Respiratory Failure

Background: Respiratory failure is a syndrome in which the respiratory system fails in one or both of its gas exchange functions: oxygenation and carbon dioxide elimination. In practice, respiratory failure is defined as a PaO₂ value of less than 60 mm Hg while breathing air or a PaCO₂ of more than 50 mm Hg. Furthermore, respiratory failure may be acute or chronic. While acute respiratory failure is characterized by life-threatening derangements in arterial blood gases and acid-base status, the manifestations of chronic respiratory failure are less dramatic and may not be as readily apparent.

Classification of respiratory failure

Respiratory failure may be classified as hypoxemic or hypercapnic and may be either acute or chronic.

Hypoxemic respiratory failure (type I) is characterized by a PaO₂ of less than 60 mm Hg with a normal or low PaCO₂. This is the most common form of respiratory failure, and it can be associated with virtually all acute diseases of the lung, which generally involve fluid filling or collapse of alveolar units. Some examples of type I respiratory failure are cardiogenic or noncardiogenic pulmonary edema, pneumonia, and pulmonary hemorrhage.

Hypercapnic respiratory failure (type II) is characterized by a PaCO₂ of more than 50 mm Hg. Hypoxemia is common in patients with hypercapnic respiratory failure who are breathing room air. The pH depends on the level of bicarbonate, which, in turn, is dependent on the duration of hypercapnia. Common etiologies include drug overdose, neuromuscular disease, chest wall abnormalities, and severe airway disorders (eg, asthma, chronic obstructive pulmonary disease [COPD]).

Distinctions between acute and chronic respiratory failure

Acute hypercapnic respiratory failure develops over minutes to hours; therefore, pH is less than 7.3. Chronic respiratory failure develops over several days or longer, allowing time for renal compensation and an increase in bicarbonate concentration. Therefore, the pH usually is only slightly decreased.

The distinction between acute and chronic hypoxemic respiratory failure cannot readily be made on the basis of arterial blood gases. The clinical markers of chronic hypoxemia, such as polycythemia or cor pulmonale, suggest a long-standing disorder.

Pathophysiology: Respiratory failure can arise from an abnormality in any of the components of the respiratory system, including the airways, alveoli, CNS, peripheral nervous system, respiratory muscles, and chest wall. Patients who have hypoperfusion secondary to cardiogenic, hypovolemic, or septic shock often present with respiratory failure.

Hypoxemic respiratory failure: The pathophysiologic mechanisms that account for the hypoxemia observed in a wide variety of diseases are ventilation-perfusion (V/Q) mismatch and shunt. These 2 mechanisms lead to widening of the alveolar-arterial oxygen difference, which normally is less than 15 mm Hg. With V/Q mismatch, the areas of low ventilation relative to perfusion (low V/Q units) contribute to hypoxemia. An intrapulmonary or intracardiac shunt causes mixed venous (deoxygenated) blood to bypass ventilated alveoli and results in venous admixture. The distinction between V/Q mismatch and shunt can be made by assessing the response to oxygen supplementation or calculating the shunt fraction following inhalation of 100% oxygen. In most patients with hypoxemic respiratory failure, these 2 mechanisms coexist.

Hypercapnic respiratory failure: At a constant rate of carbon dioxide production, PaCO₂ is determined by the level of alveolar ventilation (Va), where VCO₂ is ventilation of carbon dioxide and K is a constant value (0.863).

(Va = K x VCO₂)/PaCO₂

A decrease in alveolar ventilation can result from a reduction in overall (minute) ventilation or an increase in the proportion of dead space ventilation. A reduction in minute ventilation is observed primarily in the setting of neuromuscular disorders and CNS depression. In pure hypercapnic respiratory failure, the hypoxemia is easily corrected with oxygen therapy.

Ventilatory capacity versus demand

Ventilatory capacity is the maximal spontaneous ventilation that can be maintained without development of respiratory muscle fatigue. Ventilatory demand is the spontaneous minute ventilation that results in a stable PaCO₂. Normally, ventilatory capacity greatly exceeds ventilatory demand. Respiratory failure may result from either a reduction in ventilatory capacity or an increase in ventilatory demand (or both). Ventilatory capacity can be decreased by a disease process involving any of the functional components of the respiratory system and its controller. Ventilatory demand is augmented by an increase in minute ventilation and/or an increase in the work of breathing.

Pathophysiologic mechanisms in acute respiratory failure

The act of respiration engages 3 processes: (1) transfer of oxygen across the alveolus, (2) transport of oxygen to the tissues, and (3) removal of carbon dioxide from blood into the alveolus and then into the environment. Respiratory failure may occur from malfunctioning of any of these processes. In order to understand the pathophysiologic basis of acute respiratory failure, an understanding of pulmonary gas exchange is essential.

Physiology of gas exchange

Respiration primarily occurs at the alveolar capillary units of the lungs, where exchange of oxygen and carbon dioxide between alveolar gas and blood takes place. Following diffusion into the blood, the oxygen molecules reversibly bind to the hemoglobin. Each molecule of hemoglobin contains 4 sites for combination with molecular oxygen, 1 g of hemoglobin combines with a maximum of 1.36 mL of oxygen. The quantity of oxygen combined with hemoglobin depends on the level of blood PaO₂. This relationship, expressed as the oxygen hemoglobin dissociation curve, is not linear, but has a sigmoid-shaped curve with a steep slope between a PaO₂ of 10 and 50 mm Hg and a flat portion above a PaO₂ of 70 mm Hg. The carbon dioxide is transported in 3 main forms: (1) in simple solution, (2) as bicarbonate, and (3) combined with protein of hemoglobin as a carbamino compound.

During ideal gas exchange, blood flow and ventilation would perfectly match each other, resulting in no alveolar-arterial PO₂ difference. However, even in normal lungs, not all alveoli are ventilated and perfused perfectly. For a given perfusion, some alveoli are underventilated while others are overventilated. Similarly, for known alveolar ventilation, some units are underperfused while others are overperfused. The optimally ventilated alveoli that are not perfused well are called high V/Q units (acting like dead space), and alveoli that are optimally perfused but not adequately ventilated are called low V/Q units (acting like a shunt).

Alveolar ventilation

At steady state, the rate of carbon dioxide production by the tissues is constant and equals the rate of carbon dioxide elimination by the lung. This relationship is expressed as PaCO₂ = VCO₂ x 0.862/Va. This relationship signifies whether the alveolar ventilation is adequate for metabolic needs of the body.

The efficiency of lungs at carrying out of respiration can be further evaluated by measuring alveolar-to-arterial PaO₂ difference. This difference is calculated by the following equation:

PaO₂ = FIO₂ x (PB – PH₂O) – PaCO₂/R

For the above equation, PaO₂ = alveolar PO₂, FIO₂ = fractional concentration of oxygen in inspired gas, PB = barometric pressure, PH₂O = water vapor pressure at 37°C, PaCO₂ = alveolar PCO₂, assumed to be equal to arterial PCO₂, and R = respiratory exchange ratio. R depends on oxygen consumption and carbon dioxide production. At rest, VCO₂/VO₂ is approximately 0.8.

Even normal lungs have some degree of V/Q mismatching and a small quantity of right-to-left shunt, alveolar PO₂ is slightly higher than arterial PO₂. However, an increase in alveolar-to-arterial PO₂ above 15-20 mm Hg indicates pulmonary disease as the cause of hypoxemia.

Pathophysiologic causes of acute respiratory failure

Hypoventilation, V/Q mismatch, and shunt are the most common pathophysiologic causes of acute respiratory failure. These are described in the following paragraphs.

Hypoventilation is an uncommon cause of respiratory failure and usually occurs from depression of the CNS from drugs or neuromuscular diseases affecting respiratory muscles. Hypoventilation is characterized by hypercapnia and hypoxemia. The relationship between PaCO₂ and alveolar ventilation is hyperbolic. As ventilation decreases below 4-6 L/min, PaCO₂ rises precipitously. Hypoventilation can be differentiated from other causes of hypoxemia by the presence of a normal alveolar-arterial PO₂ gradient.

V/Q mismatch is the most common cause of hypoxemia. V/Q units may vary from low to high ratios in the presence of a disease process. The low V/Q units contribute to hypoxemia and hypercapnia in contrast to high V/Q units, which waste ventilation but do not affect gas exchange unless quite severe. The low V/Q ratio may occur either from a decrease in ventilation secondary to airway or interstitial lung disease or from overperfusion in the presence of normal ventilation. The overperfusion may occur in case of pulmonary embolism, where the blood is diverted to normally ventilated units from regions of lungs that have blood flow obstruction secondary to embolism. Administration of 100% oxygen eliminates all of the low V/Q units, thus leading to correction of hypoxemia. As hypoxemia increases the minute ventilation by chemoreceptor stimulation, the PaCO₂ level generally is not affected.

Shunt is defined as the persistence of hypoxemia despite 100% oxygen inhalation. The deoxygenated blood (mixed venous blood) bypasses the ventilated alveoli and mixes with oxygenated blood that has flowed through the ventilated alveoli, consequently leading to a reduction in arterial blood content. The shunt is calculated by the following equation:

QS/QT = (CCO₂ – CaO₂)/CCO₂ – CVO₂)

QS/QT is the shunt fraction, CCO₂ (capillary oxygen content) is calculated from ideal alveolar PO₂, CaO₂ (arterial oxygen content) is derived from PaO₂ using the oxygen dissociation curve, and CVO₂ (mixed venous oxygen content) can be assumed or measured by drawing mixed venous blood from pulmonary arterial catheter.

Anatomical shunt exists in normal lungs because of the bronchial and thebesian circulations, accounting for 2-3% of shunt. A normal right-to-left shunt may occur from atrial septal defect, ventricular septal defect, patent ductus arteriosus, or arteriovenous malformation in the lung. Shunt as a cause of hypoxemia is observed primarily in pneumonia, atelectasis, and severe pulmonary edema of either cardiac or noncardiac origin. Hypercapnia generally does not develop unless the shunt is excessive (>60%). When compared to V/Q mismatch, hypoxemia produced by shunt is difficult to correct by oxygen administration.

Frequency:

• In the US: Respiratory failure is a syndrome rather than a single disease process, and the overall frequency of respiratory failure is not well known. The estimates for individual diseases mentioned here can be found in the appropriate article.

Mortality/Morbidity: The mortality rate associated with respiratory failure varies according to the etiology. For acute respiratory distress syndrome, the mortality rate is approximately 50% in most studies. Acute exacerbation of COPD carries a mortality rate of approximately 30%. The mortality rates for other causative disease processes have not been well described.

Treatment
Medical Care: Hypoxemia is the major immediate threat to organ function. Therefore, the first objective in the management of respiratory failure is to reverse and/or prevent tissue hypoxia. Hypercapnia unaccompanied by hypoxemia generally is well tolerated and probably is not a threat to organ function unless accompanied by severe acidosis. Many experts believe that hypercapnia should be tolerated until the arterial blood pH falls below 7.2. Appropriate management of the underlying disease obviously is an important component in the management of respiratory failure.

