Brenner and Rector's The Kidney, 8th ed.

CHAPTER 60. Intensive Care Nephrology

Matthew Dollins   Michael A. Kraus   Bruce A. Molitoris



Acute Respiratory Failure, 2037



Adult Respiratory Distress Syndrome, 2038



Clinical Features, 2038



Risk Factors, 2038



Pathophysiology, 2039



Treatment, 2039



Effects on Renal Function, 2041



Hypovolemic Shock, 2041



Pathogenesis, 2041



Oxygen Consumption and Delivery, 2042



Reperfusion, 2043



Clinical Manifestations, 2043



Diagnosis, 2043



Management, 2043



Fluid Resuscitation, 2044



Crystalloid versus Colloid for Resuscitation, 2044



Vasopressors, 2045



Management of Acidosis, 2045



Effects of Hypovolemic Shock on Renal Function, 2045



Sepsis, 2045



Definition, 2045



Source of Infection and Microbiology, 2046



Pathophysiology, 2046



Clinical Features, 2048



Management, 2049



Antibiotics, 2049



Hemodynamic Support, 2049



Treatment of the Coagulation Cascade, 2049



Immunomodulatory Therapy, 2050



Hemofiltration in Sepsis, 2050



Cardiogenic Shock, 2050



Pathophysiology, 2050



Clinical Features, 2051



Evaluation, 2051



Management, 2051



Fulminant Hepatic Failure, 2053



Definition, 2053



Causes, 2053



Clinical Features, 2054



Evaluation, 2054



Management, 2055

Approximately 5% to 25% of critically ill patients will develop kidney injury during the course of their illness, [1] [2] including between 9% and 40% of patients with sepsis,[3] 20% to 40% of patients with acute respiratory distress syndrome,[4] 33% of patients with cardiogenic shock,[5] and 55% of patients with fulminant hepatic failure.[6] The nephrologist is a critical component in the care of these patients, and an understanding of the underlying pathophysiology of respiratory failure, shock, and the management of mechanical ventilation is critical. The nephrologist should understand the literature behind the move to low tidal volume ventilation because this will affect the acid base status, and has implications for bicarbonate prescriptions during renal replacement therapy. The management of shock is also a rapidly developing field, and nephrologists, who are active in the care of many of these patients, should have an understanding of this area.


Acute respiratory failure can be defined as the inability of the respiratory system to meet the oxygenation, ventilation, or metabolic requirements of the patient.[7] This may occur in a previously healthy person with pneumonia or pulmonary embolism, or complicating chronic respiratory failure in the setting of pulmonary fibrosis or chronic obstructive pulmonary disease. Respiratory failure can be divided into two main types: hypoxemic respiratory failure, which is failure to maintain adequate oxygenation, and hypercapnic respiratory failure, which is inadequate ventilation with CO2 retention.

Respiratory failure is a common occurrence in the ICU, and many of these patients develop renal failure during the course of their illness. Because nephrologists are often asked to assist with the acid-base treatment of these patients, it is important that they have an understanding of mechanical ventilation and the newer treatment strategies for acute respiratory distress syndrome (ARDS).

When patients with respiratory failure are unable to maintain their oxygenation or ventilation by noninvasive means such as supplemental oxygen or continuous positive airway pressure (CPAP/BiPAP), they require intubation and mechanical ventilation, which improves gas exchange and decreases the work of breathing. Several modes of mechanical ventilation are now available. They can be classified into (1) volume cycled ventilation, in which a certain tidal volume is delivered by the ventilator [synchronized intermittent mandatory ventilation (SIMV) and continuous mandatory ventilation (CMV)]; (2) pressure cycled ventilation, in which volume is delivered until a preset maximum pressure is reached [pressure control ventilation (PCV)]; and (3) flow cycled ventilation, in which inspiration continues until a preset flow rate is reached [pressure support ventilation (PSV)]. SIMV allows the patient to breathe spontaneously between breaths assisted by the ventilator. The physician orders a set number of breaths, delivered every minute at a certain tidal volume, which is given in synchrony with inspiratory effort if the patient is able to generate inspiration. Any breaths beyond the set number the patients must generate themselves. CMV results in the ventilator delivering a breath every time the patient generates a negative inspiratory force, or at a set rate, whichever is the higher frequency. CMV minimizes the work of breathing done by the patient, and therefore should be used in the setting of myocardial ischemia or profound hypoxemia. One problem of CMV occurs in patients who are tachypneic or have obstructive lung disease. If there is inadequate time to exhale the full tidal volume, dynamic hyperinflation (breath stacking or auto-peep) may occur, which can result in increased intrathoracic pressure, decreased cardiac output, and possibly barotrauma. PCV differs from SIMV and CMV in that the physician sets an inspiratory pressure, not a tidal volume. During inspiration, a given pressure is imposed via the circuit, and the tidal volume delivered depends on how much flow can be delivered prior to the airway pressure equilibrating with the inspiratory pressure. The tidal volume can vary from breath to breath, and thus the minute volume is variable.

Continuous positive airway pressure (CPAP) is not a true form of mechanical ventilation, but provides a supply of fresh gas at a constant, specified pressure. It is most commonly used in weaning trials or in patients without respiratory failure who require an endotracheal tube to maintain an airway. PSV is a patient-triggered mode of ventilation in which a preset pressure is maintained throughout inspiration. When inspiratory flow falls below a certain level, inspiration is terminated. PSV is commonly used in patients who require minimal support, or to assist the spontaneous breaths during SIMV. Airway pressure release ventilation (APRV) is used in a spontaneously breathing patient who is using CPAP. At the end of each ventilator cycle, the lungs are allowed to briefly deflate to ambient pressure, then rapidly reinflated to the baseline (CPAP) pressure with the next breath. The perceived advantage is that lung expansion during exhalation is maintained with CPAP, but the brief interruption of this pressure at the end of exhalation allows for further carbon dioxide elimination, as well as enhanced venous return.

In addition to the mode of ventilation, the physician prescribes the oxygen concentration to be delivered, the level of positive end expiratory pressure (PEEP), the tidal volume, and the respiratory rate. When initially intubated, patients are typically placed on a high oxygen concentration and weaned down as quickly as possible. Multiple animal studies have supported the notion of oxygen toxicity, whereby higher oxygen concentrations lead to lung injury.[8] [9] [10] [11] Studies on healthy volunteers have shown that after 6 hours on 100% oxygen, there is a change in whole lung capacity and a decrease in the vital capacity,[12] and after 24 hours, there is a reduction in lung compliance likely secondary to increased interstitial edema.[13] Although there are no conclusive studies showing the effects of high levels of inspired oxygen on the lungs during acute illness, most clinicians try to reduce the inspired oxygen concentration to 50% or less as quickly as possible.

Positive end expiratory pressure provides a continuous airway pressure above atmospheric, preventing collapse of alveoli and small airways at end-expiration. By recruiting alveoli in this way, PEEP improves functional residual capacity and oxygenation. PEEP is most commonly set between 5 cm and 20 cm H2O and titrated until adequate oxygenation is achieved. The level of PEEP directly increases airway pressures, so high levels of PEEP can result in barotrauma. PEEP also increases intrathoracic pressure and can result in a decrease in cardiac output secondary to reduced filling volumes.

The tidal volume delivered during mechanical ventilation has recently undergone a dramatic change. Traditional tidal volumes were 10 to 15 ml/kg per breath, but as will be discussed in the ARDS section, recent studies support using lower tidal volumes in patients with lung injury. Patients who are felt to have acute lung injury or ARDS are now prescribed 4 to 8 ml/kg per breath with the goal of minimizing airway pressures. Mechanically ventilated patients without significant lung disease should be prescribed a maximal tidal volume of 10 ml/kg with the goal of preventing ventilator-induced lung injury from barotrauma.

The respiratory rate is set based on the patient's minute ventilation requirement. Patients who are septic or very metabolically active often require a high minute volume to adequately eliminate CO2, and with the lower tidal volumes used now, respiratory rates are often increased. However, care must be taken in the patient with asthma or obstructive lung disease because too high of a rate can lead to air trapping if these patients with prolonged expiratory phase requirements are not allowed to exhale the complete tidal volume prior to the next breath.


The adult respiratory distress syndrome was first described in 1967 when Ashbaugh and colleagues described 12 patients with acute respiratory distress, hypoxia refractory to oxygen therapy, decreased lung compliance, and diffuse infiltrates on chest tomography.[14] This clinical entity is now referred to as the acute respiratory distress syndrome because it is recognized to occur in children as well as adults affecting up to 150,000 patients per year in the United States.[15]

Adult respiratory distress syndrome generally has a poor prognosis, with recent studies reporting a 35% to 60% mortality rate. [16] [17] The lack of a uniform definition led to difficulty in designing studies and attempts at improving outcome, so in 1994 the American-European Consensus Conference developed a definition that is widely used today.[15] This conference established two categories, acute lung injury (ALI) and ARDS depending on the severity of hypoxemia. The acute onset of hypoxemic respiratory failure with bilateral infiltrates on chest tomography, and a pulmonary artery wedge pressure of less than 18, or no clinical evidence of left atrial hypertension characterizes both ALI and ARDS. ALI is present when the criteria mentioned previously are present with an arterial oxygen tension-fraction of inspired oxygen (paO2/FiO2) ratio of less than 300, and ARDS requires the criteria mentioned previously with a paO2/FiO2 ratio of less than 200. The syndromes represent two points in the same disease spectrum, and both appear to have similar outcomes.

Clinical Features

Acute lung injury and ARDS are usually diagnosed when a patient with a known risk factor develops acute dyspnea, hypoxemia, and tachypnea. Different stages are often apparent. The acute stage is characterized by the onset of acute respiratory failure, commonly associated with hypoxemia that is refractory to supplemental oxygen. Radiographic findings include bilateral infiltrates that may be indistinguishable from cardiogenic pulmonary edema,[18] and may be patchy or symmetric. Computed tomography shows the affected areas are primarily the dependent lung zones.[19] During this phase, patients previously requiring minimal oxygen often progress to requiring mechanical support as the work of breathing increases. Pathological findings include damage to the capillary endothelial and alveolar epithelial cells.[20] This disruption of the normal barrier results in increased permeability and filling of the alveoli with protein-rich fluid and inflammatory cells.[21] There is also direct damage to type II pneumocytes, which are responsible for surfactant production. Reduction in surfactant production leads to increased surface tension within the alveoli and results in atelectasis. Interstitial edema also results in the collapse of small airways. As these non-ventilated alveoli are perfused, severe, refractory hypoxemia develops, which accounts for the shunt physiology seen in this disorder. Mechanically ventilated patients with ARDS often have very high airway pressures, a result of fewer ventilated alveoli and reduced lung compliance from the influx of inflammatory cells. This often necessitates a high minute ventilation to maintain an acceptable pCO2.

Following the acute phase, many patients recover completely, yet some develop a fibrotic phase characterized by fibrosing alveolitis, persistent hypoxemia, and further worsening of pulmonary complications.[21] Right ventricular failure can develop due to destruction of the pulmonary capillary bed. Even following the fibrotic phase, improvement in hypoxemia and lung compliance can occur gradually, with many patients returning to normal pulmonary function over 6 to 12 months.[22]

Risk Factors

Acute lung injury and ARDS can develop in association with several clinical conditions ( Table 60-1 ), not all of which directly involve the pulmonary system. The most common condition associated with ARDS is sepsis, with up to 40% of septic patients developing ARDS. [20] [23] Other common risk factors include shock, the systemic inflammatory response syndrome (SIRS), pneumonia, multiple transfusions, near drowning, aspiration, trauma, pancreatitis, burns, coronary artery bypass grafting, and disseminated intravascular coagulation. [13] [14] [24] Multiple risk factors increase the risk for ARDS synergistically.[20]

TABLE 60-1   -- Risk Factors for Acute Respiratory Distress Syndrome



Pulmonary causes









Near drowning



Non pulmonary causes






Systemic inflammatory response syndrome









Multiple blood transfusions









Coronary artery bypass grafting



Disseminated intravascular coagulation





In ARDS, damage is evident to the pulmonary capillary endothelium, which results in an increased permeability and an influx of fluid into the alveoli. Alveolar epithelial cells, which contribute to the alveolar-capillary barrier, and are involved in alveolar fluid reabsorption as well as in the pathogenesis of fibrosis are also injured. Neutrophils play a prominent role in this process because they are found in the alveoli as well as the interstitium during ARDS. Pulmonary capillary endothelial cell activation results in recruitment, adhesion, and signaling of leukocytes They are recruited into the interstitium by cellular adhesion molecules such as selectins and beta-2 integrins.[25] The neutrophils are activated by complement, IL-1, -6, -8, and -10 as well as tumor necrosis factor-α, and these activated neutrophils can then secrete other inflammatory mediators, as well as highly reactive oxidant species, proteolytic enzymes, and metabolites of arachidonic acid that can directly injure alveolar and capillary endothelial cells, allowing for fluid to leak into the alveoli with resultant edema. [26] [27] Although neutrophils are a large component of the inflammatory response, they are not a requirement because neutropenic patients can also develop ARDS. Alveolar macrophages are also involved in ARDS, elaborating cytokines that contribute to the inflammatory process as well as clearing neutrophils from the alveoli and aiding in the resolution of ARDS.

Thromboxane A2 may interact with neutrophils to accentuate cell aggregation,[28] and lipoxygenase products are released in large quantities and may contribute to pulmonary vascular changes and permeability characteristics[21]resulting in “leaky capillaries”. Release of platelet activating factor leads to platelet aggregation in the microvasculature, which results in increased pulmonary vascular resistance and pulmonary hypertension. Infiltration of the interstitium with fibroblasts occurs during the late stage, resulting in the fibrosis seen in some cases.


The management of ARDS has historically been one of support, but the high mortality rates prompted significant research into its cause and propagation. The underlying or predisposing factor should always be addressed promptly, and because sepsis is the most common cause of ARDS, a search for an undiagnosed infection should be undertaken if no clear etiology is present.

The primary mechanism of support is mechanical ventilation. The ARDSNET trial[29] recently showed that a “lung protective mechanism” of mechanical ventilation could improve survival. The goal is to provide adequate oxygenation while avoiding further trauma to the lung that can worsen existing injury.

Traditionally, tidal volumes used during mechanical ventilation were in the range of 12 to 15 ml/min. Acute lung injury, similar to human ARDS, has been observed in animals mechanically ventilated with large tidal volumes.[30] It was reasoned that overdistention of the alveoli, leading to elevated airway pressure, was a primary element in this acute lung injury. Ventilation with high airway pressures has been shown to cause increased vascular permeability, acute inflammation, alveolar hemorrhage, and radiographic infiltrates. [31] [32] In persons with acute lung injury or ARDS, the large tidal volumes are shunted to the unaffected lung because they provide the least resistance, and overdistention results in damage to these previously unaffected segments.

The ARDSNET trial[29] was designed to assess if lower tidal volumes and hence lower airway pressures resulted in a clinical benefit in ARDS. This trial compared traditional ventilation treatment, which was an initial tidal volume of 12 ml/kg ideal body weight (IBW), to a lower tidal volume group that started at 6 ml/kg IBW (IBW=50+2.3 [height in inches – 60] for males, 45.5+2.3 [height in inches-60] for females). In each group, the tidal volume was decreased in increments of 1 ml/kg to maintain the plateau pressure (the airway pressure measured after a 0.5 second inspiratory pause) below 50 for the traditional ventilation group, and below 30 for the lower tidal volume group. The minimal tidal volume was 4 ml/kg. The level of PEEP and oxygen concentration was based on a sliding protocol ( Table 60-2 ). This study was stopped early after 861 patients were enrolled because of a mortality benefit seen in the lower tidal volume group. The mortality rate was 39.8% in the group treated with traditional tidal volumes and 31.0% in the group treated with lower tidal volumes (p=0.007). As expected, the group receiving lower tidal volumes had a slightly higher PaCO2 (43 versus 36 at day 3) and lower pH (7.38 versus 7.41 at day 3) than the traditional tidal volume group.

TABLE 60-2   -- Oxygen and Positive End Expiratory Pressure Titration in the ARDSNET Trial (Goal paO2 55–80 mm Hg)
































PEEP, positive end expiratory pressure.




Since the ARDSNET trial was published, two meta-analyses have suggested that volume-limited ventilation has a short-term survival benefit compared with conventional ventilation, [33] [34] giving further support to the use of low tidal volume ventilation in patients with ARDS or ALI.

Because ARDS is a process that results in decreased lung compliance, patients can generally tolerate higher respiratory rates without the risk of air trapping that is seen in obstructive diseases such as asthma or COPD. The ARDSNET trial used a maximum respiratory rate of 35 breaths per minute. Despite this high rate, the low tidal volumes used to maintain plateau pressures below 30 resulted in a minute ventilation too low to maintain acid-base balance in many patients, a result termed permissive hypercapnia. When the arterial pH fell below 7.30 with a respiratory rate of 35, an infusion of sodium bicarbonate was started.

Given that there have been no other studies in ARDS resulting in such an improvement in mortality, this mode of ventilation must be recommended for all patients with ARDS.

In addition to low-volume ventilation, other mechanical ventilation strategies have been evaluated in ARDS. High frequency oscillatory ventilation (HFOV) uses very low tidal volumes at 4 to 250 times the usual respiratory rate. This mode of ventilation has been studied more extensively in neonates with respiratory distress syndrome,[35] and studies in adults with ARDS have been less compelling. Small, uncontrolled studies have shown an improvement in oxygenation with HFOV, [36] [37] but no study has shown a statistically significant mortality benefit,[38] and there appears to be insufficient evidence to support its routine use in ARDS.

