEY POllrlS . Early enteral nutrition is recommended in septic patients, if possible. HVC o The use of glucocorticoids in the setting of sepsis is sug- gested ifadequate fluid resuscitation and vasopressor therapy are unable to restore hemodynamic stability; there is no role for glucocorticoids in sepsis without shock. \ Specific Critical Care Topics E 2 8. Angioedema of the tongue, bottom lip, and right side of the face Anaphylaxis F IG U R

xEY POllrlS . Early enteral nutrition is recommended in septic patients, if possible. HVC o The use of glucocorticoids in the setting of sepsis is sug- gested ifadequate fluid resuscitation and vasopressor therapy are unable to restore hemodynamic stability; there is no role for glucocorticoids in sepsis without shock. \ Specific Critical Care Topics E 2 8. Angioedema of the tongue, bottom lip, and right side of the face Anaphylaxis F IG U R with tongue protrusion on admission to the emergency department. Anaphylaxis is a severe reaction caused by acute mediator Reproduced with permi$ion, from Arcani R, [,4artinez S, Gayet S. Sitagliptin and angioedema. Ann lnteln Med. 2017;167:142.143.IPMID:28554195]doi:10.7326/Ll6.0649.Copyright20lT,AmericanCollegeofPhysicians. release into the circulation, usually triggered by IgE-linked immunological responses to specific foods, medications, insect venom, Iatex, or other antigens but sometimes occur- require fluid resuscitation, with or without vasopressor therapy. ring without an allergic trigger. The mediator release results in Removal of the precipitating antigen is also important if expo various clinical manifestations such as pruritus, hypotension, sure is ongoing. Forhrnately, anaphylaxis is rarely fatal, but suc- and tissue swelling (known as angioedema) caused by capil cessful management requires early recognition and prompt lary leak from widespread inflammatory mediator release attention to supportive and disease-reversing therapies, espe (Table 62). Onset of symptoms may be immediate after antigen cially when shock or airway compromise is present. Factors that exposure or delayed, sometimes for hours or even days, increase risk for biphasic anaphylaxis (anaphylaxis occurring although more rapid onset usually signals a more severe reac 1 72 hours after resolution of the initial episode) include a tion. This capillary leak can result in distributive shock with severe initial episode and a need for more than one dose of epi- many of the same features as septic shock. Angioedema can be nephrine. When such risk exists or when there is risk for ana- life threatening when it compromises the airway. phylaxis fatality resulting from coexisting cardiovascular disease Initial treatment is with epinephrine, which may be or lack ofaccess to epinephrine or emergency services, extended administered intramuscularly or intravenously. Adjunctive observation of up to 6 hours or longer may be warranted. therapy with antihistamine medications may be used to relieve Angioedema can occur without allergic stimulus (brady symptoms of pruritus and rash. Although they are commonly kinin-mediated), sometimes in response to medications administered, evidence that glucocorticoids are useful in the (notably ACE inhibitors, even after long-term use) and some- treatment of anaphylaxis is sparse. Sometimes epinephrine times for no identifiable reason. Nonallergic angioedema usu- must be given many times or continuously to achieve clinical ally has slower onset and is not associated with urticaria, stability. Patients should be given supplemental oxygen and pruritus, or hypotension, but the tissue swelling can be clini- watched closely for signs of airway compromise, which may cally significant, especially in the airway (Figure 28), and may require intubation to maintain airway patency. Patients often require intubation. Recurrent angioedema can be hereditary

with tongue protrusion on admission to the emergency department. Anaphylaxis is a severe reaction caused by acute mediator Reproduced with permi$ion, from Arcani R, [,4artinez S, Gayet S. Sitagliptin and angioedema. Ann lnteln Med. 2017;167:142.143.IPMID:28554195]doi:10.7326/Ll6.0649.Copyright20lT,AmericanCollegeofPhysicians. release into the circulation, usually triggered by IgE-linked immunological responses to specific foods, medications, insect venom, Iatex, or other antigens but sometimes occur- require fluid resuscitation, with or without vasopressor therapy. ring without an allergic trigger. The mediator release results in Removal of the precipitating antigen is also important if expo various clinical manifestations such as pruritus, hypotension, sure is ongoing. Forhrnately, anaphylaxis is rarely fatal, but suc- and tissue swelling (known as angioedema) caused by capil cessful management requires early recognition and prompt lary leak from widespread inflammatory mediator release attention to supportive and disease-reversing therapies, espe (Table 62). Onset of symptoms may be immediate after antigen cially when shock or airway compromise is present. Factors that exposure or delayed, sometimes for hours or even days, increase risk for biphasic anaphylaxis (anaphylaxis occurring although more rapid onset usually signals a more severe reac 1 72 hours after resolution of the initial episode) include a tion. This capillary leak can result in distributive shock with severe initial episode and a need for more than one dose of epi- many of the same features as septic shock. Angioedema can be nephrine. When such risk exists or when there is risk for ana- life threatening when it compromises the airway. phylaxis fatality resulting from coexisting cardiovascular disease Initial treatment is with epinephrine, which may be or lack ofaccess to epinephrine or emergency services, extended administered intramuscularly or intravenously. Adjunctive observation of up to 6 hours or longer may be warranted. therapy with antihistamine medications may be used to relieve Angioedema can occur without allergic stimulus (brady symptoms of pruritus and rash. Although they are commonly kinin-mediated), sometimes in response to medications administered, evidence that glucocorticoids are useful in the (notably ACE inhibitors, even after long-term use) and some- treatment of anaphylaxis is sparse. Sometimes epinephrine times for no identifiable reason. Nonallergic angioedema usu- must be given many times or continuously to achieve clinical ally has slower onset and is not associated with urticaria, stability. Patients should be given supplemental oxygen and pruritus, or hypotension, but the tissue swelling can be clini- watched closely for signs of airway compromise, which may cally significant, especially in the airway (Figure 28), and may require intubation to maintain airway patency. Patients often require intubation. Recurrent angioedema can be hereditary TABLE 62. Organ Systern lnvolvenrent in Anaphyfaxis Organ System Symptoms Signs Patients With Organ lnvolved Skin and mucosa Pruritus of skin, oropharynx, genitals, palms, Flushing, urticaria, morbilliform rash, 85% soles angioedema Respiratory Dyspnea, chest and throat tightness, stridor, Wheeze, stridor, respiratory distress 70"/" cough, hoarseness, sneezing, rhinorrhea Cardiovascular Lightheadedness, chest pain, palpitations Hypotension, tachycardia > bradycardia 45% Gastrointestina I Pain, nausea, vomiting, diarrhea 45% Neurologic Anxiety, headache Encephalopathy 15%