A patient with acute respiratory failure generally should be admitted to a respiratory care or intensive care unit. Most patients with chronic respiratory failure can be treated at home with oxygen supplementation and/or ventilatory assist devices along with therapy for their underlying disease.

• Airway management
  • Assurance of an adequate airway is vital in a patient with acute respiratory distress.
  • The most common indication for endotracheal intubation (ETT) is respiratory failure.
  • ETT serves as an interface between the patient and the ventilator.
  • Another indication for ETT is airway protection in patients with altered mental status.
• Correction of hypoxemia
  • After securing an airway, attention must turn to correcting the underlying hypoxemia, the most life-threatening facet of acute respiratory failure.
  • The goal is to assure adequate oxygen delivery to tissues, generally achieved with a PaO₂ of 60 mm Hg or an arterial oxygen saturation (SaO₂) of greater than 90%.
  • Supplemental oxygen is administered via nasal prongs or face mask; however, in patients with severe hypoxemia, intubation and mechanical ventilation often are required.
• Coexistent hypercapnia and respiratory acidosis may need to be addressed. This is done by correcting the underlying cause or providing ventilatory assistance.

• Mechanical ventilation is used for 2 essential reasons: (1) to increase PaO₂ and (2) to lower PaCO₂. Mechanical ventilation also rests the respiratory muscles and is an appropriate therapy for respiratory muscle fatigue.

• Ventilator management
  • The use of mechanical ventilation during the polio epidemics of the 1950s was the impetus that led to the development of the discipline of critical care medicine.
  • Prior to the mid 1950s, negative-pressure ventilation with the use of iron lungs was the predominant method of ventilatory support.
  • Currently, virtually all mechanical ventilatory support for acute respiratory failure is provided by positive-pressure ventilation. Nevertheless, negative-pressure ventilation still is used occasionally in patients with chronic respiratory failure.
  • Over the years, mechanical ventilators have evolved from simple pressure-cycled machines to sophisticated microprocessor-controlled systems. A brief review of mechanical ventilation is presented as follows.
• Overview of mechanical ventilation
  • Positive-pressure versus negative-pressure ventilation: In order for air to enter the lungs, a pressure gradient must exist between the airway and alveoli. This can be accomplished either by raising pressure at the airway (positive-pressure ventilation) or by lowering pressure at the level of the alveolus (negative-pressure ventilation). The iron lung or tank ventilator is the most common type of negative-pressure ventilator used in the past. These ventilators work by creating subatmospheric pressure around the chest, thereby lowering pleural and alveolar pressure, and thus facilitating flow of air into the patient's lungs. These ventilators are bulky, poorly tolerated, and are not suitable for use in modern critical care units. Positive-pressure ventilation can be achieved by an endotracheal or tracheostomy tube or noninvasively through a nasal mask or face mask.
  • Controlled versus patient-initiated (ie, assisted): Ventilatory assistance can be controlled (AC) or patient-initiated. In controlled modes of ventilation, the ventilator delivers assistance independent of the patient's own spontaneous inspiratory efforts. In contrast, during patient-initiated modes of ventilation, the ventilator delivers assistance in response to the patient's own inspiratory efforts. The patient's inspiratory efforts can be sensed either by pressure or flow-triggering mechanisms Triggering mechanism).
  • Pressure-targeted versus volume-targeted: During positive-pressure ventilation, either pressure or volume may be set as the independent variable. In volume-targeted (or volume preset) ventilation, tidal volume is the independent variable set by the physician and/or respiratory therapist, and airway pressure is the dependent variable. In volume-targeted ventilation, airway pressure is a function of the set tidal volume and inspiratory flow rate, the patient's respiratory mechanics (compliance and resistance), and the patient's respiratory muscle activity. In pressure-targeted (or pressure preset) ventilation, airway pressure is the independent variable and tidal volume is the dependent variable. The tidal volume during pressure-targeted ventilation is a complex function of inspiratory time, the patient's respiratory mechanics, and the patient's own respiratory muscle activity.

• Interface between patient and ventilator (mask vs endotracheal intubation)
  • Mechanical ventilation requires an interface between the patient and the ventilator. In the past, this invariably occurred through an endotracheal or tracheostomy tube, but in recent years, an increasing trend has occurred towards noninvasive ventilation, which can be accomplished by the use of either a full face mask (covering both the nose and mouth) or a nasal mask Noninvasive ventilatory support).
  • Care of an endotracheal tube includes correct placement of the tube, maintenance of proper cuff pressure, and suctioning to maintain a patent airway.
  • Following intubation, the position of the tube in the airway (rather than esophagus) should be confirmed by auscultation of the chest and, ideally, by a carbon dioxide detector. As a general rule, the endotracheal tube should be inserted to an average depth of 23 cm in men and 21 cm in women (measured at the incisor). Confirming proper placement of the endotracheal tube with a chest radiograph is recommended.
  • The tube should be secured to prevent accidental extubation or migration into the mainstem bronchus, and the endotracheal tube cuff pressure should be monitored periodically. The pressure in the cuff generally should not exceed 25 mm Hg.
  • Endotracheal suctioning can be accomplished by either open-circuit or closed-circuit suction catheters. Routine suctioning is not recommended because suctioning may be associated with a variety of complications, including desaturation, arrhythmias, bronchospasm, severe coughing, and introduction of secretions into the lower respiratory tract.
• Specific modes of ventilatory support
  • Pressure support ventilation (PSV): PSV can be categorized as patient-initiated, pressure-targeted ventilation. With PSV, ventilatory assistance occurs only in response to the patient's spontaneous inspiratory efforts. With each inspiratory effort, the ventilator raises airway pressure by a preset amount. When the inspiratory flow rate decays to a minimal level or to a percentage of initial inspiratory flow (eg, 25% of peak flow), inspiration is terminated. During PSV, the patients are free to choose their own respiratory rate; inspiratory time, inspiratory flow rate, and tidal volume are determined, in part, by the patient's respiratory efforts. This mode of ventilation should not be used in patients with unstable ventilatory drive, and care must be exercised when the patient's respiratory mechanics are changing because of bronchospasm, secretions, or varying levels of auto–positive end-expiratory pressure (auto-PEEP).
  • Intermittent mandatory ventilation (IMV): IMV is a mode whereby mandatory breaths are delivered at a set frequency, tidal volume, and inspiratory flow rate. However, the patient can breathe spontaneously between the machine-delivered breaths. Most modern ventilators have synchronized IMV (SIMV), whereby the ventilator attempts to deliver the mandatory breaths in synchrony with the patient's own inspiratory efforts. In essence, the ventilator allows the patient an opportunity to breathe. If the patient makes an inspiratory effort during a window of time determined by the IMV rate, the ventilator delivers a mandatory breath in response to the patient's inspiratory effort. However, if no inspiratory effort is detected by the ventilator, a time-triggered breath is delivered. Compared to IMV, SIMV may improve patient comfort and may limit dynamic hyperinflation, which may occur when a preset breath is delivered immediately after the patient's spontaneous inspiratory effort (ie, prior to exhalation).
  • Assist-control ventilation: In assist-control ventilation, patients receive a fixed tidal volume and inspiratory flow rate with each inspiratory effort, regardless of their respiratory rate. However, a “back-up rate" is selected that guarantees that the patient receives a minimum number of breaths per minute. If the patient's respiratory rate falls below the back-up rate, the ventilator delivers the number of breaths necessary to reach the back-up rate; such breaths are delivered independently of any inspiratory effort by the patient.
  • Volume-control: In this mode, respiratory rate, tidal volume, and inspiratory flow rate (or inspiratory time) are fixed. This mode is used most often in heavily sedated or paralyzed patients.
  • Pressure-control: In contrast to volume control, in pressure-control mode, airway pressure is raised by a set amount at a fixed number of times per minute. The physician or respiratory therapist also sets the inspiratory-to-expiratory (I:E) ratio or the inspiratory time. This mode is used most often in heavily sedated or paralyzed patients.
  • Pressure-control inverse-ratio ventilation (PCIRV): PCIRV is a variation of simple pressure-control ventilation. In this mode, inspiration is set to be longer than expiration. The I:E ratio should rarely, if ever, exceed 3:1.
• Triggering mechanism: pressure versus flow triggering
  • In patient-initiated (assisted) ventilation, the ventilator must sense the patient's inspiratory effort in order to deliver assistance. Ventilator triggering may be based on either a pressure or a flow change.
  • With pressure-triggering, the ventilator is set to detect a certain change in pressure. The ventilator is triggered whenever airway pressure drops by the set amount. For example, in a patient on no positive end-expiratory pressure (PEEP) with a trigger sensitivity set at 1 cm water, a breath is triggered whenever airway pressure falls below -1 cm water. In a patient on 5-cm water PEEP with the same trigger sensitivity, a breath is triggered whenever airway pressure falls below +4 cm water.
  • In flow-triggering, a continuous flow of gas is sent through the ventilator circuit. In some ventilators, this continuous flow rate may be set by the physician or respiratory therapist, whereas in other ventilators, the continuous flow rate is fixed. A flow sensitivity is selected, and the ventilator senses the patient's inspiratory efforts by detecting a change in flow. When the patient makes an inspiratory effort, some of the gas that was previously flowing continuously through the circuit is diverted to the patient. The ventilator senses the decrease in flow returning through the circuit, and a breath is triggered. One problem with flow-triggering is that autotriggering sometimes results from leaks in the ventilator circuit.