The “open lung” strategy of ventilation uses higher PEEP values to recruit collapsed alveoli, thus “opening up” non aerated regions of the lung. PEEP is kept above 15 cm H2O to prevent end expiratory collapse of alveoli, TV is kept below 6 ml/kg, and the peak airway pressure is kept below 40 cm H2O using pressure-controlled inverse ratio ventilation. One study comparing a higher PEEP strategy to the lower PEEP ARDSnet strategy did not show a difference in survival.[39]

Low tidal volume ventilation clearly has an impact on the nephrologist caring for the patient with ARDS with renal failure. Permissive hypercapnia may result in significant acidosis in a patient with renal failure who is unable to excrete the daily acid load. It also means that the nephrologist may have to use a higher bicarbonate bath during hemodialysis or continuous renal replacement therapy because increasing the minute volume to improve acid-base control is often not an option. In some patients with severe ARDS, large infusions of bicarbonate may not improve acidosis as carbon dioxide is produced, which the severely injured lungs may not be able to expel adequately. Tris-hydroxymethyl aminomethane (THAM) is a buffer that accepts one proton per molecule, generating bicarbonate but not carbon dioxide. It has been shown to control arterial pH without increasing carbon dioxide in the setting of refractory respiratory acidosis.[40] THAM is excreted by the kidneys, so it is not recommended in renal failure.

How best to manage volume status in a patient with ALI/ARDS is controversial. There is substantial data from animal experiments indicating fluid restriction can reduce pulmonary edema in the setting of increased pulmonary vascular permeability, such as in ALI/ARDS.[41] Human studies include an observational study where survival in ARDS was related to negative fluid balance,[42] a study in which patients with a 25% reduction in pulmonary capillary wedge pressure had a greater survival than other patients,[43] and a study where patients with less than 1 liter of fluid gain after 36 hours of recruitment had a better survival than other patients.[44] Yet there are other data suggesting patients with ALI/ARDS may do better with a strategy that increases oxygen delivery, usually requiring volume expansion. Fluid restriction can reduce cardiac output and tissue perfusion, leading to worsening of non-pulmonary organ dysfunction that is often seen in patients with ARDS. Several trials have assessed whether providing supranormal levels of oxygen delivery will improve outcome. [45] [46] [47] [48] [49] [50] Some feel that in systemic inflammatory conditions, such as sepsis or trauma, normal cardiac output and tissue oxygen delivery may be inadequate to prevent organ dysfunction. In postoperative treatment of trauma patients, there was a trend toward decreased mortality with supranormal oxygen delivery, [45] [46] [47] but there has been no benefit in patients with ALI/ARDS, [48] [49] and one study showed an increased mortality in patients who received supranormal levels of oxygen delivery.[50] Because there is no clear benefit to supranormal oxygen delivery, which requires volume expansion, and fluid restriction can lead to worsening of non-pulmonary organ dysfunction greatly increasing mortality, maintaining euvolemia (wedge 10-14, CVP 6-12) in patients with ARDS/ALI with use of fluids as guided by evidence of organ perfusion would be the most reasonable approach at this time.

The inflammatory nature of ARDS raises the possibility that glucocorticoids may be beneficial in managing this condition. High doses of glucocorticoids have not shown benefit when given to prevent ARDS in high-risk patients, [51] [52] [53] or when given early in the course of ARDS. [51] [54] However, the persistent inflammation and fibroproliferation seen in the late stage of ARDS may be improved by corticosteroids. One small study[55] (32 patients) evaluated prolonged methylprednisolone in patients with ARDS who did not improve after 7 days of respiratory failure, and found an improvement in severity scores and mortality in those treated. A randomized, controlled trial evaluating methylprednisolone in severe late-phase ARDS has been completed by ARDSnet. Although the manuscript has not been published yet, the results were presented at a meeting of the American Thoracic Society in May 2004, suggesting no improvement in mortality.

Prone positioning has been advocated as a means to ventilate the posterior lung regions that are more often atelectatic and flooded in ARDS. Once the patient is prone, these previously dependent lung regions open, as the anterior lung regions become dependent. Several personnel are required to safely move a patient into the prone position to ensure chest tubes, IVs, and the endotracheal tube are not dislodged. Patients are rotated every 12 to 18 hours, and studies have shown improved gas exchange and oxygenation in the prone position. [56] [57] Recent studies have shown no improvement in outcomes with prone positioning, [58] [59] although in a post-hoc analysis of one study,[60]mortality at study day 10 and at ICU discharge was lower in the prone positioning patients who were in the lowest quartile paO2/FiO2 (<88 mm Hg), lowest quartile of Apache II scores, or highest quartile of tidal volume (>12 ml/kg predicted body weight).

Surfactant is normally produced by the type II pneumocytes and allows patency of alveoli at lower airway pres-sures. In ARDS, surfactant production is decreased. Animal models of lung injury have shown a benefit from inhaled surfactant therapy, [61] [62] but a trial in 725 patients with ARDS showed no benefit from an artificial surfactant given by aerosol.[63] A more recent randomized controlled trial of 40 patients found no improvement in oxygenation or ventilator-free days with surfactant, but found a dose-dependent trend toward lower mortality at study day 28 (20% to 33% versus 38%).[64]

Nitric oxide (NO) is a vasodilator that when inhaled dilates pulmonary blood vessels perfusing aerated lung units, resulting in improved ventilation-perfusion mismatch without systemic vasodilatation. Inhaled NO has been found to improve oxygenation, [65] [66] but has not been found to improve mortality. [66] [67]

The inflammatory response seen in ALI/ARDS has led to many agents in addition to corticosteroids being evaluated as possible therapy. Prostaglandin E1,[68] ketoconazole[69] (an inhibitor of thromboxane and leukotriene synthesis), ibuprofen,[70] and procysteine/N-acetylcysteine[20] have all been evaluated and found to have no benefit. In addition, treatment of sepsis prior to or early in the development of ALI/ARDS with an anti-endotoxin monoclonal antibody, anti-TNF-α and anti-Interleukin-1 have not shown benefit.[41] Intravenous N-acetylcysteine has not shown a mortality benefit, [71] [72] but has been found in small studies to reduce the number of acute lung injury days. [71] [72] [73] Studies using IL-10 and recombinant human platelet activating factor are currently in the design stages.[74]

Extracorporeal carbon dioxide removal has been investigated and found to have no effect on mortality in one randomized controlled study.[75] Partial liquid ventilation with fluorocarbon liquids, which can dissolve 17 times more oxygen compared with water, has been evaluated with encouraging results, but more trials are needed prior to this therapy becoming widespread.[41]

Effects on Renal Function

Renal dysfunction is a common occurrence in patients with ARDS/ALI. In a retrospective study of 59 patients with ARDS, Valta and co-workers[4] found that 20% to 40% of patients with ARDS had renal dysfunction. Although many patients with ARDS are also septic or hemodynamically unstable, mechanical ventilation itself has been found to be a predictor of dialysis requirement.[76] Several studies have shown that mechanical ventilation can lead to reduced renal blood flow (RBF), decreased urine output, and sodium retention. [77] [78] [79] These changes in renal function are felt to be due to multiple factors. Hypercapnia has been shown to decrease RBF.[80] It acts by directly causing renal vasoconstriction and stimulates norepinephrine release. Hypercapnia also causes systemic vasodilation, which can result in decreased systemic vascular resistance and subsequently reduced RBF.[80] Positive pressure ventilation can also result in a decrease in cardiac output. Positive intrathoracic pressure from mechanical ventilation reduces venous return to the heart, resulting in decreased effective circulating volume, and increases pressure in the pulmonary vasculature, which results in elevated right ventricular afterload, factors that result in reduced cardiac output. The reduced airway compliance seen in ARDS leads to elevated intrathoracic pressures with even relatively small tidal volumes. In addition, the intrathoracic pressure increases linearly as the positive end-expiratory pressure (PEEP) is increased. Because many patients with ARDS require a high PEEP to maintain patency of alveoli and small airways for maintenance of oxygenation, this group of patients is particularly susceptible to the hemodynamic effects of mechanical ventilation.

Not all studies have shown a decrease in renal blood flow with positive pressure ventilation,[81] and it appears that volume status may play a role in the hemodynamic response to positive pressure ventilation. Those patients who are volume depleted are more susceptible to reduced cardiac output.

Factors other than hemodynamics are likely involved in the association of acute kidney injury (AKI) with mechanical ventilation and acute lung injury. Recent studies have shown that mechanical ventilation without changes in blood pressure or central venous pressure caused flattening of epithelial cells in the canine kidney.[82] Renal tubular apoptosis and biochemical markers of renal dysfunction were found in a rabbit model of mechanical ventilation as well.[83] Hormonal changes during mechanical ventilation have been evalu-ated. ADH levels are elevated in mechanically ventilated patients, but may act primarily as a vasoconstrictor and have minimal effect on water retention. [81] [84]A sympathetically mediated increase in plasma renin activity results in a decline in GFR by reducing renal blood flow, and stimulating sodium retention via aldosterone.[85] Atrial natriuretic peptide may also be reduced as a consequence of the decreased venous return and lower atrial pressures, resulting in reduced urine output.[86] Other factors such as nitric oxide and endothelin may also play a role, but their effect remains undetermined.

Adult respiratory distress syndrome is likely an early manifestation of a systemic inflammatory process that results in multiorgan dysfunction. Studies of bronchoalveolar fluid have shown increased TNF-α, IL-1β, and IL-6 concentrations during ARDS. [87] [88] It is possible that pulmonary cytokine production is increased during ventilator-induced lung injury, leading to elevations in systemic concentrations.[89] These cytokines have been shown to cause an ARDS-like condition in rats, but their role in human ARDS has not been fully unraveled.

TNF-α has been associated with the renal injury seen in ischemia-reperfusion models, as has IL-1, IL-2, IL-8, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. [90] [91] Although the association between these cytokines, ARDS, and acute kidney injury has not been fully elucidated, it is likely ARDS represents an early stage in inflammation leading to multiorgan system failure including acute kidney injury. Whether primary cytokine production by the injured lung leads to further organ dysfunction has yet to be established.

Hypovolemic Shock

Hypovolemic shock can be defined as a reduction in effective circulating blood volume, which leads to an oxygen deficit in the tissues because oxygen supply is not able to meet oxygen demand. This imbalance in oxygen metabolism leads to reduced cellular metabolism, conversion to anaerobic metabolism, accumulation of CO2 and waste products (lactate), and, if prolonged, cellular death. Hypovolemic shock occurs most commonly from trauma and hemorrhage,[92] but can also be seen in the setting of volume depletion from vomiting, diarrhea, burns, uncontrolled diabetes mellitus, pancreatitis, or from addisonian crisis ( Table 60-3 ).

TABLE 60-3   -- Etiology of Hypovolemic Shock



Blood loss









Gastrointestinal bleeding



Massive hematuria






Aortic dissection/abdominal aortic aneurysm rupture






Splenic laceration/rupture



Hepatic laceration/rupture



Pelvis/long bone fractures



Ruptured ectopic pregnancy



Fluid losses



Diabetic ketoacidosis



Adrenal crisis












Lack of volume replacement






Comatose/found down





Loss of circulating volume is the primary stimulus for the manifestation of shock. Once 10% of circulating volume has been lost, compensatory mechanisms are activated to maintain cardiac output despite the decreased ventricular filling pressures and stroke volume ( Table 60-4 ).[93] Sympathetic discharge as well as adrenal catecholamine release leads to tachycardia, arterial vasoconstriction, and venoconstriction. [94] [95] As volume loss increases, the increase in heart rate is not able to overcome the loss of stroke volume, and cardiac output declines, which is initially detected as orthostatic hypotension and a fall in pulse pressure.[96] Once the loss of volume exceeds approximately 40%, or 20% to 25% if lost rapidly, hypotension and shock ensue.[97]

TABLE 60-4   -- Compensatory Response to Shock



Maximize intravascular volume



Redistribution of fluid to intravascular space



From interstitial compartments



From intracellular compartments



Renal adaptations



Increased aldosterone



Increased vasopressin



Maximize blood pressure



Increased sympathetic activity



Increased catecholamines



Increased angiotensin II production



Increased vasopressin



Maximize cardiac output



Sympathetic stimulation






Increased contractility



Maximize oxygen delivery



Metabolic acidosis



Increased RBC 2,3 DPG



Decreased tissue oxygen levels




During hypovolemic shock, peripheral vascular resistance is elevated as a result of several responses. These include catecholamine secretion by the adrenal glands, activation of the sympathetic nervous system, the vasoconstrictive effects of angiotensin II via activation of the renin-angiotensin-aldosterone system, and vasopressin released by the pituitary gland. [98] [99] [100] However, the rise in vascular resistance is not uniformly distributed throughout the organ systems. [95] [101] Although vasoconstriction increases vascular resistance, regional autoregulation to maintain blood flow can counteract this effect. Nitric oxide (NO) is produced by endothelial cells, which relaxes vascular smooth muscle cells,[102] and NO release may decrease responsiveness to endogenous and exogenous vasoconstrictors. [103] [104] Organs with reduced endothelium-dependent vasorelaxation have been found to have endothelial cell dysfunction, [105] [106] which may indicate that the NO-mediated relaxation provides protection against the response to shock. However, NO has been shown to inhibit mitochondrial respiration in vitro,[107] and one study[108] of 28 septic patients found an association between NO overproduction, antioxidant depletion, mitochondrial dysfunction, and decreased ATP concentration that related to organ failure. Carbon dioxide[109] and adenosine[110] may also play a role in regional autoregulation, having been shown to produce vasodilatation. The end result of these competing interactions is that blood flow is reduced to the kidneys, skin, intestines, and skeletal muscle, and increased to the heart and brain. [97] [111] [112]

Blood flow through capillaries is slowed during hypovolemic shock, with evidence that this is secondary to reduction in perfusion pressure.[113] Endothelial cell swelling may contribute,[114] and expression of endothelial adhesion molecules have been found to be up-regulated during hypovolemic shock on both the neutrophil and endothelium, [115] [116] [117] suggesting neutrophil aggregation may also contribute to sluggish capillary flow. Responses to increase the circulating volume include reabsorption of interstitial fluid into the vascular space, a result of the decline in capillary hydrostatic pressure greater than the decline in intersti-tial hydrostatic pressure.[118] The transport of protein from blood to interstitium is decreased,[119] cellular water is mobilized to the extracellular space,[120] and activation of the renin-angiotensin-aldosterone system as well as increased levels of antidiuretic hormone act to increase sodium and water reabsorption in the kidneys. Despite compensatory mechanisms to preserve the effective circulating volume, and maintain blood pressure, hypotension and shock will ensue if a large enough amount of fluid is lost. The reduction in perfusion to tissues results in an oxygen imbalance that is responsible for much of the organ failure seen in hypovolemic shock.

Oxygen Consumption and Delivery

Global oxygen delivery (Do2) is the total amount of oxygen delivered to the tissues per minute, and under resting conditions, it is more than adequate to meet the total oxygen requirements of the tissues.

Oxygen delivery is calculated by multiplying the cardiac output by the oxygen content in blood, the latter of which is dependent on the amount of dissolved oxygen (pO2), the oxyhemoglobin saturation (%HbO2), and the hemoglobin affinity for oxygen (typically expressed as 1.34):

Do2=cardiac output×(1.34)×(grams of Hb)×(%HbO2)+[(pO2 in mm Hg)×(0.003)]

Oxygen consumption (Vo2) can be measured directly from inspired and mixed expired oxygen concentrations and expired minute volume, or it may be derived from the cardiac output and arterial and venous oxygen contents:

Vo2=cardiac output×(arterial oxygen content - mixed venous oxygen content)

The amount of oxygen consumed (Vo2) as a fraction of oxygen delivery (Do2) is the oxygen extraction ratio (OER):


For a normal adult performing routine activities, Vo2 is approximately 250 ml/min with an OER of 25%, which can increase to 70% to 80% during maximal exercise.[121] In the setting of hypovolemic shock, a fall in hemoglobin or cardiac output can significantly reduce oxygen delivery to the tissues. It has been shown that below an oxygen delivery of approximately 8 ml/kg/min, oxygen uptake is maximal (near 100%),[122] and a decrease in oxygen delivery below this level results in cellular ischemia as oxygen tissue demand is not being met.

Global oxygen delivery in shock may be normal, despite evidence of cellular ischemia.[123] This is often due to the regional differences in blood flow seen in hypovolemic shock with some organs developing an oxygen debt despite normal global oxygen delivery.[121] Some authors have suggested supranormal levels of oxygen delivery may be able to overcome these regional differences and improve outcome, [124] [125] but this will be discussed later. Cellular hypoxia is manifested in several ways. Once oxygen demands exceed oxygen delivery, anaerobic metabolism ensues, with the production of lactate. Blood lactate level has traditionally been used as an indicator of tissue hypoxia, representing a balance between the production of lactate and consumption by the liver, as well as cardiac and skeletal muscle.[126] However, a single level may be unreliable, and serial levels may be more beneficial as an indicator of cellular hypoxia.[121]

Loss of function of cellular enzymes can occur during hypoxia, but there is a significant variation in sensitivity to hypoxia, with glucose oxidase being quite sensitive to hypoxia, whereas NADPH oxidase can function at 50%, and cytochrome 003 can function at 0.09% of the cellular oxygen required for glucose oxidase.[127]

Cellular ischemia in the gut may result in gastric ulcers, as well as disruption of the barrier function of the mucosa, which can result in translocation of bacteria from the bowel into the circulation. [128] [129] Hepatic ischemia can decrease the clearance of lactate,[130] drugs,[131] and centrilobular necrosis may result in elevated bilirubin and enzyme levels.[132] The spleen contracts during hypovolemic shock, releasing red blood cells into the circulation.[95]Myocardial ischemia can occur,[133] particularly in elderly patients who may have atherosclerotic coronary artery disease.