TABLE 62. Organ Systern lnvolvenrent in Anaphyfaxis Organ System Symptoms Signs Patients With Organ lnvolved Skin and mucosa Pruritus of skin, oropharynx, genitals, palms, Flushing, urticaria, morbilliform rash, 85% soles angioedema Respiratory Dyspnea, chest and throat tightness, stridor, Wheeze, stridor, respiratory distress 70"/" cough, hoarseness, sneezing, rhinorrhea Cardiovascular Lightheadedness, chest pain, palpitations Hypotension, tachycardia > bradycardia 45% Gastrointestina I Pain, nausea, vomiting, diarrhea 45% Neurologic Anxiety, headache Encephalopathy 15% 80

Specific Critical Care Topics or acquired. Hereditary angioedema, which is distinct from generally defined by a core body temperature above 40'C the more typical mast cell associated angioedema, is caused (104'F), along with encephalopathy. The elderly are particu- by activation of the complement cascade because of the lack or larly vulnerable, with added risk from comorbidities and dysfunction of C1 esterase inhibitor. Hereditary angioedema medications. Exertional heat stroke can occur in young and may cause sporadic localized edema involving the head and otherwise healthy individuals, particularly when high ambi- neck and is differentiated from mast cell-associated angi- ent temperatures are combined with physical activity and oedema by the lack of tlzpical urticarial lesions. Diagnosis is by high humidity. Extraneurologic complications can include testing for quantitative and functional levels of C1 esterase kidney and liver injury disseminated intravascular coagula- inhibitor and C4 complement levels. tion, and rhabdomyolysis. As in other forms of angioedema, treatment is supportive, If untreated, mortality in heat stroke can be up to 60'7,. sometimes with additional measures to control abnormal Centrally acting antipyretics such as NSAIDs or acetaminophen bradykinin, complement activation, or both. are not effective. For patients with nonexertional heat stroke, evaporative cooling (water mist and fans) with or without ice I(EY POITTS packs can be used to lower the core temperature to a safe target o Initial treatment of anaphylaxis is with epinephrine, which Ievel, usually 38.5 'C (101.0 'F). For exertional heat stroke, may be administered intramuscularly or intravenously. evaporative cooling may be effective, but patients who remain r Hereditary angioedema is caused by activation of the severely symptomatic despite evaporative cooling efforts some- complement cascade because of the lack or dysfunction times require immersion in ice water to bring the core tem of Cl esterase inhibitor. perature down rapidly. Because immersion therapy may be complicated by hypothermia, it is not recommended as first- Iine treatment. In older patients with nonexertional hyperther Hyperthermic Emergencies mia, ice water immersion is associatedwith increased mortality Hyperthermic emergency is defined as the elevation of core body and should not be used. temperature, usually above 40'C (104'F), causing end organ I(EY POITT dysfunction or damage, which may include alteration in mental o For patients with nonexertional heat stroke, evaporative status, seizures, kidney injury muscle rigidity, rhabdomyolysis, acute respiratory distress syndrome, and disseminated intravas cooling with or without ice packs can be used to lower cular coagulation. Common causes of hyperthermia include the core temperature to a safe target level; for exertional heat stroke, malignant hyperthermia, and neuroleptic malignant heat stroke, immersion in ice water is sometimes syndrome, all olwhich can be fatal if not recognized and treated required for severe cases. appropriately (Table 63). Malignant Hyperthermia Heat Stroke Malignant hyperthermia occurs in people with a rare, autoso Heat stroke occurs when the body's thermal regulatory mal dominant derangement in intracellular calcium metabo system is overwhelmed by an environmental heat load. It is lism that causes severe hyperthermia in response to inhaled