• Positive end-expiratory pressure
  • By maintaining airway (and hence alveolar) pressure greater than zero, PEEP may recruit atelectatic alveoli and prevent their collapse during the succeeding expiration. PEEP also shifts lung water from the alveoli into the perivascular interstitial space and helps with recruitment of alveoli. However, it does not decrease the total amount of extravascular lung water.
  • In patients with disorders such as ARDS or acute lung injury, PEEP is applied to recruit atelectatic alveoli, thereby improving oxygenation and allowing a reduction in FiO₂ to nontoxic levels (FiO₂ <0.6).>
  • In an ARDS Network trial, higher PEEP produced better oxygenation and lung compliance but no benefit to survival, time on ventilator, or nonpulmonary organ dysfunction. While sufficient PEEP is essential in ventilator management of patients with ARDS, this level varies from patient to patient. Ideal PEEP helps to achieve adequate oxygenation and decrease the requirement for high fractions of inspiratory oxygen without causing any of the harmful effects of PEEP. Current evidence does not support routine application of high PEEP strategy in people with ALI or ARDS.
  • PEEP causes an increase in intrathoracic pressure, which may decrease venous return and cardiac output, particularly in patients with hypovolemia.
• Inspiratory flow
  • In volume-targeted ventilation, inspiratory flow is a variable that is set by the physician or respiratory therapist. The inspiratory flow rate is selected on the basis of a number of factors, including the patient's inspiratory drive and the underlying disease.
  • Two flow patterns are used commonly: (1) a constant-flow (ie, square-wave) pattern and (2) a decelerating-flow pattern. With a constant-flow pattern, inspiratory flow is held constant throughout the breath, whereas with a decelerating-flow pattern, flow rises quickly to a maximal value and then decreases progressively throughout the breath.
  • In pressure-targeted ventilation, the inspiratory flow rate is a dependent variable that varies as a function of the preset pressure and the patient's own inspiratory effort. Because airway pressure is held constant while alveolar pressure rises during inspiration, the pressure difference between airway and alveoli decreases, leading to a decelerating pattern of inspiratory flow.
• Determinants of ventilator-associated lung injury
  • Mechanical ventilation is associated with a variety of insults to the lung.
  • In the past, physicians focused on barotrauma, including pneumothorax, pneumomediastinum, and subcutaneous and pulmonary interstitial emphysema. The manifestations of barotrauma likely occur because of excessive alveolar wall stress. Excessive airway pressure by itself does not appear to cause barotrauma. In critically ill patients, the manifestations of barotrauma can be subtle. For example, the earliest sign of pneumothorax in supine patients may be the deep-sulcus sign or a collection of air anteriorly along cardiophrenic angle.
  • More recently, lung damage indistinguishable from ARDS has been recognized to possibly be caused by certain patterns of ventilatory support. Early experiments in animals showed that mechanical ventilation employing high peak airway pressures and high tidal volume led to the formation of pulmonary edema. The mechanism was thought to be due to direct parenchymal injury and altered microvascular permeability secondary to high peak alveolar pressures. Recently, other investigators have shown that excessive tidal volumes resulting in alveolar overdistension are the most important factor in ventilator-associated lung injury.
  • A strategy of using low tidal volumes in patients with ARDS who are on mechanical ventilation has led to a reduced incidence of barotrauma and improved survival rates in recently published clinical trials.
• Mechanical ventilation in specific diseases

• General guidelines
  • The mode of ventilation should be suited to the needs of the patient. Following the initiation of mechanical ventilation, the ventilator settings should be adjusted based on the patient's lung mechanics, underlying disease process, gas exchange, and response to mechanical ventilation.
  • SIMV and assist-control ventilation often are used for the initiation of mechanical ventilation.
  • In patients with intact respiratory drive and mild-to-moderate respiratory failure, PSV may be a good initial choice.
• Supplemental oxygen
  • The lowest FiO₂ that produces an SaO₂ greater than 90% and a PaO₂ greater than 60 mm Hg generally is recommended.
  • The prolonged use of FiO₂ less than 0.6 is unlikely to cause pulmonary oxygen toxicity.
• Acute respiratory distress syndrome
  • The primary objective is to accomplish adequate gas exchange while avoiding excessive inspired oxygen concentrations and alveolar overdistension.
  • The traditional ventilatory strategy of delivering high tidal volumes leads to high end-inspiratory alveolar pressures (ie, plateau pressure).
  • Many investigators currently believe that repeated cycles of opening and collapsing of inflamed and atelectatic alveoli are detrimental to the lung. Failure to maintain a certain minimum alveolar volume may further accentuate the lung damage. Furthermore, transalveolar pressure (reflected by plateau pressure) exceeding 25-30 cm water is considered to be an important risk factor for stretch injury to the lungs.
  • Patients with ARDS should be targeted to receive a tidal volume of 6 mL/kg. Importantly, remember that the set tidal volume should be based on ideal rather than actual body weight. If the plateau pressure remains excessive (>30 cm water), further reductions in tidal volume may be necessary.

    ARDSNet, a prospective randomized clinical trial, demonstrated a striking reduction in hospital mortality in patient with ARDS who were ventilated with 6 ml/kg predicted body weight compared with 12 ml/kg. Patients who received the lower tidal volume strategy also had more ventilator-free and organ failure-free days. In the lower tidal volume group, the target tidal volume was 6 mL/kg of predicted body weight. This strategy may lead to respiratory acidosis, which requires either high respiratory rates and or sodium bicarbonate infusion.

  • Application of PEEP sufficient to raise the tidal volume above the lower inflection point (Pflex) on the pressure-volume curve may minimize alveolar wall stress and improve oxygenation. A pressure-volume curve can be constructed for an individual patient by measuring plateau pressures at different lung volumes. Pflex is the point at which the slope of the curve changes, indicating that the lung is operating at the most compliant part of the curve.
  • A lung-protective strategy where the PaCO₂ is allowed to rise (permissive hypercapnia) may reduce barotrauma and enhance survival.
  • In some patients with ARDS, the prone position may lead to significant improvements in oxygenation; whether this translates to improved outcome is unknown.
• Obstructive airway diseases
  • In patients with COPD or asthma, institution of mechanical ventilation may worsen dynamic hyperinflation (auto-PEEP or intrinsic PEEP [PEEPi]). The dangers of auto-PEEP include a reduction in cardiac output and hypotension (because of decreased venous return) and barotrauma.
  • The goals of mechanical ventilation in obstructive airway diseases are to unload the respiratory muscles, achieve adequate oxygenation, and minimize the development of dynamic hyperinflation and its associated adverse consequences.
  • Following the initiation of mechanical ventilation, patients with status asthmaticus frequently develop severe dynamic hyperinflation, which often is associated with adverse hemodynamic effects. The development of dynamic hyperinflation can be minimized by delivering the lowest possible minute ventilation in the least possible time. Therefore, the initial ventilatory strategy should involve the delivery of relatively low tidal volumes (eg, 8-10 mL/kg) and lower respiratory rates (eg, 8-12 breaths per min) with a high inspiratory flow rate.
  • In the absence of hypoxia, hypercapnia generally is well tolerated in most patients. Even marked levels of hypercapnia are preferable to attempts to normalize the PCO₂, which could lead to dangerous levels of hyperinflation.
  • Patients often require large amounts of sedation and occasionally paralysis until the bronchoconstriction and airway inflammation have improved.
  • If a decision is made to measure trapped-gas volume (VEI), as recommended by some investigators, an attempt should be made to keep it below 20 mL/kg. The routine measurement of VEI is not recommended because measurement of plateau pressure and auto-PEEP provide similar information and are much easier to perform.
  • Patients with COPD have expiratory flow limitation and are prone to the development of dynamic hyperinflation. Here again, the goal of mechanical ventilation is to unload the respiratory muscles while minimizing the degree of hyperinflation. The use of extrinsic PEEP may be considered in spontaneously breathing patients in order to reduce the work of breathing and to facilitate triggering of the ventilator. Care must be exercised to avoid causing further hyperinflation, and the set level of PEEP should always be less than the level of auto-PEEP.
• Facilitating patient-ventilator synchrony
  • During mechanical ventilation, many patients sometimes experience asynchrony between their own spontaneous respiratory efforts and the pattern of ventilation imposed by the ventilator. This can occur with both controlled and patient-initiated modes of ventilation.
  • In order to achieve synchrony, the ventilator must not only sense and respond quickly to the onset of the patient's inspiratory efforts, it also must terminate the inspiratory phase when the patient's “respiratory clock" switches to expiration. Asynchronous interactions, commonly referred to as “fighting the ventilator," may occur when ventilator breaths and patient efforts are out of phase. This may lead to excessive work of breathing, increased respiratory muscle oxygen consumption, and decreased patient comfort.
  • Patient-ventilator asynchrony should be minimized, and a variety of ways is available to achieve this. Modern ventilators are equipped with significantly better valve characteristics compared to older-generation ventilators. Flow-triggering (with a continuous flow rate) appears to be more sensitive and more responsive to patient's spontaneous inspiratory efforts.
  • Patient-ventilator asynchrony often occurs in the presence of auto-PEEP. Auto-PEEP creates an inspiratory threshold load and thereby decreases the effective trigger sensitivity. This may be partially offset by the application of external PEEP.
  • Sometimes, additional sedation may be necessary to achieve adequate patient-ventilator synchrony.
• Noninvasive ventilatory support
  • The application of ventilatory support through a nasal or full face mask in lieu of ETT is being used increasingly for patients with acute or chronic respiratory failure.
  • Noninvasive ventilation should be considered in patients with mild-to-moderate acute respiratory failure. The patient should have an intact airway, airway-protective reflexes, and be alert enough to follow commands.
  • In clinical trials, noninvasive positive-pressure ventilation (NPPV) has proven beneficial in acute exacerbations of COPD and asthma, decompensated CHF with mild-to-moderate pulmonary edema, and pulmonary edema from hypervolemia. Reports conflict regarding its efficacy in acute hypoxemia due to other causes (eg, pneumonia). A variety of methods and systems are available for delivering noninvasive ventilatory support.
  • The benefits of NPPV depend on the underlying cause of respiratory failure. In acute exacerbations of obstructive lung disease, NPPV decreases PaCO₂ by unloading the respiratory muscles and supplementing alveolar ventilation. The results of several clinical trials support the use of NPPV in this setting.
  • In a large randomized trial (Brochard 1995) comparing NPPV with a standard ICU approach, the use of NPPV was shown to reduce complications, duration of ICU stay, and mortality. In patients in whom NPPV failed, mortality rates were similar to the intubated group (25% vs 30%).
  • Plant and colleagues recently published the largest prospective randomized study comparing NPPV to standard treatment in patients with COPD exacerbation. NPPV was administered on the ward; the nurses were trained for 8 hours in the preceding 3 months. Treatment failed in significantly more patients in the control group (27% vs 15%), and in-hospital mortality rates were significantly reduced by NPPV (20% to 10%).
  • In addition, 3 Italian cohort studies with historical or matched control groups have suggested that long-term outcome of patients treated with NPPV is better than that of patients treated with medical therapy and/or endotracheal intubation.
  • In acute hypoxemic respiratory failure, NPPV also helps maintain an adequate PaO₂ until the patient improves.
  • In cardiogenic pulmonary edema, NPPV improves oxygenation, reduces work of breathing, and may increase cardiac output.
  • When applied continuously to patients with chronic ventilatory failure, NPPV provides sufficient oxygenation and/or carbon dioxide elimination to sustain life by reversing or preventing atelectasis and/or resting the respiratory muscles.
  • Patients with obesity-hypoventilation syndrome benefit from NPPV by reversal of the alveolar hypoventilation and upper airway obstruction.
  • Most studies have used NPPV as an intermittent rather than continuous mode of support. Most trials have used inspiratory pressures of 12-20 cm water; expiratory pressures of 0-6 cm water; and excluded patients with hemodynamic instability, uncontrolled arrhythmia, or a high risk of aspiration.
• Weaning from mechanical ventilation
  • Weaning or liberation from mechanical ventilation is initiated when the underlying process that necessitated ventilatory support has improved. In some patients, such as those recovering from uncomplicated major surgery or a toxic ingestion, withdrawal of ventilator support may be done without weaning. In patients who required more prolonged respiratory therapy, the process of liberating the patient from ventilatory support may take much longer.
  • A patient who has stable underlying respiratory status, adequate oxygenation (eg, PaO₂/FiO₂ >200 on PEEP <10>
  • Over the years, many criteria have been used to predict success in weaning, including a minute ventilation of less than 10 L/min, maximal inspiratory pressure more than -25 cm water, vital capacity more than 10 mL/kg, absence of dyspnea, absence of paradoxical respiratory muscle activity, and agitation or tachycardia during the weaning trial. However, recent studies suggest that the rapid-shallow breathing index, ie, the patient's tidal volume (in liters) divided by the respiratory rate (breaths per min) during a period of spontaneous breathing, may be a better predictor of successful extubation. In a recent study, a daily trial of spontaneous breathing in patients with a rapid-shallow breathing index of less than 105 resulted in a shorter duration of mechanical ventilation. A spontaneous breathing trial of only 30 minutes appears adequate to identify patients in whom successful extubation is likely.
  • In patients who are not yet ready to be liberated from the ventilator, one should focus on the cause of ventilator dependency, such as excessive secretions, inadequate respiratory drive, impaired cardiac function, and ventilatory muscle weakness, rather than the type of ventilator or the mode of assistance.
  • The weaning protocol could be designed with assist-control ventilation, with gradually increasing time spent in trials of spontaneous breathing or by gradually reducing the level of PSV.
  • SIMV appears to result in less rapid weaning than PSV or trials of spontaneous breathing.
  • Patient-ventilator desynchrony is an important component in a carefully designed weaning protocol.
  • Attention must be directed towards patient comfort, avoidance of fatigue, adequate nutrition, and prevention and treatment of medical complications during the weaning period.
  • Ventilator monitoring: Peak inspiratory and plateau pressures should be assessed frequently. Attempts should be made to limit the plateau pressure to less than 25 cm water. Expiratory volume is checked initially and periodically (continuously if ventilator-capable) to assure that the set tidal volume is delivered. In patients with severe airflow obstruction, auto-PEEP (PEEPi) should be monitored on a regular basis.
• Monitoring of patients with acute respiratory failure
  • A patient with respiratory failure requires repeated assessments, which may range from bedside observations to the use of invasive monitoring.
  • These patients should be admitted to a facility where close observation can be provided. Most patients who require mechanical ventilation are critically ill; therefore, constant monitoring in a critical care setting is a must.
  • Cardiac monitoring, blood pressure, pulse oximetry, SaO₂, and capnometry are recommended. An arterial blood gas determination should be obtained 15-20 minutes after the institution of mechanical ventilation. The pulse oximetry readings direct efforts to reduce FiO₂ to a value less than 0.6, and the PaCO₂ guides adjustments of minute ventilation.
• Treatment of underlying cause
  • After the patient's hypoxemia is corrected and the ventilatory and hemodynamic status have stabilized, every attempt should be made to identify and correct the underlying pathophysiologic process that led to respiratory failure in the first place.
  • The specific treatment depends on the etiology of respiratory failure.
  • In , a brief discussion of medications used to treat common causes of respiratory failure, such as cardiogenic pulmonary edema, chronic obstructive pulmonary disease, and asthma, is provided.
  • The reader is recommended to review the article specific to the disease for the workup and management of the various disorders, all of which progress by different means but ultimately converge on a final common pathway of respiratory failure.