Although restoration of flow to an ischemic organ is critical to restore function, reperfusion itself may contribute to organ damage. Reactive oxygen species are formed once ischemic tissues are reperfused,[134] and these can cause direct cellular membrane damage by lipid peroxidation, as well as leukocyte activation and transmigration by stimulating leukocyte adhesion molecule expression.[135] The activated leukocytes contribute to cellular injury by releasing proteases, elastases, as well as cytokines that increases microvascular permeability, edema, and microthrombosis.[136] Ischemia-reperfusion also activates complement, which promotes leukocyte activation as well as altering vascular permeability, resulting in edema.[137] Data suggests that calcium influx into cells during reperfusion may contribute to injury by damaging cell organelles, inhibiting respiration and activating protease and prostaglandin synthesis. [138] [139] Reperfusion injury can manifest as myocardial stunning, reperfusion arrhythmias, breakdown of the gut mucosal barrier, acute kidney injury, hepatic failure, or multiorgan dysfunction syndrome.[140] [141] [142] [143] [144]

Clinical Manifestations

Early in the course of hypovolemia or blood loss, the patient may not be hypotensive, and attention should be paid to other signs of fluid loss. Tachycardia is common, and tachypnea can occur early in the course. Orthostatic hypotension is a reliable sign, whereas dry mucosal membranes and decreased skin turgor are less reliable, but indicative of hypovolemia.[145] If the patients are conscious, they may complain of thirst or diaphoresis. Once volume losses become profound, hypotension ensues, confusion may occur, and the patient may develop oliguria and peripheral cyanosis as a result of diminished perfusion. Hypovolemic shock due to trauma or bleeding is usually apparent, but internal bleeding or other causes listed in Table 60-3 may not be as obvious. The smell of acetone on the breath may point to uncontrolled diabetes mellitus, whereas adrenocortical insufficiency can result in brown discoloration of the mucous membranes.

Acidosis can occur, often from hypoperfusion of tissues resulting in lactate production. Disseminated intravascular coagulation can also occur during hypovolemic shock, resulting in microvascular thrombi formation, and may contribute to the multiple organ dysfunction often seen after traumatic or hypovolemic shock.[146]


The initial evaluation of the patient in shock should include a determination of the cause of shock. In most cases of hypovolemic shock, it is readily apparent that trauma or blood loss is the primary cause, but care must be taken not to overlook septic, cardiogenic, or anaphylactic shock. Initial resuscitation should begin during the evaluation. In the case of external blood loss, crossmatching blood should be done while fluids are infused for resuscitation. Gastrointestinal bleeding can be evaluated and potentially treated with upper or lower endoscopy once the patient is stabilized, as well as angiography. In the event of trauma, chest radiography should be performed to rule out tension pneumothorax or hemothorax. If abdominal trauma has occurred, peritoneal lavage can be performed to assess for hemorrhage, most commonly from splenic or hepatic lacerations.[147] If the patient is stabilized, computerized tomography or ultrasound can also assess for intra-abdominal hemorrhage as well as organ injury. Laboratory tests should include complete blood count, a chemistry panel including electrolytes, creatinine, glucose, and liver function tests; arterial blood gas, arterial lactate level, blood type and crossmatch, and urinalysis. In the event of trauma or bleeding, coagulation studies should include platelet count, prothrombin time, and partial thromboplastin time. If the cause of shock is not readily apparent, an electrocardiogram should be performed to rule out myocardial infarction.


Resuscitation of the patient in shock should begin immediately, and not delayed while diagnostic procedures are undertaken. Fluid resuscitation should begin once large bore intravenous catheters are placed. The primary goal in the management of hypovolemic shock is to return circulating volume to normal, and as a result, improve tissue perfusion, substrate delivery, and oxygen balance. Some authors have suggested that raising oxygen delivery and oxygen uptake to supranormal levels in the setting of trauma and hemorrhage may improve survival. [124] [125] Oxygen delivery can be maximized by increasing the cardiac output with either volume or dobutamine; by increasing the oxygen saturation above 90%; and by increasing the hemoglobin concentration. Care must be taken when transfusing, as a higher hematocrit can actually worsen oxygen balance by increasing viscosity and reducing capillary flow.[148]Although elderly patients with myocardial infarction may benefit from transfusion to a hematocrit of 30%,[149] large transfusions of blood have been associated with multiple organ dysfunction,[150] and a liberal transfusion policy to a hemoglobin of 10 to 12 has been associated with an increased mortality.[151] Measurement of oxygen delivery and consumption also requires pulmonary artery catheter placement, which may be an independent risk for mortality,[152] thus many physicians use improvement in blood pressure, metabolic acidosis, and serial lactate levels as markers that oxygen delivery and consumption are adequate. However, improvement of oxygen delivery in this setting may not improve cellular function. Tissue oxygen tension has been found to be increased in some studies of septic animals and patients with acidosis, [153] [154] indicating that dysoxia (inadequate utilization of oxygen), not hypoxia, may contribute to acidosis and organ failure.

Gastric tonometry has been proposed as a method to monitor a patient's perfusion status, and indirectly oxygen delivery. This is a device that is inserted nasally or orally and advance to the stomach, where it indirectly measures the pH of gastric mucosal cells. A low gastric mucosal pH (pHi) may indicate two things. First, it may be an early indicator of reduced global oxygen delivery as the splanchnic bed is prone to hypoperfusion and hypoxia due to redistribution of blood flow. Second, intestinal mucosal hypoxia may result in increased permeability with increased translocation of bacteria and endotoxin, resulting in multiple organ system dysfunction. Low pHi has been found to be a good indicator of poor outcome in the intensive care setting, [155] [156] [157] but no study has convincingly proven that therapy to improve pHi has any effect on outcome. [158] [159] [160] [161] Sublingual capnometry has been evaluated as a measure of tissue perfusion, but is not in widespread use.[162]

Further treatment depends on the etiology of shock. Traumatic shock will often require surgical exploration to treat the source of bleeding. Upper gastrointestinal bleeding due to ulcers can be treated medically with intravenous proton pump inhibitors, or endoscopically by electrocautery, laser coagulation, or injection therapy. Esophageal varices can be treated with infusion of somatostatin, or interventionally with injection sclerotherapy, or a sangsten-blakemore tube. Lower gastrointestinal bleeding can be treated with endoscopic therapies. Surgery is an option for recurrent bleeding. Diabetic ketoacidosis is treated with intravenous insulin, and adrenal crisis with intravenous hydrocortisone.

Fluid Resuscitation

Fluid resuscitation is the initial therapy in hypovolemic shock because this helps restore circulating volume and oxygen delivery. The types of fluids used are quite varied ( Table 60-5 ), and controversy exists as to which agent is the most efficacious. Both colloids (high molecular weight solutions) and crystalloids (electrolyte solutions) are used to manage shock.

TABLE 60-5   -- Fluid Used for Resuscitation


Sodium Chloride (0.9%)

Ringers Lactate

Sodium Chloride (3%)

Albumin (5%)

Hetastarch (6%)

Dextran 70 +NaCl


Sodium (mEq/L)








Chloride (mEq/L)








Potassium (mEq/L)








Osmolarity (mOsm/L)








Oncotic pressure (mm Hg)








Lactate (mEq/L)








Maximum dose (ml/kg/24h)



Limited by Serum Na+





Cost (liter)










Isotonic crystalloid solutions have traditionally been used as the primary fluid for volume expansion.[152] Normal saline (0.9%) and lactated ringers are both commonly used, although large volumes of lactated ringers should be avoided in the setting of renal failure because it can result in hyperkalemia, and probably should be avoided in hepatic failure because the damaged liver may not be able to convert lactate to bicarbonate. One advantage of isotonic crystalloids may be that they replace the interstitial fluid deficits seen after hypovolemic shock,[163] because 75% of the volume infused enters the interstitial space, whereas 25% remains intravascular.[164] However, the large volume of these fluids required leads to peripheral edema that may impair wound healing,[165] and has led to the study of hypertonic crystalloid and colloid solutions, which stay within the intravascular space to a greater degree, and thus require less total volume for a similar degree of resuscitation.

Hypertonic crystalloid solutions include 3%, 5%, and 7.5% sodium chloride, and are considered plasma expanders because they act to increase the circulatory volume via movement of intracellular and interstitial water into the intravascular space.[152] The primary disadvantage of these agents is the risk of hypernatremia, and the safety of these agents depends partially on how much water can be shifted from the intracellular to extracellular space without resulting in cellular damage.

Colloids are also plasma expanders because they are composed of macromolecules, and are retained in the intravascular space to a much greater extent than isotonic crystalloids. Albumin has a molecular weight of 69,000 daltons, and a half-life of 15 to 20 days. Albumin may serve as a free radical scavenger,[166] and the increased intravascular oncotic pressure may protect the lungs and other organs from edema.[167] Dextran is a colloid agent prepared from glucose polymers. Detran-40 has a molecular weight of 40,000 daltons, and dextran-70 has a molecular weight of 70,000 daltons. Dextran-70 has a longer intravascular retention time than dextran-40,[168] but both can cause histamine release from mast cells leading to anaphylactoid reactions.[169] Hydroxyethyl starch (hetastarch) is available in several different preparations (HES 200 or HES 450). HES is a natural starch of highly branched glucose polymers, similar in structure to glycogen, with a molecular weight of 200,000 or 450,000 daltons, depending on the preparation, and a plasma half-life of approximately 17 days. Its volume expansion properties are almost identical to albumin.[168] Pentastarch has a molecular weight of 260,000 daltons, but has a higher colloid oncotic pressure than HES or albumin, thus producing more intravascular volume expansion than these two agents.[170] There is recent evidence that the starches may be able to reduce capillary leak after ischemia or trauma, thereby decreasing edema formation. [171] [172] Both HES and pentastarch may increase the amylase level in blood. Gelatins are polypeptides from bovine raw material, have a lower molecular weight than the starches or dextrans, and are poorly retained in the intravascular space. Their duration of effect is approximately 2 hours; 3.5% urea-gelatin has a high concentration of potassium, which makes it unsuitable for patients with renal failure. The gelatins are not available in the United States at this time. Newer solutions consisting of hypertonic saline to which colloids have been added include NaCl 7.5% with dextran-70, NaCl 7.2% with dextran 60, and NaCl 7.5% with hetastarch.

Crystalloid versus Colloid for Resuscitation

There has been much debate as to which type of fluid is best for resuscitation of shock. Colloids offer the theoretical advantage of expanding the intravascular space with less volume, and have been shown to increase blood pressure more rapidly than crystalloids.[173] One liter of dextran-70 increases intravascular volume by 800 ml, one liter of HES by 750 ml, one liter of 5% albumin by 500 ml, and one liter of saline by 180 ml.[174] Yet in the setting of sepsis, where there is significant capillary leak, both albumin and normal saline were found to increase interstitial volume to the same extent.[175] Small studies have also found a lower incidence of pulmonary edema during resuscitation with colloids compared with crystalloids,[176] potentially less reperfusion injury to the myocardium after colloid resuscitation,[177] and better blood flow to the myocardium.[178] Yet there is also evidence that colloids can inhibit the coagulation system, [179] [180] and cause anaphylactoid reactions.[181] Albumin has been shown in one study to have negative inotropic effects,[182] and another study found impaired salt and water excretion when albumin was used for resuscitation from shock.[183] Hetastarch may increase the risk of acute kidney injury when given for resuscitation of sepsis,[184] which may be due to inadequate free water replacement in the setting of a potent volume expander.

Meta-analyses of fluid administration and mortality have not supported a benefit for colloids over crystalloids. [185] [186] [187] [188] [189] [190] In trauma patients, Wade and colleagues[185] found no difference in survival between those receiving hypertonic saline with dextran 60 or isotonic saline, whereas Choi and colleagues[186] found crystalloids were associated with a significantly lower risk of death [relative risk (RR) 0.39[186]]. One meta-analysis[187] did find that hypertonic saline with dextran did improve survival compared to crystalloids in the setting of head injury. Several meta-analyses [188] [189] [190] have shown a trend toward increased mortality in heterogenous groups of critically ill patients resuscitated with colloids. Although the Cochrane Injuries Group Albumin Reviewers[191] found that the risk of death was significantly increased in critically ill patients who received albumin (RR 1.68[191]), a trial of 6997 ICU patients requiring fluid resuscitation compared albumin with normal saline, and found no difference in outcomes for the two groups.[192]

Volume resuscitation in critically ill patients is a matter of debate at this time, with many practitioners favoring crystalloids whereas others favor colloids. Although the available data does not strongly favor one therapy over the other, patients with profound volume deficits treated with crystalloids may benefit from the addition of colloid solutions to hasten restoration of circulating volume. A search is underway for red blood cell substitutes that can rapidly expand blood volume, as well as carry and deliver oxygen to tissues. Diaspirin cross-linked hemoglobin showed an increase in mortality when this agent was used in the management of severe traumatic shock,[193] and no agent is currently in widespread use.


The use of vasopressors in hypovolemic shock should be reserved for the setting in which adequate fluids are not yet available, or for the patient in whom adequate fluid infusion has not improved hypotension.[147] In this setting, a pulmonary artery catheter can help guide therapy because persistent shock can be caused by either peripheral vasodilatation or myocardial dysfunction. A wedge pressure of 12 mm Hg to 16 mm Hg is indicative of adequate volume expansion. Animal studies have shown that vasopressin can reverse shock unresponsive to fluids and catecholamines,[194] and can improve survival after cardiac arrest in hypovolemic shock.[195] Although vasopressin has been shown in one small study[196] to improve blood pressure in septic shock, others have suggested it can cause a reduction in cardiac output,[197] and only case series of improvement in hypovolemic shock are available. [198] [199]

Management of Acidosis

Lactic acidosis due to tissue hypoperfusion is common in hypovolemic shock. Improvement of the effective circulating volume and restoring tissue oxygen balance will diminish the production of lactate, allowing for improvement of acidosis. Yet for cases of intractable shock, metabolic acidosis may persist despite aggressive therapy.

Acidosis has been shown to decrease cardiac contractility in animal models,[200] and reduces cardiac contractility response to catecholamines.[201] However, the effect of acidosis on cardiac function in the clinical setting is less well documented. Decreased cardiac contractility in the setting of lactic acidosis may be partially due to hypoxemia, hypoperfusion, or sepsis, and establishing direct effects of the low pH are difficult.[202] In fact, many patients treated with permissive hypercapnia-low tidal volume ventilation develop acidosis that is well tolerated with minimal change in the cardiac output.[203]

Management of acidosis with sodium bicarbonate has not been shown to be beneficial. Animal models of lactic acidosis fail to show improvement in hemodynamics from sodium bicarbonate compared with normal saline, [203] [204] [205] and human studies have shown no improvement in hemodynamics or catecholamine responsiveness. [206] [207] Furthermore, bicarbonate infusion has been theorized to cause worsening intracellular acidosis because the carbon dioxide, produced when bicarbonate reacts with acids, can diffuse rapidly across the cell membrane, whereas bicarbonate cannot. Studies of intracellular pH changes have been mixed, with some showing an increase,[208] decrease,[209] [210] [211] or no change [201] [212] [213] in pH. Management of acidosis with bicarbonate has also been shown to increase hemoglobin affinity for oxygen in healthy volunteers, resulting in reduced oxygen delivery.[214]

Because there is no documented benefit, and the potential for adverse effects appears real, management of lactic acidosis should not include administration of sodium bicarbonate unless further compelling evidence becomes available.

Effects of Hypovolemic Shock on Renal Function

Acute kidney injury is a common finding in a patient with shock. Diminished perfusion to the kidneys with resultant ischemia is a primary cause. Early in hypovolemia, renal perfusion can be maintained by intrarenal production of NO and prostaglandins that have vasodilatory actions. [215] [216] However, once hypovolemia becomes severe and shock ensues, these mechanisms are not enough to prevent ischemia. Other factors seem to play a role as well. Disseminated intravascular coagulation can occur during traumatic or hypovolemic shock, and the resultant microvascular thrombi can cause renal ischemia.[146]

Hypovolemic shock has been shown to increase tumor necrosis factor-α and interleukin-1 release, [217] [218] and can activate the complement cascade.[219] These substances may contribute to acute kidney injury, and their effects of renal function are discussed more fully in the section on sepsis.


It is estimated that sepsis accounts for up to 10% of admissions to the ICU,[220] and there are 400,000 to 500,000 episodes of sepsis each year in the United States[221] resulting in greater than 100,000 deaths per year.[222] Sepsis and septic shock are common causes of acute kidney injury, and the nephrologist is frequently involved in the care of this disease. Despite improvements in our ability to monitor and treat patients in the intensive care unit, the mortality rate for sepsis has actually increased.[221] A complete understanding of the pathophysiology and newer therapeutic approaches for sepsis is critical for any clinician involved in patient care.