or acquired. Hereditary angioedema, which is distinct from generally defined by a core body temperature above 40'C the more typical mast cell associated angioedema, is caused (104'F), along with encephalopathy. The elderly are particu- by activation of the complement cascade because of the lack or larly vulnerable, with added risk from comorbidities and dysfunction of C1 esterase inhibitor. Hereditary angioedema medications. Exertional heat stroke can occur in young and may cause sporadic localized edema involving the head and otherwise healthy individuals, particularly when high ambi- neck and is differentiated from mast cell-associated angi- ent temperatures are combined with physical activity and oedema by the lack of tlzpical urticarial lesions. Diagnosis is by high humidity. Extraneurologic complications can include testing for quantitative and functional levels of C1 esterase kidney and liver injury disseminated intravascular coagula- inhibitor and C4 complement levels. tion, and rhabdomyolysis. As in other forms of angioedema, treatment is supportive, If untreated, mortality in heat stroke can be up to 60'7,. sometimes with additional measures to control abnormal Centrally acting antipyretics such as NSAIDs or acetaminophen bradykinin, complement activation, or both. are not effective. For patients with nonexertional heat stroke, evaporative cooling (water mist and fans) with or without ice I(EY POITTS packs can be used to lower the core temperature to a safe target o Initial treatment of anaphylaxis is with epinephrine, which Ievel, usually 38.5 'C (101.0 'F). For exertional heat stroke, may be administered intramuscularly or intravenously. evaporative cooling may be effective, but patients who remain r Hereditary angioedema is caused by activation of the severely symptomatic despite evaporative cooling efforts some- complement cascade because of the lack or dysfunction times require immersion in ice water to bring the core tem of Cl esterase inhibitor. perature down rapidly. Because immersion therapy may be complicated by hypothermia, it is not recommended as first- Iine treatment. In older patients with nonexertional hyperther Hyperthermic Emergencies mia, ice water immersion is associatedwith increased mortality Hyperthermic emergency is defined as the elevation of core body and should not be used. temperature, usually above 40'C (104'F), causing end organ I(EY POITT dysfunction or damage, which may include alteration in mental o For patients with nonexertional heat stroke, evaporative status, seizures, kidney injury muscle rigidity, rhabdomyolysis, acute respiratory distress syndrome, and disseminated intravas cooling with or without ice packs can be used to lower cular coagulation. Common causes of hyperthermia include the core temperature to a safe target level; for exertional heat stroke, malignant hyperthermia, and neuroleptic malignant heat stroke, immersion in ice water is sometimes syndrome, all olwhich can be fatal if not recognized and treated required for severe cases. appropriately (Table 63). Malignant Hyperthermia Heat Stroke Malignant hyperthermia occurs in people with a rare, autoso Heat stroke occurs when the body's thermal regulatory mal dominant derangement in intracellular calcium metabo system is overwhelmed by an environmental heat load. It is lism that causes severe hyperthermia in response to inhaled TABLE 63. Causes of Severe Hyperthermia Diagnosis Suggestive History Key Examination Treatment Notes Findings Heat stroke Environmental exposure Encephalopathy and Evaporative cooling Avoid ice water fever immersion if lce water immersion nonexertional

TABLE 63. Causes of Severe Hyperthermia Diagnosis Suggestive History Key Examination Treatment Notes Findings Heat stroke Environmental exposure Encephalopathy and Evaporative cooling Avoid ice water fever immersion if lce water immersion nonexertional Malignant hyperthermia Exposure to volatile Masseter muscle Stop inciting drug Monitor and treat t K* anesthetic or rigidity; t arterial Pco2 and 1 arterial Pco2 Dantrolene succinylcholine Neuroleptic malignant Typical > atypical Altered mentation, Stop the inciting drug Resolves over days to syndrome antipsychotic agent; severe rigidity, 1HR, weeks Dantrolene onset over days to t BP, hyporeflexia, no First symptom is usually weeks clonus Bromocriptine change in mental status

Malignant hyperthermia Exposure to volatile Masseter muscle Stop inciting drug Monitor and treat t K* anesthetic or rigidity; t arterial Pco2 and 1 arterial Pco2 Dantrolene succinylcholine Neuroleptic malignant Typical > atypical Altered mentation, Stop the inciting drug Resolves over days to syndrome antipsychotic agent; severe rigidity, 1HR, weeks Dantrolene onset over days to t BP, hyporeflexia, no First symptom is usually weeks clonus Bromocriptine change in mental status Severe serotonin Onset within 24 hours of Agitation, myoclonus, Stop inciting drug Resolves in 24 hours syndromeu initiation or increasing SSRI 1 reflexes, rigidity Benzod iazepines dose, gastroi ntestinal prodrome Cyproheptadine BP = blood pressure; HR = heart rate; Kr = potassium; SSRI = selective serotonin reuptake inhibitor. malignant syndrome "Not routinely considered a cause of severe hyperthermia but commonly con{used with neuroleptic 81