Consultations:

• Consultation with a pulmonary specialist and an intensivist often are required.

• Patients with acute respiratory failure or exacerbations of chronic respiratory failure need to be admitted to the intensive care unit for ventilatory support.

Activity:

Patients generally are prescribed bed rest during early phases of respiratory failure management. However, ambulation as soon possible helps ventilate atelectatic areas of the lung.

Medication
The pharmacotherapy of cardiogenic pulmonary edema and acute exacerbations of COPD is discussed here. The goals of therapy in cardiogenic pulmonary edema are to achieve a pulmonary capillary wedge pressure of 15-18 mm Hg and a cardiac index greater than 2.2 L/min/m², while maintaining adequate blood pressure and organ perfusion. These goals may need to be modified for some patients. Diuretics, nitrates, analgesics, and inotropics are used in the treatment of acute pulmonary edema.
Drug Category: Diuretics -- First-line therapy generally includes a loop diuretic such as furosemide, which inhibits sodium chloride reabsorption in the ascending loop of Henle.

Drug Name	Furosemide (Lasix) -- Administer loop diuretics IV because this allows for both superior potency and a higher peak concentration despite increased incidence of adverse effects, particularly ototoxicity.
Adult Dose	10-20 mg IV for patients symptomatic with CHF not already using diuretics 40-80 mg IV for patients already using diuretics 80-120 mg IV for patients whose symptoms are refractory to initial dose after 1 h of administration or who have significant renal insufficiency Higher doses and more rapid redosing may be appropriate for patients in severe distress
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, hepatic coma, anuria, state of severe electrolyte depletion
Interactions	Metformin decreases concentrations; conversely, furosemide interferes with the hypoglycemic effect of antidiabetic agents; also antagonizes muscle-relaxing effect of tubocurarine Auditory toxicity appears to be increased with concurrent use of aminoglycoside and furosemide; hearing loss of varying degrees may occur Anticoagulant activity of warfarin may be enhanced when taken concurrently Increased plasma lithium levels and toxicity are possible when taken concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor for electrolyte imbalance; caution with coadministration of nephrotoxic drugs

Drug Name	Metolazone (Mykrox, Zaroxolyn) -- Has been used as adjunctive therapy in patients initially refractory to furosemide. Has been demonstrated to be synergistic with loop diuretics in treating refractory patients and causes a greater loss of potassium. Potent loop diuretic that sometimes is used in combination with Lasix for more aggressive diuresis. Also used in patients with a degree of renal dysfunction for initiating diuresis.
Adult Dose	5-10 mg PO before redosing with furosemide
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, hepatic coma, encephalopathy, anuria
Interactions	Thiazides may decrease effect of anticoagulants, sulfonylureas, and gout medications; anticholinergics and amphotericin B may increase toxicity of thiazides; effects of thiazides may decrease when used concurrently with bile acid sequestrants, NSAIDs, and methenamine When coadministered, thiazides increase toxicity of anesthetics, diazoxide, digitoxin, lithium, loop diuretics, antineoplastics, allopurinol, calcium salts, vitamin D, and nondepolarizing muscle relaxants
Pregnancy	D - Unsafe in pregnancy
Precautions	Exercise caution with hepatic and renal disease, diabetes mellitus, gout, and systemic lupus erythematosus

Drug Category: Nitrates -- These agents reduce myocardial oxygen demand by lowering preload and afterload. In severely hypertensive patients, nitroprusside causes more arterial dilatation than nitroglycerin. Nevertheless, due to the possibility of thiocyanate toxicity and the coronary steal phenomenon associated with nitroprusside, IV nitroglycerin may be the initial therapy of choice for afterload reduction.

Drug Name	Nitroglycerin (Nitro-Bid, Nitrol) -- SL nitroglycerin and Nitrospray are particularly useful in the patient who presents with acute pulmonary edema with a systolic blood pressure of at least 100 mm Hg. Similar to SL, onset of Nitrospray is 1-3 min, with a half-life of 5 min. Administration of Nitrospray may be easier, and it can be stored for as long as 4 y. One study demonstrated significant and rapid hemodynamic improvement in 20 patients with pulmonary edema who were given Nitrospray. Topical nitrate therapy is reasonable in a patient presenting with class I-II CHF. However, in patients with more severe signs of heart failure or pulmonary edema, IV nitroglycerin is preferred because it is easier to monitor hemodynamics and absorption, particularly in patients with diaphoresis. Oral nitrates, due to delayed absorption, play little role in the management of acute pulmonary edema.
Adult Dose	Nitrospray: 1 puff (0.4 mg) equivalent to a single 1/150 SL; may repeat q3-5min as hemodynamics permit, not to exceed 1.2 mg Ointment: Apply 1-2 inches of nitropaste to chest wall Injection: Start at 20 mcg/min IV and titrate to effect in 5- to 10-mcg increments q3-5min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, severe anemia, shock, postural hypotension, head trauma, closed-angle glaucoma, cerebral hemorrhage
Interactions	Aspirin may increase nitrate serum concentrations; marked symptomatic orthostatic hypotension may occur when coadministered with calcium channel blockers, adjustment in dose of either agent may be necessary
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in coronary artery disease and low systolic blood pressure

Drug Name	Nitroprusside sodium (Nitropress) -- Produces vasodilation of venous and arterial circulation. At higher dosages, may exacerbate myocardial ischemia by increasing heart rate. Easily titratable.
Adult Dose	10-15 mcg/min IV; titrate to effective dose range of 30-50 mcg/min and a systolic blood pressure of at least 90 mm Hg
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, subaortic stenosis, optic atrophy, tobacco amblyopia, idiopathic hypertrophic, atrial fibrillation or flutter
Interactions	Patients receiving other hypertensive therapy may be more sensitive to sodium nitroprusside
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exercise caution with increased intracranial pressure, hepatic failure, severe renal impairment, and hypothyroidism. In renal or hepatic insufficiency, levels may increase and can cause cyanide toxicity Has potent effects on blood pressure (use only in those patients with mean arterial pressures >70 mm Hg)

Drug Category: Analgesics -- Morphine IV is an excellent adjunct in the management of acute pulmonary edema. In addition to being both an anxiolytic and an analgesic, its most important effect is venodilation, which reduces preload. Also causes arterial dilatation, which reduces systemic vascular resistance and may increase cardiac output.

Drug Name	Morphine sulfate (Duramorph, Astramorph, MS Contin) -- DOC for narcotic analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate administered IV may be dosed in a number of ways and commonly is titrated until desired effect is obtained.
Adult Dose	2-5 mg and repeated q10-15min IV unless respiratory rate is <20>
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, hypotension, potentially compromised airway with uncertain rapid airway control, respiratory depression, nausea, emesis, constipation, urinary retention
Interactions	Phenothiazine may antagonize analgesic effects of opiate agonists; tricyclic antidepressants, MAOIs, altered mental status, and other CNS depressants may potentiate adverse effects of morphine when used concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exercise caution with atrial flutter and other supraventricular tachycardias; morphine has vagolytic action and may increase the ventricular response rate; due to addictive nature, abuse also is a possibility, although this is not a significant concern in a critically ill patient

Drug Category: Inotropics -- Principal inotropic agents include dopamine, dobutamine, inamrinone (formerly amrinone), milrinone, dopexamine, and digoxin. In patients with hypotension presenting with CHF, dopamine and dobutamine usually are employed. Inamrinone and milrinone inhibit phosphodiesterase, resulting in an increase of intracellular cyclic AMP and alteration in calcium transport. As a result, they increase cardiac contractility and reduce vascular tone by vasodilatation.