The American College of Chest Physicians/Society of Critical Care Medicine consensus conference in 1991 led to a uniform definition of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock[223] ( Table 60-6 and Fig. 60-1 ). SIRS describes the common systemic response to a wide variety of clinical insults ( Table 60-7 ). It is characterized by two or more of the following: (1) temperature more than 38°C or less than 36°C; (2) heart rate more than 90 beats/min; (3) respiratory rate >20 breaths/min; (4) white blood cell count more than 12,000 cells/mm3, less than 4,000 cells/mm3, or more than 10% immature neutrophils. Sepsis is present when SIRS is diagnosed in the setting of a confirmed infection. Severe sepsis is defined as sepsis plus either organ dysfunction or evidence of hypoperfusion or hypotension. Septic shock is a subset of severe sepsis and is present when sepsis-induced hypotension persists despite fluid resuscitation, and is accompanied by hypoperfusion abnormalities or organ dysfunction. In a study of 2527 patients who met SIRS criteria in a single ICU, the mortality rate was found to increase as patients fulfilled more criteria and advanced along the spectrum. The mortality of patients with two SIRS criteria was 7%, three SIRS criteria 10%, four SIRS criteria 17%, sepsis 16%, severe sepsis 20%, and septic shock 46%.[224]

TABLE 60-6   -- Definition of SIRS, Sepsis, Severe Sepsis, Septic Shock



SIRS: Presence of two or more of the following



Temperature >38°C or <36°C



Heart rate >90 beats/min



Respiratory rate >20 breaths/min



White blood count >20,000/mm3, <4000/mm3, or >10% immature neutrophils



Sepsis: SIRS in the presence of documented infection



Severe sepsis: Sepsis with hypotension, hypoperfusion, or organ dysfunction

Septic shock: Sepsis with hypotension despite volume resuscitation and evidence of organ dysfunction or hypoperfusion


SIRS, systemic inflammatory response syndrome.




FIGURE 60-1  The spectrum of systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and multiorgan dysfunction syndrome (MODS).


TABLE 60-7   -- Common Causes of Systemic Inflammatory Response Syndrome




















Autoimmune diseases



Source of Infection and Microbiology

In the 1960's and 1970's, gram-negative organisms were the most common causes of septic shock,[225] but gram-positive organisms have now increased in prevalence. Gram-negative organisms are now estimated to be responsible for 25% of all cases of sepsis, with gram-positive organisms responsible for 25%, mixed gram positive and gram negative 20%, fungal 3%, anaerobic organisms 2%, and 25% of organisms unknown.[226] The most common gram-negative organisms are Escherichia coli (25%), Klebsiella (20%), and Pseudomonas aeruginosa (15%). The most common gram-positive organisms are Staphylococcus aureus (35%), Enterococcus (20%), and Coagulase negative staphylococcus (15%).[226] The most common primary sites of infection in sepsis are the respiratory tract (50%), intra-abdominal/pelvis (20%), urinary tract (10%), skin (5%), and intravascular catheters (5%).[226]

There has been a rise in the incidence of sepsis and septic shock over the past several decades.[226] Factors that are potentially responsible include the increasing number of immunocompromised people, from acquired immunodeficiency syndrome or cytotoxic and immunosuppressant therapy, and the increase in interventional procedures. Other risk factors for sepsis include malnutrition, alcoholism, malignancy, diabetes mellitus, advanced age, and chronic renal failure.[221]


Although much has yet to be learned about the pathophysiology of sepsis, scientific advances have shed light on many of the factors that lead to the complex cascade that can result in septic shock and death. It has been hypothesized that the manifestations of sepsis result from excessive inflammatory response to bacterial organisms.[227] Gram-negative bacteria contain lipopolysaccharide (LPS) as a cell wall component, which can activate macrophages, as well as the complement cascade.[228] Gram-positive bacteria produce exotoxins, which can activate T cells and macrophages,[227] and release cell membrane components that can activate the inflammatory process.[229] Both pro-inflammatory and anti-inflammatory components are released in response to bacterial invasion, and these two systems are usually tightly controlled to destroy the infection while preventing damage to the host.[226] It is theorized now that sepsis is a result of an imbalance in these two processes, with the pro-inflammatory component overexpressed, [226] [230] [231] [232] however it has been shown that neutrophils in critically ill patients demonstrate functional abnormalities, including reduced migration, superoxide production, and bacterial killing, all factors that may impair host defense. [233] [234] Whether this neutrophil dysfunction leads to worsening of the sepsis syndrome in unknown.

Pro-inflammatory cytokines released in response to infectious stimuli include tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8). Anti-inflammatory cytokines include interleukin-10, interleukin-13, and transforming growth factor-β (TGF-β). TNF-α and IL-1 have wide-ranging effects, including activation of macrophages, lymphocytes and neutrophils, increasing expression of adhesion molecules, and increasing production of other pro-inflammatory cytokines.[226] Anti-inflammatory cytokines reduce the production of IL-1 and TNF-α, and inhibit antigen presentation to T- and B-lymphocytes. Animal models have demonstrated that cytokines are a key component of sepsis, with infusions of TNF-α and IL-1 producing a state similar to septic shock, [235] [236] [237] and administration of antibodies to these cytokines resulting in attenuation of the shock-like state. [237] [238] [239] [240]

Other mediators of sepsis include metabolites of the arachidonic cascade such as prostaglandin E2 (PGE2), prostaglandin I2 (PGI2), and thromboxane A2. PGE2 causes vasodilatation seen in septic shock,[226] whereas thromboxane A2 causes platelet and leukocyte aggregation and vasoconstriction.[241] Platelet activating factor (PAF) is produced by many cells in response to inflammatory stimuli,[242] amplifies many cytokines released in sepsis, and stimulates leukocyte activation and adherence to endothelial cells.[226]

Recently, interest has developed in the role nuclear factor-kB (NF-kB) plays in multiple disease processes. NF-kB is a transcription factor located in the cytoplasm of most cell types.[243] Stimulation of the cells by cytokines or byproducts of bacterial and viral infection leads to translocation of NF-kB from the cytoplasm to the nucleus, where it regulates transcription of target genes.[244] It appears that the genes affected by NF-kB activate and modulate cytokines, chemokines, and receptors involved in diseases such as sepsis, SIRS, ARDS, and multiorgan dysfunction.[245] Research is ongoing to see the extent NF-kB is involved in the processes mentioned previously, and if its activation can be regulated.

The coagulation system also plays a role in the manifestation of sepsis. Levels of protein C are decreased, [236] [246] and its conversion to activated protein C, which inhibits thrombosis ( Fig. 60-2 ), is down-regulated during sepsis.[247] Antithrombin III, which is an inhibitor of thrombin and factor X, has been found to be dramatically reduced in septic shock.[248] Tissue factor pathway inhibitor, which inhibits the highly thrombogenic compound tissue factor, has also been found to be reduced in the setting of sepsis.[246] These factors contribute to the widespread microvascular thrombosis that occurs during sepsis, a result of which is reduction in perfusion to various tissues,[249] which may lead to the multiorgan dysfunction syndrome (MODS) seen in many patients with sepsis.

FIGURE 60-2  Proposed actions of activated protein C in modulating the systemic inflammatory, procoagulant, and fibrinolytic host responses to infection. The inflammatory and procoagulant host responses to infection are intricately linked. Infectious agents and inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1 activate coagulation by stimulating the release of tissue factor from monocytes and the endothelium. The presentation of tissue factor leads to the formation of thrombin and fibrin clot. Plasminogen-activator inhibitor 1 (PAI-1) is a potent inhibitor of tissue plasminogen activator, the endogenous pathway for lysing a fibrin clot.  (From Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human Activated Protein C for severe sepsis. N Engl J Med 344(10):699–709, 2001.)



Toll-like receptors (TLRs) are proteins that recognize specific patterns on pathogens. Ten human TLRs have been identified, and when stimulated, they initiate a cascade of signaling events leading to the production of multiple cytokines and effector molecules, including TNF-α, IL-1, and IL-6, and appear to be the primary transducers of the inflammatory response to invading microorganisms.[250] Yet TLR signaling is necessary for host defense because animals with a TLR 4 mutation have higher mortality rates when injected with live gram-negative bacteria.[251] TLRs are present in cells of the innate immune system, as well as solid organs. The kidney expresses most of the TLRs, but TLR 2 and 4 have been most extensively studied because they have a potential role in mediating gram-positive and gram-negative signaling, respectively. A possible role for local renal TLRs in mediating renal failure is being evaluated. TLR4 knockout mice have been found to be protected against renal failure in an LPS model of sepsis, and when kidneys from wild-type animals were transplanted into a TLR4 knockout strain, significant kidney injury developed.[252] It is thus possible that local TLRs directly mediate the kidney injury seen in sepsis.

Clinical Features

Sepsis is a systemic process, and is defined by clinical manifestations. Common clinical manifestations include changes in body temperature (fever or hypothermia), tachycardia, tachypnea, and leukocytosis or leukopenia. Many of the signs and symptoms of sepsis are induced by the inflammatory cytokines. Fever, for example, can be caused by TNF-α and IL-1,[221] and the failure to develop fever has been associated with increased mortality.[253]Hypoglycemia, hyperglycemia, hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, and hypophosphatemia can also be seen. Tachycardia is a common, but nonspecific manifestation. Patients with severe sepsis and septic shock have hypotension, due in part to nitric oxide release,[254] as well as due to decreased effective circulating volume. The intravascular volume depletion is related to several factors, including decreased systemic vascular resistance (SVR),[255] increased microvascular permeability, and increased insensible losses. Once volume resuscitated, most patients with septic shock have evidence of hyperdynamic cardiovascular function with a normal or elevated cardiac output and decreased SVR.[255] Despite these findings from pulmonary artery catheterization, the heart may not be as hyperdynamic because it should given the clinical setting. Studies have shown that sepsis induces a depression in myocardial function, [256] [257] characterized by elevated left ventricular end-diastolic volume and decreased left ventricular systolic work index. This myocardial depression is believed to be caused by a myocardial depressant substance, which has not been fully identified. Leading candidates are TNF-α and IL-1,[258] but nitric oxide has also been shown to have a negative effect on systolic function.[259]

Tachypnea and hypoxemia are common in sepsis, and the acute respiratory distress syndrome (ARDS) has been reported to occur in up to 40% of patients with sepsis.[260] Many view ARDS as an initial manifestation of multiorgan dysfunction syndrome, and believe it represents diffuse endothelial injury resulting from the exaggerated inflammatory response. [260] [261] [262] [263]

Adrenal insufficiency is a common finding in septic shock, with a reported incidence of 25% to 40%. [264] [265] [266] Some authors now feel the threshold for diagnosing adrenal insufficiency should be a cortisol level below 25 mg/ml to 30 mg/ml, instead of the usual 18 mg/ml to 20 mg/ml, and low dose (1–2 mg) ACTH stimulation should be used for diagnosis because it represents physiologic stress levels of ACTH, in contrast to the standard ACTH stimulation test, which uses doses that are 100-200 fold higher than maximal stress levels of ACTH.[267] It is also advocated that if a fluid-resuscitated patient is hypotensive and requires pressors, a baseline cortisol less than 25 mg/ml should be considered diagnostic of adrenal insufficiency.[268]

Disseminated intravascular coagulation (DIC) is often seen in sepsis, and is characterized by enhanced activation of coagulation, with intravascular fibrin formation and deposition. The resulting microvascular thrombi can reduce blood flow to portions of organs, contributing to the onset of MODS. A reduction in circulating coagulation factors and platelets is often seen because they are consumed in the production of microthrombi, and this can lead to bleeding episodes.[269] Laboratory studies in DIC typically show thrombocytopenia, with an elevation of the prothrombin time, activated partial thromboplastin time, as well as D-dimer.

Central nervous system alterations are frequently found in patients with sepsis,[270] and septic encephalopathy is the most common form of encephalopathy in intensive care units.[271] Impaired mitochondrial function and oxygen extraction by the brain, increased permeability of the blood-brain barrier, and disruption of astrocyte end-feet, all caused by inflammatory mediators, contribute to the diffuse neuronal injury seen in septic encephalopathy.[272]Confusion, disorientation, lethargy, agitation, obtundation, and coma are the common clinical manifestations.

Critical illness polyneuropathy is a common occurrence in the setting of sepsis, and is often first recognized when the patient cannot be weaned from ventilatory support.[270] This illness is caused by axonal degeneration, is characterized by hyporeflexia, weakness distally greater than proximally, and normal or slightly elevated creatine kinase levels,[226] and may take up to 6 months for recovery.[270]

Renal dysfunction is found in 9% to 40% of patients with sepsis,[273] and the mortality rate in these patients is greater than 50%.[274] The clinical manifestations vary from acute tubular necrosis to bilateral cortical necrosis. Hypotension is commonly seen in sepsis, and renal hypoperfusion likely plays a major role in the incidence of acute kidney injury (AKI), as does the administration of nephrotoxic agents to manage sepsis. However, studies evaluating renal blood flow have had conflicting results, with some showing reduction in global renal blood flow, [275] [276] whereas others showed no reduction in renal blood flow or GFR. [277] [278] It is apparent that there are other factors involved in AKI induction. TNF-α released from mesangial cells causes leukocyte accumulation in the glomerulus, as well as apoptotic death of glomerular endothelial cells.[279] IL-1 can induce vasoconstriction, neutrophil aggregation, and further cytokine release.[280] PAF levels, which are increased in sepsis and correlate with the severity of AKI,[281] increase both afferent and efferent arteriolar resistance, producing a decline in the glomerular filtration rate (GFR).[282] Endothelin-1 is secreted in response to septic mediators, including TNF-α, [283] [284] and has been found to cause renal vasoconstriction,[285] as well as inhibition of sodium and water reabsorption by the collecting duct. [286] [287] Thromboxane A2 decreases GFR and renal blood flow, and preferentially vasoconstricts the afferent arteriole.[288] Leukotrienes are released in endotoxemia[289] and also reduce GFR and renal blood flow.[288] Other mediators implicated in septic AKI include the renin-angiotensin system, atrial natriuretic factor, IL-1, adenosine, and catecholamines.[223] The role of DIC and diminished levels of activated protein C in the generation of microvascular thrombi has been discussed, and the diminished renal perfusion caused by the thrombi likely contributes to septic AKI. No specific pharmacologic therapy for septic AKI has proven beneficial.

As improvements in care of the critically ill patient have been developed, death from the initial disease process in sepsis has become less common, patients have lived longer, and the development of the multiorgan dysfunction syndrome has become more common. MODS is now the most common cause of death among patients with sepsis.[290] The exact pathophysiologic mechanism leading to MODS has not been fully defined, but mitochondrial dysfunction, microvascular thrombi, hypoperfusion, ischemia/reperfusion injury, circulating inflammatory factors, diffuse endothelial cell injury, bacterial-toxin translocation, and increased tissue nitric oxide are all potential contributors. [274] [291] [292]


The management of sepsis is primarily based on eradication of the infection and supporting the patient's hemodynamics and other organ systems. Activated protein C has been approved for use in sepsis, but other immunomodulatory therapies are still being evaluated.


Identifying the source of sepsis should be one of the primary goals while treatment is being initiated. Antibiotic choice often depends on the suspected site of infection. Initial antibiotic therapy usually requires multiple antibiotics to cover the likely pathogens,[226] and if culture results identify a source, coverage can be narrowed. Double antibiotic coverage is indicated in the management of Pseudomonas aeruginosa infection, febrile-neutropenic patients, and severe intra-abdominal infections.[293] If no organism is isolated, initial broad spectrum antibiotics can be continued so long as the patient is improving. Immediate institution of antibiotic therapy is critical because there is a 10% to 15% higher mortality in patients not treated promptly.[293] A full discussion of antibiotic selection is beyond the scope of this chapter.

Hemodynamic Support

Intravascular volume depletion, peripheral vasodilatation, and increased microvascular permeability all contribute to hypotension seen in severe sepsis and septic shock,[226] and aggressive volume resuscitation should be the primary initial therapy.[294] The fluid requirements for resuscitation are very large, and often underestimated by the clinician. Up to 10 liters of crystalloid are often required in the first 24 hours.[294] Boluses of fluid should be given until blood pressure, heart rate, or evidence of end-organ perfusion such as urine output have improved. Early therapy is crucial, and a recent study showed that early, goal-directed therapy using central venous pressure, mean arterial pressure, hematocrit, and central venous oxygen saturation as end points improved mortality.[295] Crystalloids and colloids are both used for resuscitation, and there is no evidence-based advantage of one over another.

Despite adequate fluid resuscitation, many patients remain hypotensive,[226] and these patients require vasopressor agents. Dopamine and norepinephrine are both considered first choice vasopressors in the Surviving Sepsis Campaign guidelines.[296] However, chronotropic sensitivity to dopamine is increased in sepsis; thus tachycardia and arrhythmias may limit its use.[226] Norepinephrine is as effective in raising blood pressure as dopamine, but has less cardiac effects; it does not raise cardiac output as much as dopamine, and causes less tachycardia.[297] Phenylephrine has purely alpha effects, and fewer risks of tachyarrhythmias, but experience in septic shock is limited.[297]Epinephrine can be used for refractory hypotension, but has been shown to cause a rise in serum lactate levels.[297] Vasopressin is produced in the posterior pituitary gland and has both vasoconstrictor and antidiuretic properties. Vasopressin levels rise 20- to 200-fold in shock states,[298] but patients with septic shock have been found to have significantly lower vasopressin levels than patients with cardiogenic shock.[299] Vasopressin use in septic shock has been shown to spare norepinephrine use as well as maintain mean arterial pressure and cardiac index.[300] Although norepinephrine causes profound constriction of glomerular afferent arterioles, vasopressin has been shown to constrict the glomerular efferent arteriole, thus increasing the glomerular filtration rate.[301] Vasopressin can cause coronary artery vasoconstriction leading to MI, and because it does not have positive inotropic actions, the increased afterload during vasopressin use may decrease cardiac output.[301] Dobutamine has been used in sepsis to improve oxygen delivery, but can potentiate hypotension due to B2-mediated vasodilatation. Dobutamine is recommended for patients with a low cardiac index (<2.5 L/min/m2) after volume resuscitation,[290] but if profound hypotension is present (systolic blood pressure <80 mm Hg), should be used in conjunction with an agent with more peripheral vasoconstrictor effects such as norepinephrine or phenylephrine.