Drug Name	Dopamine (Intropin) -- Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effects depend on the dose. Lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation are produced by higher doses. Positive inotropic agent at 2-10 mcg/kg/min that can lead to tachycardia, ischemia, and dysrhythmias. Doses >10 mcg/kg/min cause vasoconstriction, which increases afterload.
Adult Dose	5 mcg/kg/min IV and increase at increments of 5 mcg/kg/min IV to dose of 20 mcg/kg/min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, pheochromocytoma, ventricular fibrillation
Interactions	Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects, thus, lower dosage
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Closely monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure during infusion; prior to infusion, correct hypovolemia with either whole blood or plasma, as indicated; monitoring of central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia

Drug Name	Norepinephrine (Levophed) -- Used in protracted hypotension following adequate fluid replacement. Stimulates beta1- and alpha-adrenergic receptors, which in turn increases cardiac muscle contractility and heart rate, as well as vasoconstriction. As a result, increases systemic blood pressure and cardiac output. Adjust and maintain infusion to stabilize blood pressure (eg, 80-100 mm Hg systolic) sufficiently to perfuse vital organs.
Adult Dose	0.05-2 mcg/kg/min IV titrated according to hemodynamic response not to exceed 10 mcg/kg/min
Pediatric Dose	0.05-0.1 mcg/kg/min IV titrated according to hemodynamic response; not to exceed 1-2 mcg/kg/min
Contraindications	Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended
Interactions	Atropine sulfate may enhance the pressor response of norepinephrine by blocking the reflex bradycardia caused by norepinephrine; effects increase when administered concurrently with tricyclic antidepressants, MAOIs, antihistamines, guanethidine, methyldopa, and ergot alkaloids
Pregnancy	D - Unsafe in pregnancy
Precautions	Correct hypovolemia before administering norepinephrine; extravasation may cause severe tissue necrosis; therefore, administer into large vein; use with caution in occlusive vascular disease

Drug Name	Dobutamine (Dobutrex) -- Produces vasodilation and increases inotropic state. At higher dosages, may cause increased heart rate, thus exacerbating myocardial ischemia. Strong inotropic agent with minimal chronotropic effect and no vasoconstriction.
Adult Dose	2.5 mcg/kg/min IV initially; generally therapeutic in the range of 10-40 mcg/kg/min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, idiopathic hypertrophic subaortic stenosis, atrial fibrillation or flutter
Interactions	Beta-adrenergic blockers antagonize effects of nitroprusside; general anesthetics may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Following an MI, use dobutamine with caution; correct hypovolemia before using

Drug Category: Bronchodilators -- These agents are an important component of treatment in respiratory failure caused by obstructive lung disease. These agents act to decrease muscle tone in both small and large airways in the lungs. This category includes beta-adrenergics, methylxanthines, and anticholinergics.

Drug Name	Terbutaline (Brethaire, Bricanyl) -- Acts directly on beta2-receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.
Adult Dose	0.25 mg (0.25 cc of 1-mg/mL concentration) SC; not to exceed 0.5 mg SC q4h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, tachycardia resulting from cardiac arrhythmias
Interactions	Concomitant use with beta-blockers may inhibit bronchodilatory, cardiac, and vasodilatory effects of beta-agonists; coadministration of MAOIs with beta-sympathomimetics may result in severe hypertension, headache, and hyperpyrexia, which may result in a hypertensive crisis MAOIs also may potentiate activity of beta-adrenergic agonists on vascular system Coadministration of oxytocic drugs (eg, ergonovine with terbutaline) may result in severe hypotension
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in coronary disease; through intracellular shifts, may decrease serum potassium levels, which can produce adverse cardiovascular effects; however, decrease usually is transient and may not require supplementation

Drug Name	Albuterol (Proventil) -- Beta-agonist useful in the treatment of bronchospasm. Selectively stimulate beta2-adrenergic receptors of the lungs. Bronchodilation results from relaxation of bronchial smooth muscle, which relieves bronchospasm and reduces airway resistance.
Adult Dose	5 mg/mL of solution for nebulization, usually mixed as 0.5-1 cc with 2.5 cc of water and nebulized prn in acute setting
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to albuterol, adrenergic amines, or related products
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation induced by albuterol; cardiovascular effects may increase when coadministered with MAOIs, inhaled anesthetics, tricyclic antidepressants, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, or cardiovascular disorders

Drug Name	Theophylline (Theo-Dur, Slo-bid, Theo-24) -- Has a number of physiological effects, including increases in collateral ventilation, respiratory muscle function, mucociliary clearance, and central respiratory drive. Partially acts by inhibiting phosphodiesterase, elevating cellular cyclic AMP levels, or antagonizing adenosine receptors in the bronchi, resulting in relaxation of smooth muscle. However, clinical efficacy is controversial, especially in the acute setting.
Adult Dose	Target concentration: 10 mcg/mL Dosing = (target concentration - current level) x 0.5 (ideal body weight); alternatively, 1 mg/kg results in approximately 2 mcg/mL increase in serum levels
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to theophylline, xanthines, or related products; uncontrolled arrhythmias; hyperthyroidism
Interactions	Aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics may decrease effects; effects may be increased by coadministration with allopurinol, beta-blockers, ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and interferon
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in tachyarrhythmias, hyperthyroidism, and patients with compromised cardiac function; do not inject IV solution faster than 25 mg/mm; patients diagnosed with pulmonary edema or liver dysfunction are at greater risk of toxicity because of reduced drug clearance

Drug Name	Ipratropium bromide (Atrovent) -- Anticholinergic medication that appears to inhibit vagally mediated reflexes by antagonizing action of acetylcholine, specifically with the muscarinic receptor on bronchial smooth muscle. Vagal tone can be significantly increased in COPD; therefore, this can have a profound effect. Dose can be combined with a beta-agonist because ipratropium may require 20 min to begin having an effect.
Adult Dose	0.5 mg/nebulizer treatment
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Albuterol and ipratropium together are more efficacious than either one alone Drugs with anticholinergic properties (eg, dronabinol) may increase toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not indicated for initial treatment of acute episodes of bronchospasm; caution in narrow-angle glaucoma, prostatic hypertrophy, and bladder neck obstruction

Drug Category: Corticosteroids -- Have been shown to be effective in accelerating recovery from acute COPD exacerbations and are an important anti-inflammatory therapy in asthma. While they may not make a clinical difference in the ED, they have some effect 6-8 h into therapy; therefore, early dosing is critical.

Drug Name	Methylprednisolone (Solu-Medrol, Depo-Medrol) -- Usually given IV in ED for initiation of corticosteroid therapy, although PO should theoretically be equally efficacious.
Adult Dose	The optimal dosage is uncertain 125 mg IV q6h often administered for the first 24-48 h of therapy
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Clearance may decrease when coadministered with estrogens; when coadministered with digoxin, may increase digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin also may increase metabolism of glucocorticoids; therefore, consider increasing maintenance dose; monitor patients for hypokalemia with concurrent use of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Multisystem Organ Failure of Sepsis

Background: In 1914, Schottmueller wrote, "Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes sign of illness." The definition did not change significantly over the years because sepsis and septicemia were considered to refer to a number of ill-defined clinical conditions in addition to bacteriemia. In practice, the terms were often used interchangeably; however, less than one half of the patients who have signs and symptoms of sepsis have positive blood culture results.

In the late 1960s, several reports appeared describing remote organ failure (eg, pulmonary failure, liver failure) as a complication of severe sepsis. In 1975, a classic editorial by Baue was entitled "Multiple, progressive or sequential systems failure, a syndrome of the 1970s." This concept was formulated as the basis of a new clinical syndrome. Several terms were cloned thereafter, such as multiple organ failure, multiple system organ failure, and multiple organ system failure, to describe this evolving clinical syndrome of otherwise unexplained progressive physiological failure of several interdependent organ systems. More recently, the term multiple organ dysfunction syndrome (MODS) has been proposed as a more appropriate description.

Multiorgan failure from sepsis

Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic inflammation and widespread tissue injury. In this syndrome, tissue is removed from the original insult that displayed the signs of inflammation, such as vasodilatation, increased microvascular permeability, and leukocyte accumulation. Multiple organ dysfunction is a continuum, with incremental degrees of physiological derangements in individual organs; it is a process rather than an event. Alteration in organ function can vary widely from a mild degree of organ dysfunction to frank organ failure. The degree of organ dysfunction has a major clinical impact. The term MODS is defined as a clinical syndrome in which the development of progressive and potentially reversible physiological dysfunction in 2 or more organs or organ systems induced by a variety of acute insults, including sepsis, is characteristic.

In 1991, the American College of Chest Physicians/Society of Critical Care Medicine Consensus Panel developed definitions of the various stages of sepsis, which are as follows:

• Infection is a microbial phenomenon in which an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by these organisms is characteristic.
• Bacteremia is the presence of viable bacteria in the blood.
• Systemic inflammatory response syndrome (SIRS) may follow a variety of clinical insults, including infection, pancreatitis, ischemia, multiple trauma, tissue injury, hemorrhagic shock, or immune-mediated organ injury.
• Sepsis is a systemic response to infection. This is identical to SIRS, except that it must result from infection.
• Septic shock is sepsis with hypotension (systolic BP <90>
• MODS is the presence of altered organ function in a patient who is acutely ill such that homeostasis cannot be maintained without intervention. Primary MODS is the direct result of a well-defined insult in which organ dysfunction occurs early and can be directly attributable to the insult itself. Secondary MODS develops as a consequence of a host response and is identified within the context of SIRS. The inflammatory response of the body to toxins and other components of microorganisms causes the clinical manifestations of sepsis.

The sepsis syndrome is recognized clinically by the presence of 2 or more of the following:

• Temperature greater than 38°C or less than 36°C
• Heart rate greater than 90 beats per minute
• Respiratory rate greater than 20 breaths per minute or a PaCO2 in arterial gas less than 32 mm Hg
• WBC count greater than 12,000 cells/mL, less than 4000 cells/mL, or greater than 10% band forms

Pathophysiology:

Pathogenesis

Sepsis has been referred to as a process of malignant intravascular inflammation. Normally, a potent, complex, immunologic cascade ensures a prompt protective response to microorganism invasion in humans. A deficient immunologic defense may allow infection to become established; however, an excessive or poorly regulated response may harm the host through maladaptive release of indigenously generated inflammatory compounds.

Lipid A and other bacterial products release cytokines and other immune modulators that mediate the clinical manifestations of sepsis. Interleukins, tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and other colony-stimulating factors are produced rapidly within minutes or hours after interactions of monocytes and macrophages with lipid A. TNF release becomes a self-stimulating process (an autocrine), and release of other inflammatory mediators, including interleukin-1 (IL-1), platelet activating factor, IL-2, IL-6, IL-8, IL-10, INF, and eicosanoids, further increases cytokine levels. This leads to continued activation of polymorphonuclear leukocytes (PMNs), macrophages, and lymphocytes; proinflammatory mediators recruit more of these cells (a paracrine process). All of these processes create a state of destructive immunologic dissonance.

Sepsis is described as an autodestructive process that permits extension of the normal pathophysiologic response to infection to involve otherwise normal tissues and results in MODS.

Specific organ involvement

Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune from the consequences of the inflammatory excesses of sepsis.

Circulation

Significant derangement in autoregulation of circulation is typical of sepsis. Vasoactive mediators cause vasodilatation and increase the microvascular permeability at the site of infection. Nitric oxide plays a central role in the vasodilatation of septic shock. Also, impaired secretion of vasopressin may occur, which may permit persistence of vasodilatation.