Several studies have examined whether resuscitation of septic patients to pre-determined end points of global oxygen delivery improves outcome. Earlier studies showed no benefit, [40] [58] [302] but enrolled patients up to 72 hours after admission. A more recent study showed early therapy to a central venous oxygen saturation level (Scvo2) of 70% improved mortality.[295] This was accomplished by sequentially giving fluids to a target CVP of 8 mm Hg to 12 mm Hg, followed by red blood cell transfusion to a hematocrit of 30%, followed by dobutamine infusion to a maximum of 20 mg/kg/min until the Scvo2 reached 70%. The Surviving Sepsis Campaign guidelines now recommend targeting a CVP of 8 mm Hg to 12 mm Hg, MAP>65 mm Hg, urine output>0.5 ml/kg/hr, and Scvo2>70%.[296]

Treatment of the Coagulation Cascade

Disseminated intravascular coagulation is a common finding, and has been discussed earlier. Management of the underlying condition will accelerate resolution of DIC. No specific therapy is recommended for DIC unless severe or life-threatening hemorrhage occurs, at which time replacement with platelets, fresh frozen plasma, and possibly cryoprecipitate is indicated.[246]

The finding that protein C levels are reduced in sepsis and are associated with an increased risk of death[87] led to the study of activated protein C (APC) in the management of sepsis. The PROWESS trial[303] was a randomized, controlled trial that evaluated APC in 1690 septic patients. Patients were eligible if they had known or suspected infection, three or more signs of SIRS, and at least one organ dysfunction. Patients were treated with placebo or a continuous infusion of APC for 96 hours. Patients treated with APC had a 19.4% reduction in the relative risk of death, and an absolute reduction in the risk of death of 6.1%. A post hoc analysis of this study by the Food and Drug administration,[304] however, found that the benefit of APC seemed to be restricted to patients with more severe illness (an Acute Physiology and Chronic Health Evaluation [APACHE II] score of 25 or more). A study is currently underway to assess the efficacy of APC in patients with an APACHE II score of less than 25. PROWESS was the first randomized controlled trial to show a survival benefit of a therapeutic intervention in sepsis. Because APC acts on the coagulation system, there is an increased risk of bleeding associated with its use, and the incidence of serious bleeding in the treated group in PROWESS was higher than in the controls (3.5% versus 2.0%) despite fairly stringent criteria to exclude those at risk for bleeding. Activated protein C should be considered in all patients at high risk for death from sepsis (APACHE II score > 25, sepsis-induced multiple organ failure, septic shock, or sepsis-induced ARDS). A recent study[305] showed no benefit from APC in septic patients at low risk of death (APACHE II score < 25 or single organ dysfunction). Patients with conditions that were exclusion criteria in the PROWESS trial, including pregnancy, breast feeding, chronic renal failure requiring dialysis, acute pancreatitis without a known source of infection, cirrhosis, and HIV infection with CD4+ count less than 50/mm3 should be evaluated carefully. Care should also be taken in the patient at risk for bleeding because this is the main side effect. Antithrombin III has been the subject of many clinical studies in sepsis, [306] [307] [308] [309] and has shown an improvement in DIC. However, no clinical study has shown a survival advantage with AT III. These studies were all of small size, and a large multicenter study would better address the role of ATIII. Recombinant tissue factor pathway inhibitor has been shown to be beneficial in animal models of septic shock, [310] [311] but has not shown survival benefit in human studies.[312] Site inactivated factor VIIa, which competitively inhibits factor VIIa from binding to tissue factor and initiating coagulation, has been shown to prevent sepsis-induced acute lung injury and acute kidney injury in baboons,[313] but has not been evaluated in humans.

Immunomodulatory Therapy

Corticosteroids have long been the subject of studies in sepsis, the rationale being that minimization of the inflammatory cascade could improve outcome. Short-term therapy with glucocorticoids has not improved outcome in sepsis,[314] and a meta-analysis of 10 studies showed no beneficial effect.[315] Yet two recent small studies (40 and 41 patients) did show an improvement in outcome, [316] [317] and a randomized, placebo-controlled trial of hydrocortisone 50 mg IV every 6 hours plus fludrocortisone 50 mg daily via a nasogastric tube for 7 days in patients with septic shock showed a significantly lower 28-day mortality rate in the treated group (55%) compared with patients who received placebo (61%).[318] Low-dose corticosteroids (200–300 mg/day in 3 to 4 divided doses for 7 days) is now recommended for patients with septic shock who, despite adequate fluid resuscitation, require vasopressor therapy.[296] A 250 mg ACTH stimulation test can be used to determine responders (>9 mg/dl increase in cortisol 30 to 60 minutes after ACTH administration), and corticosteroid therapy can be discontinued in these patients. Fludrocortisone (50 mg orally once daily) can be added to the regimen.

Antibodies to TNF have been studied in sepsis, and although most studies have found no benefit, [60] [319] [320] a recent study showed a risk-adjusted relative reduction in mortality of 14.3% for septic patients with an interleukin-6 level of more than 1000 pg/ml when treated with anti-TNF antibody.[321]

Studies have been done to evaluate the benefit of anti-endotoxin,[322] PAF antagonists,[323] bradykinin antagonists,[324] prostaglandin antagonists, [325] [326] IL-1 receptor antagonists,[327] nonselective nitric oxide synthase inhibitor,[328] n-acetyl cysteine,[329] granulocyte colony-stimulating factor,[330] and IVIG[331] in sepsis, and none have been shown to be beneficial. A recent study assessing C1-inhibitor in 40 patients found an improvement in serum creatinine at day three and four, but no survival benefit.[332]

Hemofiltration in Sepsis

The role of cytokines in sepsis and septic shock has led to the theory that removing them by hemofiltration may improve outcomes. Many studies have evaluated the effect of hemofiltration on cytokine levels and have shown clearance of cytokines, including TNF, [333] [334] IL-1, [333] [335] [336] IL-6, [231] [337] and IL-8,[337] by hemofiltration. Although a few studies have shown a reduction in the amount of cytokines in the plasma with hemofiltration,[338] [339] the preponderance of studies have shown no reduction in plasma cytokine levels. [340] [341] [342] [343] [344] [345] The high production rate and rapid endogenous clearance of many cytokines[346] likely results in the amount being removed by hemofiltration to be too minor to change circulating levels. It also appears that a large percentage of the clearance of cytokines occurs as a result of adsorption to the dialysis membrane,[347] which becomes saturated after a short time, limiting the clearance.

In animal models, hemofiltration has improved survival in some studies, [348] [349] but these studies initiated hemofiltration before or shortly after the septic insult, which is generally not possible in clinical practice. Studies using a true infection model have not shown an effect on survival. [350] [351] Prospective human studies to evaluate the benefit of hemofiltration in sepsis have generally been small. Reduction in the hyperdynamic response, including improved systemic vascular resistance,[352] improvement in APACHE II scores,[353] improvement in vasopressor requirement,[354] and beneficial hemostatic changes[355] have been found. One prospective uncontrolled study found that short-term (4 hour) high-volume hemofiltration improved septic shock in 11 of 20 patients treated,[356] but no randomized controlled trial at this time has shown an improvement in survival when hemofiltration is used for sepsis. Recent studies have shown that adsorption coupled with hemofiltration[357] and high-volume ultrafiltration with frequent membrane changes[347] may improve cytokine clearance, but currently there is no evidence to support the routine use of hemofiltration for sepsis.


Cardiogenic shock is a state of decreased cardiac output in the setting of adequate intravascular volume, resulting in inadequate tissue perfusion. The diagnosis can be made clinically by the findings of poor tissue perfusion such as oliguria or cool extremities, along with the hemodynamic criteria of sustained hypotension (systolic blood pressure <90 mm Hg), reduced cardiac index (<2.2 L/min/m2), and congestion (pulmonary capillary wedge pressure > 18).[358]

Cardiogenic shock occurs in 4.2% to 7.2% of myocardial infarctions [359] [360] and is the most common cause of death among patients suffering from myocardial infarction.[361] The first series, in 1967, evaluating the outcome of cardiogenic shock found a mortality of 81%,[362] but a multicenter trial in 2000 found a mortality rate of 60%.[363] Also, the in-hospital mortality rate from ischemic cardiogenic shock in the National Registry of Myocardial Infarction (NRMI) decreased from 60.3% in 1995 to 47.9% in 2004, presumably due to more aggressive revascularization.[364]

The most common cause of cardiogenic shock is massive myocardial infarction,[365] but can also be caused by a smaller infarction in a patient with reduced left ventricular function, acute mitral regurgitation (from papillary muscle rupture), rupture of the interventricular septum, myocarditis, end-stage cardiomyopathy, valvular heart disease, tamponade, or hypertrophic cardiomyopathy. In the SHOCK (should we emergently revascularize occluded arteries for shock) registry and trial[363] of 1422 patients with cardiogenic shock, 79% of patients had left ventricular failure as the cause of shock, whereas 6.9% had severe mitral regurgitation, 3.9% had ventricular septal rupture, 2.8% had isolated right ventricular shock, and 1.4% had tamponade. Shock may be found at presentation in patients with acute myocardial infarction, but can be delayed. In the SHOCK registry, mean time to development of shock was 7 hours after infarction.[363]


In patients with myocardial infarction or ischemia, cardiogenic shock may occur once 40% of the myocardium is lost.[365] The resultant clinical sequelae can potentiate the myocardial damage. Hypotension and tachycardia can increase ischemia in this setting. Coronary blood flow is dependent on the duration of diastole, which is significantly shortened in the patient with tachycardia, resulting in reduced perfusion of the already ischemic myocardium.[365]The elevated wall stress resulting from left ventricular dilatation and pump failure increases myocardial oxygen requirements, which also worsens ischemia.[365] The cellular hypoxia seen in ischemia leads to a reduction in ATP levels, and eventual myocyte swelling.[366] Apoptosis of myocytes occurs after myocardial infarction,[367] and may contribute to the state of reduced cardiac output.

Clinical Features

Hypotension is universal in cardiogenic shock. Tachycardia is often present, but in the SHOCK registry, the mean heart rate was 96.[368] Arrhythmias may be present, and jugular venous distention, pulmonary rales, and a third heart sound are usually found. Signs of hypoperfusion may include confusion, mottling of the skin, and oliguria. In a study of 118 patients with cardiogenic shock, acute kidney injury occurred in 33% of patients within 24 hours, and increased mortality from 53% to 87%.[9] Multiple organ failure develops in many patients, primarily due to ischemia from decreased cardiac output. However, systemic inflammation may play a role in many patients. High plasma levels of IL-6 have been associated with multiple organ failure in this population,[369] 18% of patients in the SHOCK registry showed signs of severe systemic inflammation, leading to a diagnosis of suspected sepsis,[370] and a minority of patients develop distributive shock, possibly secondary to occult sepsis or mesenteric ischemia.[371] Lactic acidosis may also occur from hypoperfusion.[372]


The primary goal in the evaluation of cardiogenic shock is to determine the primary cause. As stated previously, myocardial infarction (MI) with reduced left ventricular systolic function is the most common cause,[362] and is often readily apparent on physical exam. However, other causes of shock, such as sepsis, hypovolemia, and pulmonary embolism, must be considered. An electrocardiogram (ECG) should be performed on arrival, and if an inferior MI is suspected, a right-sided ECG should be performed to evaluate for right-sided involvement. Routine blood tests including cardiac enzymes should be performed, a Foley catheter should be placed to monitor urine output, and a chest radiograph should be obtained.

Echocardiography is a valuable tool to confirm the diagnosis of cardiogenic shock, and can evaluate for potential mechanical causes that require surgical intervention, such as mitral regurgitation, papillary muscle rupture, tamponade, or left ventricular free wall rupture.

Although brain natriuretic peptide (BNP) has been found to be effective in the diagnosis of congestive heart failure (CHF), it is not typically used in the diagnosis of cardiogenic shock. BNP is a 32-aa polypeptide found in the cardiac ventricles. BNP release from the ventricles, and therefore serum levels, are indirectly proportional to ventricular volume expansion and pressure overload.[373] A BNP level greater than 100 pg/ml has a sensitivity of 82% for CHF, increasing to 99% for NYHA class IV CHF.[368] BNP levels have been found to correlate closely with New York Heart Association (NYHA) classification, with mean levels in NYHA class IV to be greater than 900 pg/ml.[374] BNP levels have also been found to decline as pulmonary capillary wedge pressure decreases,[375] making it a possible monitoring tool in the management of severe CHF.


Airway management and maintenance of adequate oxygenation should be the first concern during resuscitation. Bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP) can improve oxygenation and prevent intubation in severe congestive heart failure,[376] although use in cardiogenic shock has not been well studied. Intubation and mechanical ventilation may be required if supplemental oxygen or noninvasive ventilation cannot maintain adequate oxygenation with minimal work of breathing.

Patients treated with beta-blockers, ace-inhibitors, and nitrates for myocardial infarction that subsequently develop shock should have these agents discontinued because they may worsen the clinical state. Patients with mechanical causes of shock should be evaluated for surgical repair.

A minority of patients with cardiogenic shock may develop hypotension without evidence of pulmonary edema.[377] In these patients, a fluid challenge of 100 cc to 250 cc of normal saline should be given. In the patient who does not respond to fluids, or has pulmonary congestion, inotropic agents should be administered.

Dobutamine is primarily a β1 agonist, but is a weak β2 and a stimulator, and can improve myocardial contractility and cardiac output. Dobutamine is the drug of first choice when the systolic blood pressure (SBP) is greater than 80 mm Hg, but it can induce hypotension as a result of the β2 effect, so should either not be used when blood pressure is less than 80 mm Hg, or used in conjunction with another vasopressor. Dobutamine may worsen tachycardia, and can cause arrythmias,[378] and has not been shown to improve outcomes in patients with cardiogenic shock.

Dopamine should be used when the SBP is less than 80 mm Hg. At low doses (<5 mg/kg/min) β1 effects predominate, and as the dose is increased, a effects become more prevalent. Ischemia of the periphery, tachycardia, and arrhythmias can occur.[378] Norepinephrine is a pure a agonist and can be used when there is an inadequate response to dopamine. Vasopressin has been shown in a retrospective study to increase mean arterial pressure without affecting pulmonary capillary wedge pressure or cardiac index.[379]

Milrinone and amrinone are phosphodiesterase inhibitors (PDE) that increase cyclic amp levels in the myocardium. Increased cAMP increases intracellular calcium in the myocyte, leading to increased contractility. These agents increase inotropicity and cardiac output, without increasing myocardial oxygen consumption.[380] They do not induce direct tachycardia, but do cause a peripheral vasodilatation, which can lead to hypotension and reflex tachycardia, and they may cause arrhythmias. Amrinone, as well as dopamine and dobutamine, may also improve myocardial mitochondrial function during shock.[381] Although several small studies have shown improved hemodynamics with PDE inhibitors, a recent meta-analysis on the effectiveness of catecholamines and PDE inhibitors concluded that such treatment provides little evidence for improved symptoms and may not be safe.[382]

If hemodynamics have stabilized after the initiation of pressors, management of pulmonary edema with diuretics may be initiated. Direct vasodilator therapy can then be considered to decrease preload and afterload, which can improve ischemia. Sodium nitroprusside and nitroglycerin both have short half-lives, and can be carefully titrated, observing for worsening of the hemodynamic state.

Recombinant human brain natriuretic peptide (BNP) has been found to increase cardiac output, decrease pulmonary capillary wedge pressure and systemic vascular resistance, and improve natriuresis and diuresis in decompensated heart failure. [383] [384] It is FDA approved for management of NYHA class IV CHF, but is controversial in patients with CKD. A study in 2005 found a decline in GFR during use of BNP for acute decompensations of heart failure,[385] whereas another study found no effect on renal function.[386] BNP has not been evaluated in cardiogenic shock.

Several drugs are being evaluated for management of decompensated heart failure and cardiogenic shock. Toborinone is a PDE inhibitor that does not induce tachycardia or increase myocardial oxygen consumption in stable congestive heart failure patients. Levosimendan acts by enhancing myofilaments sensitivity to calcium. It has positive inotropic effects, but does not increase intracellular calcium, thus reducing risk of arrhythmia or increased oxygen consumption. Endothelial receptor antagonism is being evaluated as vasodilator therapy.

The SHOCK II randomized clinical trial will evaluate nitric oxide inhibition in cardiogenic shock. NO has a biphasic effect on myocardial function. At low levels, it promotes coronary and myocardial relaxation, but at high levels, NO results in adverse effects and is associated with decreased contractility and reduced effect of β-adrenergic stimulation. Two small studies of NO blockade in cardiogenic shock have been published, one showing improvement in MAP and wedge pressure,[387] and one showing improvement in 4-month survival compared to placebo.[388]

Intra-aortic balloon pumping (IABP) can improve diastolic blood pressure,[389] improve coronary perfusion,[390] and increase cardiac output.[389] In the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-1) trial, patients who had early IABP placement had a trend toward improved survival,[391] and the SHOCK trial found a lower in-hospital mortality in patients who received IABP.[392] A recent study evaluated 23,180 patients with cardiogenic shock, 7268 of whom had IABP. IABP was associated with a significant reduction in mortality among patients who received thrombolytic therapy (67% versus 49%), but was not of benefit in patients treated with primary angioplasty (45% versus 47%).[393] IABP has been shown to increase clot lysis when used in conjunction with thrombolytics in animal models,[394] likely due to increased coronary blood flow, and this may explain the improved mortality when IABP and thrombolytics are used together.