Central circulation: Changes in both systolic and diastolic ventricular performance occur in sepsis. Through the use of the Frank Starling mechanism, cardiac output often is increased to maintain the BP in the presence of systemic vasodilatation. Patients with preexisting cardiac disease are unable to increase their cardiac output appropriately.

Regional circulation: Sepsis interferes with the normal distribution of systemic blood flow to organ systems; therefore, core organs may not receive appropriate oxygen delivery.

Microcirculation is the key target organ for injury in sepsis syndrome. A decrease in the number of functional capillaries causes an inability to extract oxygen maximally, which is caused by intrinsic and extrinsic compression of capillaries and plugging of the capillary lumen by blood cells. Increased endothelial permeability leads to widespread tissue edema of protein-rich fluid.

In severe sepsis and septic shock, microcirculatory dysfunction and mitochondrial depression cause regional tissue distress, therefore, regional hypoxia persists. This condition is termed microcirculatory and mitochondrial distress syndrome (MMDS). Sepsis-induced inflammatory autoregulatory dysfunction persists and oxygen need is not matched by supply, leading to multiorgan system dysfunction.

Redistribution of intravascular fluid volume resulting from reduced arterial vascular tone, diminished venous return from venous dilation, and release of myocardial depressant substances causes hypotension.

Pulmonary dysfunction

Endothelial injury in the pulmonary vasculature leads to disturbed capillary blood flow and enhanced microvascular permeability, resulting in interstitial and alveolar edema. Neutrophil entrapment within the pulmonary microcirculation initiates and amplifies the injury to alveolar capillary membranes. Acute respiratory distress syndrome (ARDS) is a frequent manifestation of these effects.

Gastrointestinal dysfunction and nutrition

The GI tract may help propagate the injury of sepsis. Overgrowth of bacteria in the upper GI tract may be aspirated into the lungs, producing nosocomial pneumonia. The normal barrier function of the gut may be affected, allowing translocation of bacteria and endotoxins into the systemic circulation and extending the septic response. Septic shock usually causes ileus, and the use of narcotics and sedatives delays institution of enteral feeding. The optimal level of nutritional intake is interfered with in the face of high protein and calorie requirements.

Liver

By virtue of the role of the liver in host defense, the abnormal synthetic functions caused by liver dysfunction can contribute to both the initiation and progression of sepsis. The reticuloendothelial system of the liver acts as a first line of defense in clearing bacteria and their products; liver dysfunction leads to a spillover of these products into systemic circulation.

Renal dysfunction

Acute renal failure often accompanies sepsis due to acute tubular necrosis. The mechanism is by systemic hypotension, direct renal vasoconstriction, release of cytokines (eg, TNF), and activation of neutrophils by endotoxins and other peptides, which contribute to renal injury.

Central nervous system dysfunction

Involvement of the CNS in sepsis produces encephalopathy and peripheral neuropathy. The pathogeneses is poorly defined.

Mechanisms of organ dysfunction and injury

The precise mechanisms of cell injury and resulting organ dysfunction in sepsis are not understood fully. Multiorgan dysfunction syndrome is associated with widespread endothelial and parenchymal cell injury because of the following proposed mechanisms:

• Hypoxic hypoxia: The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation of tissue oxygen delivery, and contributes to organ dysfunction. Microvascular and endothelial abnormalities contribute to the septic microcirculatory defect in sepsis. The reactive oxygen sepsis, lytic enzymes, and vasoactive substances (nitric oxide, endothelial growth factors) lead to microcirculatory injury, which is compounded by the inability of the erythrocytes to navigate the septic microcirculation.
• Direct cytotoxicity: The endotoxin, TNF-alpha, and nitric oxide may cause damage to mitochondrial electron transport, leading to disordered energy metabolism. This is called cytopathic or histotoxic anoxia, an inability to utilize oxygen even when it is present.
• Apoptosis: Apoptosis (programmed cell death) is the principal mechanism by which dysfunctional cells are eliminated normally. The proinflammatory cytokines may delay apoptosis in activated macrophages and neutrophils, but other tissues, such as the gut epithelium, may undergo accelerated apoptosis. Therefore, derangement of apoptosis plays a critical role in tissue injury of sepsis.
• Immunosuppression: The interaction between proinflammatory and anti-inflammatory mediators may lead to an imbalance. An inflammatory reaction or immunodeficiency may predominate, or both may be present.

Coagulopathy

Subclinical coagulopathy signified by a mild elevation of the thrombin or activated partial thromboplastin time (aPTT) or a moderate reduction in platelet count is extremely common, but overt disseminated intravascular coagulation (DIC) is rare. Deficiencies of coagulation system proteins, including protein C, antithrombin 3, and tissue factor inhibitors, cause coagulopathy.

Characteristics of sepsis that influence outcomes

Clinical characteristics that relate to the severity of sepsis include an abnormal host response to infection, the site and type of infection, the timing and type of antimicrobial therapy, the offending organism, and the development of shock, underlying disease, and the patients' chronic health condition. The location of patient at the time of septic shock also relates to the severity of sepsis.

Frequency:

• In the US: Current estimates suggest that the incidence of sepsis is greater than 500,000 cases per year. Approximately 40% of patients who are septic may develop shock. Patients who are at risk include those with positive blood cultures. Prevalence rates for SIRS of sepsis vary from 20-60%.

• Internationally: A French study in 1996 found that severe sepsis was present in 6.3% of all ICU admissions.

Mortality/Morbidity: Mortality from multiorgan dysfunction syndrome remains high. Mortality rates from ARDS alone is 40-50%. Once additional organ system dysfunction occurs, the mortality rate increases as much as 90%.

Treatment
Medical Care: The treatment of patients with septic shock consists of the following 3 major goals: (1) Resuscitate the patient from septic shock using supportive measures to correct hypoxia, hypotension, and impaired tissue oxygenation. (2) Identify the source of infection and treat with antimicrobial therapy, surgery, or both. (3) Maintain adequate organ system function guided by cardiovascular monitoring and interrupt the pathogenesis of multiorgan system dysfunction.

The principles in the management of septic shock based on current literature include the following components:

1. Early recognition
2. Early and adequate antibiotic therapy
   
3. Source control
   
4. Early hemodynamic resuscitation and continued support
   
5. Corticosteroids (refractory vasopressor-dependent shock)
   
6. Drotrecogin Alpha (severely ill if APACHE II score > 25)
   
7. Tight glycemic control
   
8. Proper ventilator management with low tidal volume in patients with ARDS

• General supportive care
  • Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion. Treatment beyond these supportive measures includes a combination of several parenteral antibiotics, removal or drainage of infected foci, treatment of complications, and pharmacologic interventions to prevent further harmful host responses.
  • Administer supplemental oxygen to any patient who is septic with hypoxia or respiratory distress. If the patient's airway is not secure or respirations are inadequate, perform endotracheal intubation and mechanical ventilation.

• Intravascular volume resuscitation
  • All patients with sepsis require supplemental fluids. Assessment of the patient's volume and cardiovascular status guides the amount and rate of infusion. For adult patients who are hypotensive, administer an isotonic crystalloid solution (sodium chloride 0.9% or Ringer lactate) in boluses of 500 mL (10 mL/kg in children), with repeat clinical assessments after each bolus. Administer repeat boluses until signs of adequate perfusion are restored. A total of 4-6 L may be required. Monitor patients for signs of volume overload, such as dyspnea, pulmonary crackles, and pulmonary edema, on chest radiograph. Improvement, stabilization, and normalization of the patient's mental status, heart rate, BP, capillary refill, and urine output indicate adequate volume resuscitation.
  • In some patients, clinically assessing the response to volume infusion may be difficult. By monitoring the response of central venous pressure or pulmonary artery occlusion pressure (PAOP) to fluid boluses, the physician can assess these patients. A control venous pressure of 10-15 mm Hg, a PAOP greater than 18 mm Hg, or a rise in the PAOP by 5 mm Hg or more following fluid bolus indicates adequate volume resuscitation. Such patients are susceptible to volume overload; therefore, administer further fluid carefully. Colloid resuscitation (with albumin or pentastarch) has no proven benefit over isotonic crystalloid resuscitation (normal saline or Ringer lactate).

• Empirical antimicrobial therapy
  • Administer initial antibiotics. Selection of particular agents is empirical and is based on an assessment of the patient's underlying host defenses, the potential sources of infection, and the most likely responsible organisms. Antibiotics must be broad spectrum and cover gram-positive, gram-negative, and anaerobic bacteria because all classes of these organisms produce identical clinical pictures. Administer antibiotics parenterally in doses adequate to achieve bactericidal serum levels. Many studies have found that clinical improvement correlates with the achievement of serum bactericidal levels rather than the number of antibiotics administered.
  • Include coverage directed against anaerobes in the therapy of patients with intraabdominal or perineal infections. Antipseudomonal coverage is indicated in patients with neutropenia or burns. Patients who are immunocompetent usually can be treated with a single drug with broad-spectrum coverage, such as a third-generation cephalosporin. Patients who are immunocompromised usually require dual antibiotic coverage with broad-spectrum antibiotics with overlapping coverage. Within these general guidelines, no single combination of antibiotics is clearly superior to others.