Intra-aortic balloon pumping has been reported to have a complication rate between 2.6% and 15%, with a mortality rate of 0.05% to 0.4%. [395] [396] Most of the complications were vascular, with major bleeding occurring in 4.6%, and limb ischemia occurring in 3.3% of patients.[396] A study of 71 patients found a rate of bacteremia and sepsis to be 15% and 12%, respectively.[397] Acute kidney injury was not reported as a complication in these studies, likely because the associated shock made attribution of acute kidney injury to IABP difficult.

The outcome of cardiogenic shock in the setting of myocardial infarction is directly related to the patency of the involved coronary arteries.[398] Therefore, interventions to open occluded arteries are crucial. Thrombolytics have been shown to be able to reduce the incidence of shock when given for acute myocardial infarction,[362] but once shock is established, there is conflicting data. The GISSI trial[399] found a similar in-hospital mortality between patients with cardiogenic shock treated with streptokinase (69.9%), and controls (70.1%). However, the SHOCK trial registry of 1190 patients found a lower in-hospital mortality among patients treated with thrombolytics (54%) compared to those who did not receive thrombolytic therapy (64%),[392] and a study of 23,180 patients in the National Registry of Myocardial Infarction 2 found a mortality rate of 59% for patients receiving only thrombolytic therapy compared with 77% in the group who received no reperfusion therapy.[395]

Despite the apparent benefit of thrombolytics, recent evidence has favored an even more aggressive approach to the management of cardiogenic shock. The SHOCK trial[400] randomized patients to early revascularization or initial medical stabilization, with 63% of the latter group receiving thrombolytics. The early revascularization group had a similar 30-day mortality compared with the medical therapy group (47% versus 56%, p = 0.11), but 6-month mortality[400] (50% versus 63%, p < 0.03), and 1-year mortality[401] (53% versus 66%, p < 0.03) were improved. The survival benefit was limited to patients younger than 75 years old, however other studies have reported different outcomes. In the Shock registry,[402] there was an improved mortality rate in elderly patients who received early revascularization compared with those who had delayed or no revascularization, and a multicenter study of 310 patients older than 75 years old undergoing percutaneous coronary intervention (PCI) reported a hospital mortality rate of 46%.[403] The choice of revascularization in the SHOCK trial was individualized, but generally PCI (64% of procedures) was used for one or two vessel disease, and surgery for left main stenosis or three vessel disease. The mortality in the medical treatment group is lower than in many other studies, and may be related to aggressive use of thrombolytics (63% of patients) and IABP (86% of patients). Other, small studies suggest that administration of platelet glycoprotein IIb/IIIa inhibitor to coronary stenting may improve outcomes further. [404] [405]

Ventricular assist devices have been used in peri-infarction cardiogenic shock, acute myocarditis, and post-cardiotomy shock to bridge patients to either recovery of adequate myocardial function or transplantation.[406]

As stated, acute kidney injury develops in one third of patients in cardiogenic shock, often necessitating a continuous modality of renal replacement therapy (CRRT), given the hemodynamic instability. CRRT in the critically ill will be discussed later.

Ultrafiltration by CRRT has not been evaluated in cardiogenic shock, but it has been proposed as a treatment for severe refractory heart failure, even in patients without renal failure.

Chronic heart failure results in neuroendocrine activation that is initially a response to the decreased effective circulating volume, but eventually serves to worsen heart failure as volume overload progresses. [407] [408] The renin-angiotensin-aldosterone system (RAAS) is activated, resulting in renal sodium and water retention as a result of increased aldosterone. The sympathetic nervous system is activated, and along with angiotensin II, results in peripheral vasoconstriction, which increases wall stress on the left ventricle, worsening heart failure. This increased wall stress due to volume and pressure overload results in ventricular remodeling, which potentiates heart failure,[404]resulting in a further activation of the RAAS. Arginine vasopressin release results in both vasoconstriction and free water retention. In patients who are diuretic resistant, there is no pharmacological means to remove fluid and potentially shut down the cycle of neuroendocrine activation and worsening heart failure. Ultrafiltration, either by continuous or intermittent methods, has been proposed to accomplish this. [405] [409]

A study of 32 patients[410] found that circulating renin, aldosterone, and norepinephrine levels were highest in patients with the most advanced heart failure (NYHA class III to IV and urine output <1000 ml/24 hrs), and treating with ultrafiltration led to significant reductions in these values along with a nearly 500% increase in diuresis (379 ml/24 hrs to 2195 ml/24 hrs), and a doubling of natriuresis (30 mEq/L to 63 mEq/L). However, those patients with urine output of greater than 1000 ml per day were found to have a reduction in diuresis and natriuresis in this study. In addition to improving the cycle of neuroendocrine activation, ultrafiltration has been proposed to improve refractory heart failure by removing the “myocardial depressant factor”, which has been found in ultrafiltrate.[411]

Most studies have been retrospective or case reports. Studies that have been performed have shown that ultrafiltration can improve the hemodynamics in patients with acute heart failure,[412] and have shown that patients can respond to ultrafiltration with improved diuresis, reduced heart failure symptoms, and improved sensitivity to diuretics, [413] [414] [415] [416] but there is conflicting data that hemofiltration may offer no benefit. [417] [418] Unfortunately, all of the studies in this area are small.

Although hemofiltration may improve congestive heart failure in some patients, removal of intravascular volume may not be tolerated by all, and can clearly lead to permanent renal dysfunction. The choice of patients to undergo hemofiltration for refractory heart failure should be made very carefully, and the risks of permanent renal failure should be discussed with the patient in advance.


Fulminant hepatic failure is an acute, and frequently fatal, process that results in severe metabolic abnormalities, neurological complications, and often multiorgan failure. Treatment in a critical care setting is required, and has helped improve the survival of many of these patients over the past several decades,[419] although mortality still remains high. Liver dialysis has been investigated as a possible treatment for encephalopathic patients, and if it becomes widespread, may fall under the domain of the nephrologist.


Acute liver failure from hepatocyte dysfunction results in decreased protein levels, diminished synthesis of clotting factors, manifested by prolongation of the prothrombin time and a decrease in the level of factor V, and often cerebral edema. Fulminant hepatic failure (FHF) is defined as severe acute liver failure, in a patient with no preexisting liver disease, with encephalopathy developing within 2 weeks of the first manifestation of liver disease, which is usually jaundice.[420] Liver failure that is complicated by the onset of encephalopathy between 3 and 12 weeks after the onset of jaundice has been termed subfulminant hepatic failure (SFHF).[420] Because the rate of onset of this disease process is an indicator of prognosis, with the patients having the most rapid onset of encephalopathy also having the best chance of recovery, a newer definition has been proposed to classify fulminant and subfulminant hepatic failure.[421] Hyperacute, acute, and subacute liver failure are defined by the amount of time between the onset of jaundice and the development of encephalopathy (0 to 7 days, 8 to 28 days, and 29 days to 12 weeks, respectively). The survival of hyperacute liver failure has been reported to be 36%, whereas acute has a survival of 7% and subacute 14%.[412] The most common cause of hyperacute liver failure is acetaminophen overdose, although hepatitis A and B can also result in this condition. Acute liver failure is predominantly caused by viral hepatitis and drug reactions,[422] whereas subacute liver failure is most often caused by a hepatitis in which no viral cause can be found.[423]

Patients with chronic liver disease can also develop decompensation with complications similar to acute hepatic failure, except they typically do not develop brain edema.


There are many causes for FHF, and there are regional variations in the etiology. Acute viral hepatitis is the leading cause of FHF worldwide, although the vast majority of cases of viral hepatitis do not manifest as FHF.[424] Hepatitis A virus (HAV) is the most common cause of hepatitis worldwide, but accounts for less than 1% of all cases of FHF.[424] Of all the viral causes of FHF, HAV has the best prognosis with greater than 60% of patients surviving without a transplant.[425] HAV does not lead to chronic hepatitis, and is diagnosed by the presence of HAV anti-IgM antibodies.

Hepatitis B virus (HBV) currently accounts for approximately 15% of cases of FHF in the United States,[422] and 23% in Europe.[424] Coinfection with hepatitis D virus (acquiring HBV and HDV simultaneously) is found in up to 30% of cases of FHF with hepatitis B.[426] Superinfection with HDV can occur in a patient known to have HBV, and can lead to FHF. Hepatitis C virus (HCV) coinfection with HBV may also precipitate FHF.[427] The diagnosis of acute HBV infection is based on the presence of anti-IgM antibodies to HbcAg because HbsAg is often not detected in the acute setting.

Hepatitis C virus has traditionally not been felt to be a cause of FHF, but one recent study identified HCV RNA in 19% of patients with FHF.[428] A cause and effect between HCV and FHF has not been fully established at this time. Hepatitis E virus (HEV) is known to cause FHF, particularly in the third trimester of pregnancy, and is endemic in Asia and Africa. To date no causes of FHF in the United States have been attributed to HEV,[427] but should be considered in patients who have traveled to, or emigrated from endemic areas. Herpes simplex virus and cytomegalovirus have been reported to cause FHF, but usually in the setting of immunosuppression or pregnancy. Adenovirus,[429] human herpes virus 6,[430] Epstein-Barr virus, and influenza virus type B have also been reported to cause FHF.[431] In patients with FHF that is suspected to be viral in origin, 10% to 20% of all cases cannot be identified, and has been termed non-A, non-B, non-C FHF. This disease usually has a subacute presentation, and does not seem to recur after liver transplantation.[422]

Drug toxicity is the second most common cause of FHF, either by direct hepatotoxic effect or by an idiosyncratic reaction. Acetaminophen is the most common drug to cause FHF in the United States and United Kingdom. Acetaminophen is partially converted to the toxic metabolite N-acetyl-p-benzoquinone-imine (NADQI), which is neutralized by reacting with glutathione. If the amount of acetaminophen ingested acutely or chronically overwhelms the ability of glutathione to inactivate NADQI, hepatotoxicity occurs. Persons with depleted glutathione stores from alcoholism or malnutrition are more susceptible to the hepatotoxicity, as are persons taking p450 enzyme inducing drugs. Single doses of as low as 10 g can lead to FHF, but doses within the therapeutic range taken chronically by alcoholics can also lead to FHF. Halothane is known to be hepatotoxic, but is rarely used now in clinical practice. The newer halogenated agents enflurane, methoxyflurane, and isoflurane have a much lower risk of hepatotoxicity. Halothane hepatotoxicity is idiosyncratic, and there is cross-reactivity between the halogenated agents. Many other drugs have been associated with ALF and FHF, including NSAIDS, isoniazid, phenytoin, valproic acid, sulfonamides, propylthiouracil, amiodarone, and ectasy (methyldioxyamphetamine). A thorough history is critical for diagnosing drug related FHF, which can be difficult in a profoundly encephalopathic patient.

Ingestion of the mushroom Amanita phalloides is a rare but well-recognized cause of FHF. Hepatic, pancreatic, renal, and cerebral damage can occur as a result of the toxin a-amantin.[432] Profuse watery diarrhea and abdominal pain develop within 24 hours of ingestion and last 1 to 6 days prior to the development of liver failure. As little as three mushrooms may lead to FHF.

Wilson disease presents as FHF in 10% of cases. This disease may be associated with hemolytic anemia secondary to massive copper release from the liver, and Kayser-Fleischer rings on slit-lamp examination. Although no set of laboratory values can distinguish Wilson disease from other causes of FHF,[433] a low ceruloplasmin level and a low serum alkaline phosphatase are suggestive. Rapid recognition is key because this condition is 100% fatal without a liver transplantation.[421] Other conditions that can present as fulminant hepatic failure are listed in Table 60-8 .

TABLE 60-8   -- Additional Causes of Fulminant Hepatic Failure

Autoimmune hepatitis

Metastatic tumor

Acute fatty liver of pregnancy

Budd-Chiari syndrome

HELLP syndrome

Portal vein thrombosis

Reye syndrome

Right heart failure

Malignant hyperthermia

Acute rejection of liver transplantation




Clinical Features

Fulminant hepatic failure presents with a variety of symptoms. Nausea and vomiting may be the first indicators, followed by jaundice. Encephalopathy may develop rapidly. Several metabolic disorders result from the loss of hepatocyte function. Hypoglycemia results from impaired gluconeogenesis, high insulin levels, and the inability to utilize stored glycogen. Metabolic acidosis is a consequence of poor tissue perfusion and inability to clear lactate. Hypokalemia and hyponatremia also occur frequently. By definition, fulminant hepatic failure requires that encephalopathy be present, the etiology of which is felt to be multifactorial.[434] Ammonia, nitric oxide, manganese, and inhibition of the Na+K+ATPase pump in neuronal cells may all play a role in acute hepatic encephalopathy.[435] Increased production or diminished clearance of “endogenous” benzodiazepines may contribute to hepatic encephalopathy, [436] [437] and enhanced gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission has also been postulated to have an effect.[438] Hepatic encephalopathy is graded on a scale of 1 to 4 as listed in Table 60-9 . Strong consideration should be given to intubation for airway protection as encephalopathy progresses through stage 3.

TABLE 60-9   -- Stages of Hepatic Encephalopathy

Stage 1: Euphoria, anxiety, disruption of sleep, shortened attention span, mild confusion, slight asterixis

Stage 2: Slurred speech, lethargy, inappropriate behavior, asterixis, hypoactive reflexes, loss of continence

Stage 3: Marked confusion, incoherent speech, hyperactive reflexes, somnolent but “arousable”

Stage 4: Coma, unresponsive to pain, lacking asterixis




Cerebral edema has been found in 40% of patients with FHF and advanced encephalopathy.[439] In patients dying with FHF, uncal or cerebellar herniation (or both) was found to be the cause of death in 80%.[440] The rapid increase in water content of the brain results from increased permeability of the blood-brain barrier.[441] The edematous brain is confined by the cranium, leading to increased intracranial pressure and decreased cerebral perfusion.[442]Cerebral edema is manifested clinically by abnormal pupillary reflexes, systemic hypertension, and bradycardia. Decerebrate posturing and brain stem respiratory patterns are classic, but late findings. Invasive monitoring by a subdural transducer does have a risk of bleeding and infection, [439] [443] but in the sedated and ventilated patient may be the only mechanism to assess intracranial pressure (ICP). Some authors have recommended ICP monitoring for all patients with grade 3 and 4 encephalopathy, [444] [445] and ICP monitoring has been shown to improve the outcome of liver transplantation by excluding those patients with low cerebral perfusion pressure (MAP– ICP) who likely have permanent neurological damage. [446] [447] However, there is currently no consensus on which patients should receive ICP monitoring.[437] Most patients who recover from FHF with associated cerebral edema have full recovery of neurologic function, but permanent brain damage can occur.[448]

Patients with ALF are often found to have profound circulatory changes. A reduction in the systemic vascular resistance, which manifests as hypotension, is common, and has been attributed to high levels of circulating endotoxin and tumor necrosis factor.[446] There is also microthrombi formation in small vessels, resulting in diminished perfusion of metabolically active tissues.[437] These two factors combine to reduce oxygen delivery and extraction, resulting in anaerobic metabolism, and contributing to the lactic acidosis and multiorgan failure seen in many patients. Coagulopathy is a common finding in FHF. Half of all patients develop thrombocytopenia,[449] caused by consumption, reduced bone marrow production, or, in a patient with pre-existing liver disease, hypersplenism. Reduced production of factors I, II, V, VII, IX, and X lead to an increase in the prothrombin time (PT). A reduction in Factor V is seen rapidly because it has a short half-life. The level of factor V is often used as a marker of disease progression, and is considered an independent prognostic factor.[419] The synthesis of coagulation factors II, IX, and X may also be reduced, prolonging the partial thromboplastin time (PTT). Disseminated intravascular coagulation may be seen resulting from a combination of factors, including the release from necrotic hepatocytes of thromboplastic material, platelet activation from circulating bacterial endotoxins not cleared by the liver, and expression of tissue factor on activated endothelial cells stimulating the extrinsic coagulation cascade.[450] Although hemorrhage is uncommon, the gastrointestinal tract is the most common site of bleeding, and intracranial hemorrhage may rarely occur spontaneously.[451]

Bacterial infections may occur in up to 80% of patients with ALF,[452] caused in part by diminished opsonic activity,[453] complement deficiency, and impaired neutrophil function.[454] Fungal infections are also common, the predominant organisms being candida albicans or glabrata and aspergillus. There may be an absence of clinical signs of infection in FHF, so a high index of suspicion must be maintained, particularly when patients have a sudden deterioration. Prophylactic antibiotics have not been shown to be beneficial,[455] but are commonly used.

Renal dysfunction is common, present in up to 55% of all patients with FHF.[448] Direct toxicity can be a result of acetaminophen overdose, radiocontrast, or antibiotic use. The circulatory changes seen in FHF predispose patients to renal dysfunction because they have reduced renal blood flow.[437] Hepatorenal syndrome is a well recognized occurrence and is discussed in Chapter 27 . Many patients with FHF develop severe renal dysfunction requiring renal replacement therapy (RRT), and studies comparing intermittent renal replacement therapy with continuous modes found a significant increase in ICP with intermittent RRT,[456] but no increase with continuous renal replacement therapy (CRRT). [457] [458] There was also no increase in ICP with the CRRT, but a significant increase with intermittent methods. [457] [458] CRRT should be considered first-line therapy, even in hemodynamically stable patients with FHF.


Initial laboratory tests should include chemistry profiles, coagulation studies, complete blood count, toxicology screen, viral serologies, ceruloplasmin (in patients younger than 40 years), creatinine kinase, and urinalysis. Transaminases can be strikingly high, but the levels do not predict outcome. Increases in Bilirubin, prothrombin, and a reduction in factor V do have prognostic value and should be observed closely.

Signs of cardiac or renal failure should prompt consideration of Swan-Ganz catheter placement because the intravascular volume status can be difficult to determine otherwise in FHF. Sepsis must be evaluated for, including a search for fungal infections.

Intravenous H2 blockers are considered routine to prevent gastric bleeding in the setting of coagulopathy. Liver biopsy is needed for diagnosis in a minority of cases because the etiology is usually evident. Transjugular biopsy has become the favored method in the setting of coagulopathy because it has less risk of bleeding than the percutaneous approach.[459]


There are few causes of FHF for which specific therapy is useful. Acetaminophen toxicity should be treated with N-acetyl cysteine (NAC), which enhances the availability of glutathione, and administration up to 36 hours after an overdose of acetaminophen may improve outcome.[460] Therefore NAC should be given anytime acetaminophen overdose is suspected, even if levels are undetectable. The oral dose is 140 mg/kg initially, followed by 70 mg/kg every four hours for 17 doses. When given intravenously, the dose is 150 mg/kg bolus followed by 70 mg/kg IV every four hours for 12 doses. Acyclovir should be used for herpes simplex infection and lamivudine has been proven to be of some benefit for hepatitis B infection.[461] Acute fatty liver of pregnancy and the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome require immediate delivery of the fetus. Amanita poisoning should be treated with high-dose penicillin (300,000 to 1 million U/kg/day),[462] which has an antagonistic effect on the mushroom toxin, amatoxin, and sylibin (20 to 48 mg/kg/day),[463] which blocks the hepatocellular uptake of amatoxin. The remainder of therapy for FHF is supportive. Fluid resuscitation is often required in the acute setting because there is hypotension from decreased systemic vascular resistance, as well as increased endothelial permeability, which leads to redistribution. Albumin and fresh frozen plasma have traditionally been considered first-line agents for fluid resuscitation [421] [464] because these patients often have renal sodium retention with ascites formation, and saline tends to lead to third spacing. FFP continues to be used as a first-line agent for volume resuscitation, although there are no studies to support its use over normal saline. Once volume resuscitation is complete, dextrose with 0.45% normal saline should be used for maintenance fluids, with careful monitoring of serum electrolytes.

Hypotension that persists after fluid resuscitation is adequate, as evidenced by a wedge pressure of 12 to 14, requires vasopressors. Norepinephrine is most commonly used due to its preferential effect on peripheral alpha receptors.

In the seriously ill patient, intravenous NAC has been used to improve cardiac output and oxygen extraction, particularly in the setting of pressor use, which may increase tissue hypoxia due to vasoconstriction. Studies of NAC for this purpose have not been consistent, with some showing a benefit,[465] and others showing no improvement in oxygen extraction or markers of tissue hypoxia.[466] Epoprostenol, a prostacyclin that has microcirculatory vasodilatation properties, has been studied in patients receiving vasopressors and found to improve oxygen delivery and the oxygen extraction ratio,[467] but in a study of patients with renal failure, intravenous prostacyclin was found to decrease blood pressure and significantly reduce the cerebral perfusion pressure.[468]

The management of hepatic encephalopathy is directed at limiting the production of ammonia and avoiding benzodiazepines. Most ammonia is derived from intestinal bacteria, and lactulose can help reduce the absorption of ammonia, although it has not been shown to impact survival in patients with advanced encephalopathy.[469] Neomycin has been used, but has not been shown to be useful in hepatic encephalopathy.[470] It also has the potential for ototoxicity and nephrotoxicity, and therefore should be avoided. Flagyl is used to reduce intestinal bacteria and decrease ammonia production. Flumazenil, a benzodiazepine antagonist has been shown to offer short-term improvement in encephalopathy.[471]

Cerebral edema is a common cause of death in patients with FHF and should be treated aggressively. When ICP monitoring is performed, the cerebral perfusion pressure (CPP) should be maintained above 50. An ICP greater than 30 and a CPP less than 40 for 2 hours has been associated with permanent neurological damage. [442] [469] Raising the head of the bed to 20 to 30 degrees may improve ICP. Fever can increase ICP and should be aggressively treated. Mannitol is commonly used in doses of 0.5 to 1.0 g/kg, and is effective in reducing the ICP in patients with normal renal function. A diuresis of twice the volume of mannitol given should be expected in one hour. This dose can be repeated but the serum osmolality must be monitored and mannitol stopped when the osmolality reaches 320 mOsm/kg. Mannitol can lead to intravascular volume depletion and acute kidney injury, and its use in patients with ongoing renal dysfunction will likely lead to acute kidney injury. In the setting of renal failure, mannitol can be coupled with hemofiltration to maintain the osmotic effect. Twice the volume of mannitol administered should be removed by ultrafiltration to ensure this effect.[437] Hyperventilation to a Pco2 to 30 is routinely used to transiently reduce the intracranial pressure, but one study showed this had no benefit,[472] and a Pco2 below 24 is associated with cerebral vasoconstriction.[473] Agitation should be kept to a minimum. If the previously mentioned measures are inadequate to keep the CPP above 50, pentobarbital may be used to induce coma. Hypothermia has been evaluated in one small study, but is not considered standard of care.[474]

Most patients with FHF develop coagulopathy, but spontaneous hemorrhage is uncommon.[41] Parenteral vitamin K should be given for 3 days if coagulopathy develops, and fresh frozen plasma should only be given for bleeding or in advance of invasive procedures. Other therapies including insulin and glucagon,[475] corticosteroids,[476] and exchange transfusion[477] have not been shown to be beneficial, whereas plasmapheresis has had mixed results, and is not widely used. [478] [479]

Patients with acute liver failure are placed at the top of the liver transplant list, but the shortage of donor organs means that many will die waiting for transplantation. The King's College criteria ( Table 60-10 ) are utilized to help decide when a patient should be listed for a transplant. Contraindications include uncontrolled intracranial hypertension, sepsis, adult respiratory distress syndrome, and dependence on pressors.[424] Transplantation of human hepatocytes into the splenic bed has been tried with some success.[480] Living related transplants have been used in Japan for FHF with a reported 1-year survival of 90% in a series of 14 patients,[481] and has been used successfully in the United States.[482]

TABLE 60-10   -- King's College Criteria for Liver Transplantation

Acetaminophen overdose patient

Arterial pH < 7.3 with any degree of encephalopathy

INR >6.5

Creatinine > 3.4 mg/dl in presence of grade III or IV encephalopathy

Non-acetaminophen related liver failure

INR > 6.5 with encephalopathy or any three of the following variables:

Age <10 or >40

Etiology: idiopathic nonviral hepatitis, idiosyncratic drug reaction

Jaundice >7 days before onset of encephalopathy

Serum bilirubin >17.5 mg/dl

INR >3.5

Modified from Shakil AO, Kramer D, Mazariegos GV, et al: Acute liver failure: Clinical features, outcome analysis, and applicability of prognostic criteria. Liver Transpl 6:163, 2000.

INR, international normalized ratio.





Although the toxins that lead to hepatic encephalopathy as well as the other manifestations of FHF have not been identified, extracorporeal detoxification has been examined as a way to remove these toxins, and potentially improve outcome. The Liver Dialysis unit utilizes hemodiabsorption (hemodialysis with a thick suspension of pulverized sorbents replacing the dialysate solution in the dialyzer) to remove potential toxins from the blood. The small particle size of the charcoal provides 300,000 M2 of surface area, much more area for absorption than typical charcoal columns that only have a few thousand M2.[483] Blood is pumped at a rate of 200 ml/min to 250 ml/min, and toxins pass directly across the cellulose membrane where they bind to the small particles of charcoal or cation exchangers in the sorbent solution. Treatment of 6 hours daily for 5 days was studied in a trial of patients with either FHF or acute on chronic liver disease.[484] Fifty-six patients were enrolled, 31 treated with Liver Dialysis, 25 as controls. In the acute on chronic liver failure group, 72% of those treated with Liver Dialysis had recovery of liver function or improvement to transplantation, whereas only 36% of the control group had these outcomes (p = .036), but patients with FHF showed no benefit from treatment with Liver Dialysis. It is unclear why the difference was so striking between the acute on chronic liver failure group and the FHF group, but it has been postulated that the toxins in FHF are more protein bound, such as the toxins of sepsis, and are not removed as effectively.[480] Both groups did show an improvement in neurologic outcomes after treatment, with over 50% of treated patients showing improvement in encephalopathy.

Another sorbent system that has been developed for management of hepatic failure is the molecular adsorbent recirculating system (MARS). In this system, a non-albumin permeable polysulfone dialysis membrane is used, with blood perfused on one side and 20% albumin on the dialysate side. Albumin bound substances such as bilirubin, bile acids, tryptophan, and fatty acids are cleared across the membrane to the dialysate albumin,[485] which is regenerated by passing through a charcoal column, followed by an anion exchange resin column and finally dialyzed against a bicarbonate buffered dialysate to remove the small toxins such as ammonium and aromatic amino acids. Results of trials are similar to Liver Dialysis, with improvement in outcomes in acute on chronic liver failure, but not FHF, and improved encephalopathy scores in both groups.[462] MARS was also found in one small study of 13 patients to improve survival in hepatorenal syndrome,[486] with none of 5 patients treated with hemodiafiltration alone alive at 7 days, whereas 3 of 8 patients also treated with MARS were alive at 7 days and 2 of 8 alive at 30 days. MARS is available in Europe for patients with liver failure, but is currently available for investigational use only in the United States.

The high mortality rate in FHF patients awaiting a liver transplant has made clear the need for a temporary support system that can act as a “bridge” until the failing liver regenerates, or until liver transplantation is available. A bioartificial liver (BAL) is a device in which hepatocytes are inoculated into one side of a semi-permeable membrane. Blood is passed into a plasma separator, the plasma is warmed, oxygenated, and then passed through the device that houses the hepatocytes.[487] The membrane acts to prevent antibodies from entering the cell compartment from the plasma, but allows hepatocytes to extract oxygen, nutrients, and toxins from the plasma, and allows metabolites to pass from the hepatocytes into the plasma. The current BAL devices undergoing clinical trials are using either porcine hepatocytes or immortalized human hepatocytes. Three BAL devices using porcine hepatocytes have been evaluated in phase I trial and found to be safe, but only one, the HeatAssist, has been evaluated in a larger study.[488] In this study of 171 patients, including 147 with FHF or SFHF, no survival advantage was found in patients treated with BAL compared to controls. But when the subgroup of FHF/SFHF was controlled for transplantation, there was a significant improvement in relative risk for mortality in those treated with the BAL. One BAL device utilizing immortalized human hepatocytes had similar positive results in early evaluation,[489] but in a randomized, controlled trial of 24 patients demonstrated no survival benefit.[490] Further trials are needed to assess the efficacy of these devices.

Renal Replacement Therapy in the Intensive Care Unit

Acute kidney injury in the ICU is a grave situation. ICU patients suffer multiple organ failure concomitant with or prior to the onset of AKI. These patients are more likely to be septic, volume overloaded, and profoundly acidotic. They often require blood pressure support and mechanical ventilation and they are twice as catabolic as patients with acute kidney injury outside the ICU setting. Secondary to these co-morbidities the ICU AKI patient is likely to require renal replacement therapy. Those ICU patients who develop AKI and require renal replacement therapy have significantly higher mortalities. Clermont and colleagues compared mortality in ICU patients without AKI, those with AKI not requiring RRT, those with ESRD on RRT, and those with AKI requiring RRT. The respective mortalities in these populations were 5%, 23%, 11%, and 57%.[491] An increase in mortality clearly reflected a worse overall medical co-morbid condition, but also suggested an effect on worsening mortality of renal failure. [491] [492] Whether dose, timing, or type of renal replacement therapy can have an effect on their outcome has just recently become an area of intense research to the nephrology and ICU communities.[493]

Historically, the decision to initiate renal replacement therapy was based on severe life-threatening complications of renal failure. Little attention had been placed on the nuances of the ICU patient with acute kidney injury. Hence renal replacement therapy in the ICU had been administered with similar goals and techniques applied in the outpatient dialysis setting. Although a large body of literature exists for the outpatient ESRD population, it should not be assumed to apply in the ICU setting. There are marked differences in these populations: the principle of “steady-state” kinetics are not applicable in AKI. The PCR of patients in the ICU is typically twice that of other populations.[494] [495] Furthermore, severe volume overload not only influences ultrafiltration requirements but also changes solute distribution volumes, and the use of vasopressors may decrease the efficiency of renal replacement therapy. Finally, adequate therapy including the timing of RRT initiation and dose has not been defined for AKI.

Decisions regarding how to deliver RRT in the ICU should be made with every effort to improve the patient's mortality and morbidity. When approaching the patient who requires renal replacement therapy the following questions should be asked: What access is best? When is it best to initiate RRT? Which RRT modality should be utilized? What degree of solute clearance is required?

Indications for Renal Replacement Therapy

Indications for initiation of RRT in the ICU should be expanded over those for initiation of RRT for ESRD. The presence of AKI requiring renal replacement therapy is associated with a significant rise in ICU mortality. Mehta appropriately separated indications for RRT in the ICU into “renal replacement” therapy and “renal support” therapy.[496] The indications for renal replacement are similar to those typically used for initiation of dialysis in ESRD patients, albeit expanded in the care of the ICU patient. The mnemonic AEIOU is useful when considering replacement therapy in the ICU.

Acidosis has historically been an indication for RRT when associated with azotemia. RRT is initiated as the serum bicarbonate declines and intravenous supplementation is inadequate or unacceptable due to sodium overload. However, with continuous renal replacement therapies lactic acidosis can be controlled successfully and acidosis secondary to permissive hypercapnia can be modified.

Electrolyte abnormalities are an indication for RRT in the ICU. Although hyperkalemia is the most common indication for intervention, all electrolyte abnormalities can be modified with RRT. Sodium can usually be modified with changes in free water intake/delivery but in rare instances RRT may be necessary. Calcium, phosphate, and uric acid abnormalities, as seen in tumor lysis syndrome and hypercalcemia from any cause, may require RRT to correct.

Intoxications frequently require RRT—Lithium, Theophylline, Ethylene Glycol, Methanol, Aspirin, Phenobarbital, and Cytoxan overdoses may all be managed with RRT.

Volume overload is often and easily managed with RRT, but is usually reserved for patients with oligoanuria unresponsive to diuretics. These patients are initiated on a form of RRT when they have pulmonary edema, severe hypertension, or significant edema.

Uremia is also an indication for RRT. Unfortunately, no clear definition of uremia in the ICU patient exists. Certainly mental status changes and pericarditis are easily defined complications of renal failure, they occur late in the course, and likely should not be markers for initiation of therapy.

Renal support indications as defined by Mehta[496] represent a change in therapy from ameliorating the conditions directly resulting from lack of intrinsic renal function to one that supports the patient and the effects of the complications from other organ failure. The goal of therapy becomes increasing survival time to allow for recovery of multiple organ systems including the recovery of renal function. Potential indications for renal support are extensions of renal replacement and novel approaches for care in the ICU. Volume overload without oligoanuria or even significant azotemia is an example of renal support. Continuous renal replacement therapies can be used in the patient with total body overload, with less than adequate urine output, despite a response to diuretics. Renal support can allow for administration of total parenteral nutrition, fluid removal in congestive heart failure, and total fluid management in the patient with multiorgan failure. A patient in the ICU may require inputs of greater than 3 liters per day if nutrition is maintained and antibiotics or blood products are required ( Table 60-11 ). Continuous therapies allow for continuous fluid removal in excess of input despite hypotension or pressor requirements. Postoperative mortality rises with the percentage of body weight increase in the ICU[497] and CRRT allows for this fluid removal postoperatively, potentially reducing morbidity and mortality. In addition fluid removal with continuous therapies has been shown to maintain urine output and GFR when compared to intermittent therapies by Manns and colleagues.[498] Finally, McDonald and co-workers have demonstrated better nutrition in the ICU patient on CRRT versus intermittent therapy.[499]

TABLE 60-11   -- Daily Fluid Requirements for a Typical Patient in the Intensive Care Unit

Fluid Administration in the Intensive Care Unit


Volume (l/day)

Medications (antibiotics/pressors)


Blood products


Alimentation (TPN, enteral feeds)


Total obligate input

3–7 liters/day


TPN, total parenteral nutrition.




Knowing when to initiate RRT in the ICU is a complex decision. Traditionally, waiting for a life-threatening indication for renal replacement has dictated timing. However, as we consider renal support requirements, and the extremely high mortality in these patients, earlier intervention seems appropriate. Gettings and associates retrospectively reviewed survival in trauma patients receiving CRRT in the ICU. Both groups received equivalent clearances and had similar characteristics. However, the group initiated on CRRT earlier, with a BUN less than 60 mg/dl (mean 42) had a survival of 39% compared to only 20% when CRRT was initiated after the BUN exceeded 60 mg/dl (mean 96).[500]

In the absence of controlled trials, definitive guidelines are not available. If the patient in the ICU is approached with consideration of renal support as well as renal replacement as proposed by Mehta, the patient should be initiated on extracorporeal therapy when clinical prowess suggests an improvement can be obtained over the next 24 hours that outweighs the risk. Similarly, the decision to withhold RRT in the ICU should be based on the estimation that a lack of intervention with an extracorporeal therapy will not be detrimental to the patient. In other words, if return of renal function is likely or conservative management with furosemide or other therapies are likely to succeed without harm to the patient, it is reasonable to observe the patient without extracorporeal therapy.