• Vasopressor supportive therapy
  • When proper fluid resuscitation fails to restore hemodynamic stability and tissue perfusion, initiate therapy with vasopressor agents. These agents are dopamine, norepinephrine, epinephrine, and phenylephrine. These vasoconstricting drugs maintain adequate BP during life-threatening hypotension and preserve perfusion pressure for optimizing flow in various organs. Maintain the mean BP required for adequate splanchnic and renal perfusion (mean arterial pressure [MAP] of 60 or 65 mm Hg) based on clinical indices for organ perfusion.
  • If the patient remains hypotensive despite volume infusion and moderate dose dopamine, start a direct vasoconstrictor (eg, norepinephrine) at a dose of 0.5 mcg/kg/min in and titrated to support a systolic BP of 90 mm Hg. While potent vasoconstrictors (eg, norepinephrine) traditionally have been avoided because of their adverse events on cardiac output and renal perfusion, human data has shown that norepinephrine can reverse septic shock in patients unresponsive to volume and dopamine. These patients require invasive hemodynamic monitoring with arterial lines and pulmonary artery catheters. A brief discussion of the hemodynamic drugs used to support patients who are critically ill and septic follows:
  • Vasopressor therapy
    • Dopamine: A precursor of norepinephrine and epinephrine, dopamine has varying effects based on the doses. A dose of less than 5 mcg/kg/min results in vasodilation of renal, mesenteric, and coronary beds. At a dose of 5-10 mcg/kg/min, beta-1-adrenergic effects induce an increase in cardiac contractility and heart rate. At doses about 10 mcg/kg/min, alpha-adrenergic effects lead to arterial vasoconstriction and an increase in BP. Dopamine is effective in increasing MAP in patients who are hypotensive with septic shock after volume resuscitation. The BP increases primarily as a result of an inotropic effect and, thus, is useful in patients who have concomitant reduced cardiac function. The undesirable effects are tachycardia, increased pulmonary shunting, potential to decrease splanchnic perfusion, and increased pulmonary arterial wedge pressure.
    • Epinephrine: Epinephrine can increase MAP by increasing the cardiac index, stroke volume, systemic vascular resistance, and heart rate. Epinephrine may increase oxygen delivery and consumption and decreases splanchnic blood flow. Epinephrine administration is associated with an elevation of systemic and regional lactate concentrations. The use of epinephrine is recommended in patients who are unresponsive to traditional agents. The undesirable effects are an increase in lactate concentration, a potential to produce myocardial ischemia and arrhythmias, and a reduction in splanchnic flow.
    • Norepinephrine: Norepinephrine is a potent alpha-adrenergic agonist with minimal beta-adrenergic agonist effects. Norepinephrine can successfully increase BP in patients who are septic and remain hypotensive following fluid resuscitation and dopamine. The dose of norepinephrine may vary from 0.2-1.35 mcg/kg/min; doses as large as 3.3 mcg/kg/min have been used because alpha-receptor down regulation may occur in sepsis. In patients who are septic, indices of regional perfusion, such as urine flow and lactate concentration, have improved following norepinephrine infusion. Two recent trials have shown that a significantly greater proportion of patients treated with norepinephrine were successfully resuscitated as opposed to patients treated with dopamine. Therefore, use norepinephrine early, and do not withhold it as a last resort. The studies have shown no effects on splanchnic oxygen consumption and hepatic glucose production, provided adequate cardiac output is maintained.
    • Phenylephrine: Phenylephrine is a selective alpha-1 adrenergic receptor agonist primarily used in anesthesia to increase BP. Although studies are limited, phenylephrine increased the MAP in patients who are septic and hypotensive with an increase in oxygen consumption and potential to reduce cardiac output. Phenylephrine may be a good choice when tachyarrhythmias limit therapy with other vasopressors.
    • Inotropic therapy: Although myocardial performance is altered during sepsis and septic shock, cardiac output usually is maintained in the patients who are septic and have been volume resuscitated. Data from the 1980s and 1990s suggested a linear relationship between oxygen delivery and oxygen consumption (pathologic supply dependency), indicating that oxygen delivery was likely insufficient to meet the metabolic needs of the patient. However, recent investigations have challenged the concept of pathologic supply dependency and the practice of elevating cardiac index and oxygen delivery (hyperresuscitation) because these interventions have not been shown to improve patient outcome. Therefore, the role of inotropic therapy is uncertain unless the patient has an inadequate cardiac index, MAP, mixed venous oxygen saturation, and urine output despite optimal volume resuscitation and vasopressor therapy.
    • Renal-dose dopamine: The use of renal-dose dopamine in sepsis is a controversial issue. In the past, low-dose dopamine was routinely used in many units because of the presumed renal protective effects. Dopamine at a dose of 2-3 mcg/kg/min is known to initiate diuresis by increasing renal blood flow in healthy animals and volunteers. Multiple studies have not demonstrated a beneficial effect with prophylactic or therapeutic low-dose dopamine administration in patients who are critically ill. Low-dose dopamine does not protect the patient from developing acute renal failure, and there is no data stating that it preserves mesenteric profusion; the routine use of this practice is not recommended. Aggressively resuscitating patients with septic shock, maintaining adequate perfusion pressure, and avoiding excessive vasoconstriction are effective measures to protect the kidneys.

• Recombinant human-activated protein C
  • The inflammatory mediators are known to cause activation of coagulation inhibitors of fibrinolysis, thereby causing diffuse endovascular injury, multiorgan dysfunction, and death. Activated protein C is an endogenous protein that not only promotes fibrinolysis and inhibits thrombosis and inflammation but also may modulate the coagulation and inflammation of severe sepsis. Sepsis reduces the level of protein C and inhibits conversion of protein C to activated protein C. Administration of recombinant activated protein C inhibits thrombosis and inflammation, promotes fibrinolysis, and modulates coagulation and inflammation.
  • A recent publication by the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group demonstrated that the administration of recombinant human activated protein C (drotrecogin-alpha, activated) resulted in lower mortality rates (24.7% vs 30.8%) in the treated group compared with placebo. Treatment with drotrecogin-alpha, activated was associated with reduction in the relative risk of death by 19.4% (95% CI, 6.6-30.5) and an absolute reduction in risk of death by 6.1%, (P=.005).
• Corticosteroids
  • While theoretical and experimental animal evidence exists for the use of large doses of corticosteroids in those with severe sepsis and septic shock, all randomized human studies (except 1 from 1976) found that corticosteroids did not prevent the development of shock, reverse the shock state, or improve the 14-day mortality rate. Therefore, no support exists in the medical literature for the routine use of high doses of corticosteroids in patients with sepsis or septic shock. A meta-analysis of 10 prospective, randomized, controlled trials of glucocorticoid use did not report any benefit from corticosteroids. Therefore, high-dose corticosteroids should not be used in patients with severe sepsis or septic shock.
  • Although further studies await further confirmation, current recommendations are as follows:
    • Drotrecogin alpha (activated protein C) is the only widely accepted drug specific to the therapy of sepsis. Drotrecogin Alpha should be considered for patients with APACHE II scores greater than 25.
    • The main side effect of Drotrecogin alpha is bleeding.
    • Recent trials of stress-dose glucocorticoids (Briegel, 1999; Cartlet, 1999) demonstrated positive results of stress-dose administration of corticosteroids in patients with severe and refractory shock. Although further confirmatory studies are awaited, stress-dose steroid coverage should be provided to patients who have the possibility of adrenal suppression.
  • he following key points summarize use of corticosteroids in septic shock:
    • Older, traditional trials of corticosteroids in sepsis were likely unsuccessful due to high doses and poor patient selection.
    • Recent trials with low-dose (physiologic) dosages in select patient populations (vasopressor dependent and possibly relative adrenal insufficiency) patients have resulted in improved outcome.
    • orticosteroids should be initiated for patients with vasopressor-dependent septic shock.
    • A cosyntropin stimulation test may be performed to identify patients with relative adrenal insufficiency defined recently as failure to increase levels to more than 9 mcg/dL.
    • Tight glycemic control has recently become a prominent emphasis in the care of critically ill patients, and recent data has been extrapolated to potentially apply to septic populations. A 2001 Belgian study of surgical intensive care unit (ICU) patients that remained in the ICU for more than 5 days showed a 10% mortality benefit in those with tighter glycemic control. The glucose levels for these patients were maintained between 80 and 110 mg per deciliter through use of intensive insulin therapy. The benefit of glycemic control appears to result more from aggressive avoidance of the detrimental effects of hyperglycemia rather than the potential therapeutic effect of insulin.
    • Based on the current evidence, the Surviving Sepsis Campaign recommends maintaining a glucose level of less than 150 mg/dL (Dellinger, 2004).
    • Tight glycemic control has been shown to improve mortality in post-operative surgical patients including and particularly those with sepsis
    • The Surviving Sepsis Campaign recommends that glucose levels in the septic patient should be kept at less than 150 mg/dl

    Surgical Care: Take patients with infected foci to surgery after initial resuscitation and administration of antibiotics for definitive surgical treatment. Little is gained by spending hours stabilizing the patient when an infected focus persists.

    Consultations:

    • Patients who do not respond to therapy or are in septic shock require admission to an ICU for continuous monitoring and observation. Consultation with a critical care physician or internist with expertise is appropriate.
    • Seek consultation with an appropriate surgeon for patients with suspected or known infected foci, especially for patients with a suspected abdominal source.

Medication
The proven medical treatments for septic shock are restoration of intravascular volume and broad-spectrum empirical antibiotic coverage. All other medical therapies, while theoretically attractive, have not reduced morbidity or mortality.
Drug Category: Isotonic crystalloids -- Standard fluid used for initial volume resuscitation. These fluids expand the intravascular and interstitial fluid spaces. Typically, approximately 30% of administered isotonic fluid remains intravascular; therefore, large quantities may be required to maintain an adequate circulating volume.

Drug Name	Normal saline (NS) and Ringer lactate (RL) -- Both fluids essentially are isotonic and have equivalent volume restorative properties. While some differences exist between metabolic changes observed with administration of large quantities of either fluid, for practical purposes and in most situations, the differences are clinically irrelevant. No demonstrable difference in hemodynamic effect, morbidity, or mortality exists between resuscitation with either NS or RL. The amount of intravascular fluid requirements are related to the degree of vascular endothelial injury and impaired vasomotor tone; thus, not only may very large quantities of fluids be required initially, but continual fluid resuscitation often is required during the initial days of management of these patients.
Adult Dose	1-2 L IV initially, with reassessment of hemodynamic response; amounts required during the first few hours typically are 4-5 L
Pediatric Dose	Not established
Contraindications	Pulmonary edema in which added fluid promotes more edema and may lead to development of ARDS
Interactions	None reported
Pregnancy	A - Safe in pregnancy
Precautions	Closely monitor cardiovascular and pulmonary function; stop fluids when the desired hemodynamic response is observed or pulmonary edema develops; interstitial edema is a major complication; edema in an extremity is unsightly but not a significant complication; edema in brain or lungs is potentially fatal

Drug Category: Colloids -- Resuscitation fluids used because they provide an oncotically active substance that expands plasma volume to a greater degree than isotonic crystalloids and reduces the tendency to pulmonary and cerebral edema. Approximately 50% of the administered colloid remains intravascular.

Drug Name	Albumin 5% (Albuminar, Albunex) -- Used for treatment of certain types of shock or impending shock. Useful for plasma volume expansion and maintenance of cardiac output. Solution of normal saline and 5% albumin is available for volume resuscitation.
Adult Dose	250-500 mL IV over 20-30 min, with reassessment of hemodynamic response
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pulmonary edema; protein load of 5% albumin
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	No proven benefit of colloid resuscitation over isotonic crystalloids is known; protein load tends to exacerbate renal insufficiency, a potential complication of septic shock; studies document an increased incidence of renal failure in patients with colloid resuscitation

Drug Category: Antibiotics -- Empirical antibiotics that cover the infecting organism and are started early are the only other proven medical treatment for septic shock. In order to provide the necessary coverage, broad-spectrum and/or multiple antibiotics are started. Monotherapy is possible in adults who are not immunocompromised with either antipseudomonal penicillin or a carbapenem. Combination therapy in adults involves 1 of the following: a third-generation cephalosporin plus anaerobic coverage (clindamycin or metronidazole) or a fluoroquinolone plus clindamycin. Administer all initial antibiotics intravenously in patients with septic shock.

Drug Name	Cefotaxime (Claforan) -- Used for treatment of septicemia. Also used for treatment of gynecologic infections caused by susceptible organisms. Third-generation cephalosporin with enhanced gram-negative coverage, especially to Escherichia coli, Proteus species, and Klebsiella species. Has variable activity against Pseudomonas species.
Adult Dose	1-2 g IV q4h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid may decrease cefotaxime clearance, causing an increase in cefotaxime levels; furosemide and aminoglycosides may increase nephrotoxicity when used concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in severe renal impairment; associated with severe colitis

Drug Name	Ceftriaxone (Rocephin) -- Used because of an increasing prevalence of penicillinase-producing microorganisms. Inhibits bacterial cell wall synthesis by binding to 1 or more of the penicillin-binding proteins. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested.
Adult Dose	1 g IV q6-12h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid may decrease ceftriaxone clearance, causing an increase in ceftriaxone levels; ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity when used concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; use with caution in breastfeeding women and in patients allergic to penicillin

Drug Name	Cefuroxime (Zinacef) -- Second-generation cephalosporin that maintains gram-positive activity of the first-generation cephalosporins and adds activity against E coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis. Condition of the patient, severity of the infection, and susceptibility of the microorganism determine proper dose and route of administration.
Adult Dose	1.5 g IV q8h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Alcoholic beverages consumed concurrently within <72>
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Administer one half the dose to patients with creatinine clearance of 10-30 mL/min; administer one fourth the dose to patients with a creatinine clearance of <10>

Drug Name	Ticarcillin/clavulanate (Timentin) -- Antipseudomonal penicillin plus a beta-lactamase inhibitor that provides coverage against most gram-positives (variable coverage against Staphylococcus epidermidis and none against methicillin-resistant Staphylococcus aureus [MRSA]), most gram-negative organisms, and most anaerobes.
Adult Dose	3.1 g (ticarcillin 3 g and claculanate 0.1 g) IV q4-6h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe pneumonia; do not treat bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis with an oral penicillin during acute stage
Interactions	Tetracyclines may decrease effects; high concentrations may physically inactivate aminoglycosides if administered in the same IV line; probenecid may increase penicillin levels; effects when administered concurrently with aminoglycosides are synergistic
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Perform CBCs prior to initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; perform urinalysis, BUN, and creatinine determinations during therapy, and adjust dose if these values become elevated; if renal impairment is known or suspected, adjust dose and monitor blood levels; these measures avoid possible neurotoxic reactions

Drug Name	Piperacillin/tazobactam (Zosyn) -- Inhibits the biosynthesis of cell wall mucopeptide and is effective during the stage of active multiplication. Has antipseudomonal activity.
Adult Dose	3/0.375 g (piperacillin 3 g and tazobactam 0.375 g) IV q6h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; do not treat severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis with an oral penicillin during the acute stage
Interactions	Tetracyclines may decrease the effects; high concentrations may physically inactivate aminoglycosides; probenecid may increase penicillin levels; effects when administered concurrently with aminoglycosides are synergistic
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Perform CBCs prior to initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; perform urinalysis, BUN, and creatinine determinations during therapy, and adjust dose if these values become elevated; if renal impairment is known or suspected, adjust dose and monitor blood levels; these measures avoid possible neurotoxic reactions

Drug Name	Imipenem and cilastatin (Primaxin) -- Carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes. Used for treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to their potential for toxicity.
Adult Dose	500 mg IV q6h
Pediatric Dose	<12> >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cyclosporine may increase CNS adverse effects of both agents; coadministration with ganciclovir may result in generalized seizures
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in renal insufficiency; avoid use in children <12>

Drug Name	Meropenem (Merrem) -- Carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem.
Adult Dose	1 g IV q8h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid may inhibit renal excretion of meropenem, increasing meropenem levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication

Drug Name	Clindamycin (Cleocin) -- Primarily used for its activity against anaerobes. Has some activity against streptococcus and methicillin-sensitive S aureus (MSSA).
Adult Dose	600-900 mg IV q8h
Pediatric Dose	5-10 mg/kg IV q8h
Contraindications	Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium
Pregnancy	D - Unsafe in pregnancy
Precautions	Dose adjustment may be necessary in severe hepatic dysfunction; no adjustment is necessary in renal insufficiency; associated with severe and possibly fatal colitis

Drug Name	Metronidazole (Flagyl) or Ciprofloxacin (Cipro) -- Metronidazole: Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Usually employed in combination with other antimicrobial agents, except when it is used for Clostridium difficile enterocolitis in which monotherapy is appropriate. Ciprofloxacin: Fluoroquinolone with variable activity against streptococci, MSSA, S epidermidis, and most gram-negative organisms. No activity against anaerobes.
Adult Dose	Metronidazole: Loading dose: Infuse 15 mg/kg IV over 1 h or 1 g for a 70-kg adult Maintenance dose: Infuse 7.5 mg/kg IV over 1 h q6-8h or 500 mg for a 70-kg adult; administer 6 h following the loading dose; not to exceed 4 g in 24 h Ciprofloxacin: 1400 mg IV q12h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Metronidazole: Potentiates anticoagulant effect of warfarin; agents that alter hepatic P450 system affect its clearance; phenytoin and phenobarbital may decrease half-life; may reduce metronidazole clearance and increase toxicity; may increase effect of anticoagulants; may decrease lithium and phenytoin clearance, increasing their toxicity; disulfiramlike reactions may occur when used concurrently with orally ingested ethanol (although the risk for most patients may be slight, exercise caution) Ciprofloxacin: Antacids, iron salts, and zinc salts may interfere with GI absorption of fluoroquinolones, resulting in decreased serum levels; administer antacids 2-4 h before or after fluoroquinolones; cimetidine may interfere with metabolism fluoroquinolones and reduce therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations significantly; ciprofloxacin may increase theophylline and caffeine concentrations and prolong duration of action; may increase nephrotoxic effect of cyclosporine; digoxin serum levels may be increased when used concurrently with ciprofloxacin; monitor digoxin levels; may increase effects of anticoagulants; monitor PT
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Metronidazole: Pregnancy category B; adjust dose in patients with severe hepatic disease because they may metabolize metronidazole slowly; monitor patients for seizures and the development of peripheral neuropathy Ciprofloxacin: Pregnancy category C; in prolonged therapy, perform periodic evaluations of organ system functions, including renal, hepatic, and hematopoietic; patients diagnosed with renal function impairment may require a dose adjustment; prolonged or repeated antibiotic therapy may result in bacterial or fungal overgrowth of nonsusceptible organisms, resulting in secondary infections; take appropriate measures to prevent further complications

Drug Category: Activated protein C analogs -- Exert antithrombic effects, have indirect profibrinolytic activity, and may have anti-inflammatory effect.

Drug Name	Drotrecogin alfa (Xigris) -- Indicated for reduction of mortality in patients with severe sepsis associated with acute organ dysfunction and at high risk of death. Recombinant form of human activated protein C that exerts antithrombotic effect by inhibiting factors Va and VIIIa. Has indirect profibrinolytic activity by inhibiting plasminogen activator inhibitor-1 (PAI-1) and limiting formation of activated thrombin-activatable-fibrinolysis-inhibitor. May exert anti-inflammatory effect by inhibiting human tumor necrosis factor (TNF) production by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced inflammatory responses within microvascular endothelium.
Adult Dose	24 mcg/kg/h IV continuous infusion for 96 h; ideally, initiate within 48 h of sepsis onset
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; increased risk of bleeding (eg, active internal bleeding, recent hemorrhagic stroke, recent intraspinal or intracranial surgery, recent or current trauma, presence of epidural catheter, intracranial neoplasm, cerebral herniation, severe head trauma)
Interactions	None reported; coadministration with drugs that affect hemostasis may increase risk of bleeding (eg, warfarin, heparin, thrombolytics, glycoprotein IIb/IIIa inhibitors)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Bleeding is most common serious adverse effect; caution with conditions that increase risk of bleeding including INR >3, concurrent therapeutic heparin (>15 U/kg/h), within 6 wk of GI bleeding episode, within 3 d of thrombolytic therapy, within 7 d of platelet inhibitors administration, within 3 mo of ischemic stroke, intracranial arteriovenous malformation or aneurysm, known bleeding diathesis, chronic severe hepatic disease; stop infusion if clinically significant bleeding occurs

Drug Category: Vasopressor supportive therapy -- If patient does not respond to several liters of isotonic crystalloid (usually 4 or more) or evidence of volume overload is present, the depressed cardiovascular system can be stimulated by inotropic and vasoconstrictive agents.

Drug Name	Dopamine (Inotropin) -- Used to treat hypotension in fluid-resuscitated patients. Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect depends on the dose. Lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation in health volunteers, but probably have no measurable effect in patients who are critically ill. Higher doses produce cardiac stimulation, tachycardia, and vasoconstriction.
Adult Dose	In hypotensive hyperdynamic shock: starting dose of 2-5 mcg/kg/min IV; titrate as needed to maintain a MAP >60 mm Hg; may be increased by 1-4 mcg/kg/min q10-30min IV until satisfactory response; not to exceed 20 mcg/kg/min Maintenance dose: <20>
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; tachycardia; pheochromocytoma; ventricular tachyarrhythmias
Interactions	Phenytoin, alpha-adrenergic and beta-adrenergic blockers, general anesthesia, and MAO inhibitors increase and prolong the effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor urine flow, cardiac output, pulmonary wedge pressure, and BP closely during the infusion; prior to infusion, correct hypovolemia with either whole blood or plasma, as indicated; monitoring of central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia

Drug Name	Norepinephrine (Levophed) -- As with dopamine, it is used to treat hypotension following adequate fluid-volume replacement. Norepinephrine stimulates beta 1-adrenergic and alpha-adrenergic receptors, which increase arterial tone and cardiac contractility. As a result, systemic BP and coronary blood flow increases with norepinephrine, though myocardial oxygen demand also may increase. After obtaining a response, adjust infusion rate to maintain a MAP greater than 60 mm Hg. BP levels below this threshold are insufficient to perfuse vital organs while increasing pressures much greater than 70 mm Hg, using vasopressors does not further increase tissue blood flow.
Adult Dose	0.05-2 mcg/kg/min IV; titrate to effect
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; known hypovolemia; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended
Interactions	Atropine sulfate may enhance pressor response of norepinephrine by blocking reflex bradycardia caused by norepinephrine
Pregnancy	D - Unsafe in pregnancy
Precautions	Correct blood-volume depletion, if possible, before administering norepinephrine therapy; extravasation may cause severe tissue necrosis, administer into a large vein; use with caution in patients with occlusive vascular disease

Drug Name	Vasopressin (Pitressin) -- Has vasopressor and antidiuretic hormone (ADH) activity. Although vasopressin does not increase BP in healthy subjects, it markedly increases vasomotor tone in patients with septic shock. It also increases water resorption at the distal renal tubular epithelium (ADH effect) and promotes smooth muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). Vasoconstriction also is increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels. Vasopressin is not yet routinely used to treat hypotension in septic shock. The dosage of vasopressin used for hypotension is one-tenth that used to treat upper GI bleeding from varices.
Adult Dose	Suggested dose: 0.01-0.05 U/min IV; titrate dose as needed
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; coronary artery disease
Interactions	Lithium, epinephrine, demeclocycline, heparin, and alcohol may decrease the effects of vasopressin; conversely, chlorpropamide, urea, fludrocortisone, and carbamazepine potentiate its effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in cardiovascular disease, seizure disorders, nitrogen retention, asthma, or migraine; excessive doses may result in hyponatremia