Vascular Access

Vascular access in the ICU is an important and often overlooked aspect of extracorporeal therapy. Poor access can lead to significant recirculation and inadequate flows, resulting in less efficient therapy and delivery of less than prescribed Kt/V with intermittent hemodialysis. Poor access flow and high recirculation are also detrimental in continuous therapies. Increases in hematocrit in the system, resulting from recirculation, rises leads to clotting of the extracorporeal circuit. Factors determining catheter function include location of catheter placement and catheter design. Other factors of unstudied significance primarily include patient characteristics.

Most present day non-cuffed dialysis catheters are manufactured using polyurethane. This is fairly firm for easy insertion but relaxes when remaining at body temperature. These catheters are placed via the Seldinger technique. Some catheters are made of silicone; these are thicker walled and more flexible. Placement of these catheters requires a peel away sheath or stiffening stylet. Non-cuffed catheters range in length from 15 cm to 24 cm. The 15 cm catheters are designed for placement via the right internal jugular vein. Although in most men and larger women 19 cm to 20 cm may be required to reach the superior vena cava/right atrial junction. Catheters 20 cm and longer are designed for the left internal jugular and femoral approaches.

Cuffed catheters are designed for a tunneled placement. In general these are placed when expected use of the catheter exceeds two to three weeks.[501] These catheters are silicone, hence more flexible than acute catheters, and longer. Placement is performed with a modified Seldinger technique using a peel away sheath, and is more technically challenging. Cuffed hemodialysis catheters vary in length from 50 cm to 90 cm and are designed for internal jugular, femoral, trans-hepatic, or translumbar placement.

Catheter tip design varies by manufacturer. Designs include step tip (with or without sideholes), single lumen with a septum (varying geometric designs), split tip, or two separate single lumen catheters. Studies comparing design variations, in patients, have not been performed with the acute catheters. Presently all seem to have adequate initial flow and function when placed in the internal jugular vein. Cuffed dialysis catheters have been studied in patients. Achieved blood flow using either the split tip catheter, large step tip catheters (14.5 french), and twin catheters was similar to blood pump setting as measured with ultrasound dilution—100% of desired flow at blood pump 300 cc/min and 93% to 95% of flow at 400 cc/min. A 15.5 french step tip tunneled dialysis catheter had lower flows—97% of desired flow at 300 cc/min and only 82% at blood pump speed of 400 cc/min. [502] [503] [504]

Recirculation has been measured by catheter design and catheter placement. Recirculation in non-tunneled dialysis catheters varies by location. Studies have demonstrated significantly higher recirculation values in femoral vein catheters than central-subclavian or internal jugular veins. Most catheter recirculation is less than 5% in the subclavian or internal jugular veins. [504] [505] However, in the femoral vein, catheter recirculation may exceed 50% with a mean of 20% to 30% at blood pump speeds of 300 cc/min. The amount of recirculation increases with blood pump speed and decreases when catheter length exceeds 19 cm.[501] Catheter design may also play a role in recirculation.

When catheter recirculation has been studied in cuffed tunneled dialysis catheters, the recirculation in the split tip catheter design was superior. At blood flows of 400 cc/min the split tip design had a mean recirculation of 1.3% to 4.9% compared to 5.2% with 14.5 french step tip catheters, 5.7% to 7.2% with 15.5 french split tip catheters, and 10.9% with twin catheters. [502] [503] [504]

In the acute dialysis unit flow and recirculation can be measured with ultrasound dilution at varying pump speeds to maximize clearance with IHD. Also recirculation can be monitored with CRRT on a daily basis and catheters changed or repositioned if recirculation rises. This theoretically could reduce or eliminate the degree of anticoagulation required and improve the circuit life of the CRRT system. However, the value of this approach to date has not been evaluated.

Despite improved flow and function of the subclavian placement versus femoral vein, the subclavian access should be avoided whenever possible. Subclavian catheter insertion is associated with an unacceptable rate of central vein thrombosis and stenosis.[506] This damage to the vessels leads to loss of future arteriovenous fistulas and graft sites, and frequently in patients with acute kidney injury, it is difficult to determine who might need chronic renal replacement therapy either at discharge or in the future. Despite the well-documented problems with subclavian catheters and clear guidelines,[501] a surprisingly high number of subclavian catheters are still used. According to the 2002 DOPPS study, 18% of European acute catheters and 46% of acute catheters in the United States are subclavian.[507] Dialysis catheters in the ICU should be placed in the internal jugular or the femoral position, the right internal jugular is usually preferred, and femoral catheter length should exceed 19 cm.

Care of the Catheter

Catheter care is designed to prevent malfunction and infection. Malfunction is usually related to thrombus or fibrin sheath formation. Prevention with any particular type of locking solution is not proven. Most institutions continue to use heparin or 4% citrate. When catheter dysfunction is present, line reversal may be successful and has acceptable recirculation characteristics as demonstrated by Twardowski.[508] Alternatively, locking agents are used based on local preferences but no controlled data are available to demonstrate effectiveness.

Infection is prevented by use of excellent local care and observation of DOQI guideline number 15 ( Table 60-12 ).[501] In addition, Oliver and colleagues[509] have demonstrated improved infection rates in acute catheters with the use of local antibiotic ointment on a dry gauze at the exit site. Finally, the risk of bacteremia is associated with the development of an exit site infection and duration of catheter use. For femoral catheters, the risk of infection rises dramatically after 1 week and the risk of IJ catheter associated bacteremia rises after 3 weeks.[510] It is reasonable to try to limit catheter duration to within these periods. Once catheter exit site infection is recognized, the catheter should be removed as risk of bacteremia rises within days—2% at 24 hours and 13% at 48 hours.[510] Catheter-associated bacteremia is treated with catheter removal and intravenous antibiotics.[501]

TABLE 60-12   -- Recommendations for the Care of the Temporary Hemodialysis Access

Catheter Care Item


Catheter insertion site

Femoral—Single use, severe CHF, use in bed-bound; use in ICU when other sites too risky.


Internal jugular—Preferred site when accessible (lowest recirculation and lowest risk of stenosis).


Subclavian—Avoid due to risk of stenosis.

Catheter placement

Femoral—Use >19 cm catheter. Consider monitoring recirculation to optimize efficiency.


Internal jugular and subclavian—right, use 15–20 cm catheters. Left approach needs 20 cm–24 cm catheters. Place tip at SVC/RA junction.

Exit site care

Dressing care and catheter manipulations performed by trained staff.


Examine catheter site each dialysis.


Dressing—Dry gauze with skin disinfection, use povidone iodine ointment or mupirocin ointment with dressing changes.


Use sterile technique at all times; patient and nurse wear mask. Nurse wears gloves.


Adapted from Rolando N, Gimson A, Wade J, et al: Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology 17:196–201, 1993.

Duration of use

Femoral—Less than 1 week


Internal jugular—Less than 3 weeks


From Lee WM: Management of acute liver failure. Semin Liver Dis 16:369–378, 1996.


CHF, congestive heart failure; SVC/RA, superior vena cava/right atrial.




Modalities of Renal Replacement Therapy

Of the therapies of RRT available in the ICU, a superior modality has not been definitively demonstrated. CRRT offers recognized advantages in continuous fluid and solute control but has never been convincingly shown to improve mortality. Intermittent hemodialysis (IHD) can be performed and recently attention has shifted to increasing the frequency above traditional thrice weekly. Slow low efficient daily dialysis (SLEDD) increases volume control and solute clearance when compared to IHD and approaches CRRT. Peritoneal dialysis (PD) is also used in the ICU but requires an intact peritoneal cavity. A decision regarding which modality is selected depends on local preferences, cost, and availability of therapies. However, ideally the therapy should be tailored to the needs of the ICU patient. Regardless of the RRT utilized, the goals should always be to improve the patient's fluid, electrolyte, and acid base balances, allowing for the greatest chance of renal and patient recovery.

Continuous Renal Replacement Therapies

With the advent of safe placement of double lumen venous catheters, the CRRT options in general have developed into continuous venovenous modalities. Continuous arterial venous therapies, as initially described by Kramer in the 1970's, have the advantage of blood flow and filtration determined by blood pressure. This gives the theoretical advantage of fewer hypotensive episodes. Arterial venous circuitry also requires a simple, low volume extracorporeal system with low resistance, thus obviating the need for expensive and complex pump-assisted devices. However, this therapy cannot obtain the higher volumes of ultrafiltration required for consistent metabolic control.[511] Arterial venous circuitry also requires a large bore femoral artery catheter with a risk of vascular complication estimated to up to 10%.[512] For these reasons arterial venous forms of CRRT are not widely used.

Pump-assisted circuits provide multiple options for fluid, electrolyte, and metabolic control (Figs. 60-3 and 60-4 [3] [4]). In slow continuous ultrafiltration (SCUF) the extracorporeal system is simplified to include a blood system hooked inline with a high efficiency or high flux membrane. As blood passes through the membrane, plasma water and solutes pass through the membrane to allow formation of an ultrafiltrate, which is discarded. No replacement fluids or dialysate fluids are required. Although SCUF is a purely convective modality, the ultrafiltrate volume is limited to inputs plus desired losses and hence not enough volume to control azotemia or significant metabolic disorders. This therapy is reserved for patients with residual renal function, but high volumes of input and/or significant fluid overload with a “relative” oliguria.

FIGURE 60-3  Continuous renal replacement circuitry. Circuits will also include a pre-pump port for anticoagulant administration, a post filter air detector and pressure monitoring for access, filter, and filtrate. A, Circuitry for slow continuous ultrafiltration. B, Pre-filter replacement for continuous venovenous hemofiltration. Note, in some systems the replacement may be post blood pump but pre dialysis filter. C, Post filter replacement continuous venovenous hemofiltration. D, Schematic of continuous venovenous hemodialysis. E, Circuit of continuous venovenous hemodiafiltration. Replacement fluid could be added pre or post pump and pre filter, or replacement fluid could be added post filter.


FIGURE 60-4  Illustration of pre and post blood composition as blood traverses a hemodialysis filter versus blood composition pre and post filter using hemofiltration. A, Note the significant clearance of small molecules by diffusion in hemodialysis. Comparatively, in hemofiltration, there is little change in solute concentration, except for a rise in hematocrit. The clearance in hemofiltration is solely convective. B, In hemofiltration a change in blood solute concentration is achieved by adding replacement fluid.


Continuous renal replacement therapy modalities designed for fluid and metabolic control require higher volumes of ultrafiltrate and hence require replacement fluid, dialysate fluid, or a combination of both. Continuous venovenous hemofiltration (CVVH) is an extracorporeal circuit with a double lumen venous catheter hooked to an extracorporeal system with a blood pump, high efficiency or high flux dialysis membrane, and replacement fluid. As in SCUF, pure convection produces the ultrafiltrate; however, much greater volumes are generated. Volume status and metabolic improvements are maintained by the addition of replacement fluid in the circuit. Replacement fluid can be added pre or post filter. Pre filter replacement carries a benefit of less hemoconcentration within the dialysis membrane but decreases clearances up to 15%.[513] Post filter replacement maintains efficiency of the circuit but may be associated with an increase in thrombosis of the extracorporeal circuit.[514] Continuous venovenous hemodialysis (CVVHD) is an extracorporeal circuit with a double lumen venous catheter hooked to an extracorporeal system with a blood pump, high efficiency or high flux dialysis membrane, and dialysate fluid. As in intermittent hemodialysis, the dialysate runs countercurrent to the blood pathway. As in other forms of CRRT, low efficiency is maintained by limiting dialysate volume to 1 to 3 liters per hour. While considered a diffusive therapy, certainly convection occurs due to high permeability of the membrane and back filtration. The degree of back filtration and convective clearance is likely to vary by membrane and has not been studied to date. However, Brunet and co-workers has shown significant middle molecule clearance with a PAN dialyzer (Gambro M100) and a dialysate rate of 2 liters per hour. Beta2 microglobulin clearance was 80% of that achieved with 2 liters per hour of CVVH therapy.[513]

Continuous venovenous hemodiafiltration (CVVHDF) consists of an extracorporeal circuit with a double lumen venous catheter hooked to an extracorporeal system with a blood pump, high efficiency or high flux dialysis membrane, and both replacement and dialysate fluid. In general, this combination is used to increase clearance; others utilize CVVHDF to simplify citrate delivery for anticoagulation. [515] [516] Clearly, both diffusive and convective forces determine solute clearances.

Intermittent Therapies

Conventional hemodialysis is typically delivered in the ICU setting three to four times a week with a standard Kt/V prescribed similar to that of ESRD.[517] Recently Schiffl and colleagues demonstrated improved mortality and renal recovery when the frequency was increased to daily.[518] Multiple studies have demonstrated an improvement in survival with use of biocompatible membranes.[519] Conventional hemodialysis is diffusional with ultrafiltration added as desired or tolerated to control fluid overload. Blood flow with intermittent therapies in the ICU ranges between 200 cc/min to 500 cc/min. It may be varied to reduce recirculation or improve hemodynamic tolerance of therapy. Dialysate composition and flow are similar to ESRD therapy with dialysate flows of 500 to 800 cc/min. Duration of therapy is typically 3 to 5 hours. SLEDD has been developed to be a hybrid therapy between the continuous and intermittent therapy. Blood flows and dialysate flows are slowed to 200 to 300 cc/min and 100 cc/min respectively, and the therapy is prolonged to 8 to 12 hours daily. [511] [520] This slower form of dialysis theoretically allows for more hemodynamic stability with increased clearances when compared to conventional hemodialysis. SLEDD also allows for time off the extracorporeal circuit, allowing for time for the patient to travel to diagnostic studies. Because SLEDD utilizes standard hemodialysis machinery, dialysate is generated on line and the cost is potentially lower than that of CRRT, particularly if ICU personnel can be trained to monitor the dialysis session obviating the need for dialysis nurses to be bedside for the 8 to 12 hours of therapy.

Peritoneal dialysis (PD) can also be utilized in the ICU. An intact peritoneum is required and a temporary or permanent PD catheter is placed. Standard peritoneal dialysis solutions can be used. Clearance is convective and diffusive. Increasing dextrose concentration in the dialysate and increasing frequency of exchanges adjusts the quantity of ultrafiltration. Transport kinetics are likely quite variable between patients and have not been studied in the setting of AKI. Successful peritoneal dialysis has been described in the ICU setting with adequate results,[521] but recently PD has been demonstrated to be inferior to CRRT in AKI due to sepsis and malaria.[522] Peritoneal dialysis offers the advantages of lack of anticoagulation and vascular problems, hemodynamic stability, and are performed with relatively inexpensive and simple systems. The disadvantages include the need for an intact peritoneum, hyperglycemia, potential respiratory embarrassment due to increased abdominal pressure, risk of peritonitis, and less clearance than can be obtained with SLEDD or CRRT.

Prescription and Comparisons of Therapeutic Options

Unlike ESRD, there are no established standards of therapy in AKI. Absence of steady state, variable excesses of body water, variable protein catabolic rates, variable frequency of therapies, and potential lack of correlation of urea as a marker for toxins in AKI hamper quantification of delivered therapy. An adequate dose of dialysis, the lowest clearance that maximizes survival and decreases morbidity, has not been established.

Liao and colleagues modeled the dose capabilities of renal replacement therapies in acute kidney injury.[523] This allows a comparison of removal of urea, inulin, and Beta2 microglobulin between commonly used prescriptions of these extracorporeal therapies. Liao and co-workers modeled clearances of IHD, SLEDD, and CVVH to compare clearances. Based on a 70 kg male with 10 kg of volume excess and an initial BUN of 90 mg/dl, comparisons were modeled with CVVH of 3 liters per hour with pre-filter dilution, daily (6/week) IHD of 4 hours duration with a blood flow of 350 cc/min and dialysate flow of 600 cc/min, and SLEDD performed 7 days per week for 12 hours with a blood flow of 300 cc/min and dialysate flow of 100 cc/min. Using these assumptions the equivalent renal clearance (EKR) of urea, inulin, and Beta2 microglobulin were estimated with each therapy. Relative to SLEDD and daily IHD effective urea clearance was 8% and 60% higher in CVVH (EKR of urea in cc/min with CVVH is 33.7, SLEDD is 31.3 and IHD 21.1). Differences in clearance of middle molecules was even more pronounced in CVVH (EKR of inulin in cc/min was 11.8 with CVVH, 5.4 with IHD, and 3.0 with SLEDD. EKR of Beta2 microglobulin was 18.2 in CVVH, 7.0 in IHD, and 4.2 in SLEDD). These superior middle molecule clearances achievable with CVVH are due to the combination of convective clearance and continuous operation. This prescriptive model must be clinically validated.

Even if the adequate dose of dialysis was known, substantial barriers remain in obtaining this dose. With intermittent hemodialysis, Evanson has shown that delivered dose of dialysis was significantly below prescribed (Kt/V prescribed 1.25+/-0.47 and delivered 1.04+/-0.49).[517] Schiffl and co-workers also noted this in their comparison of daily versus thrice weekly dialysis.[518] This difference between prescribed and delivered dose of dialysis can be attributed to difficulty in obtaining and maintaining blood flows secondary to hemodynamic instability, inability to achieve adequate ultrafiltration, shortened treatment times due to hemodynamic instability or studies, and catheter malfunction. Recently Venkataraman and colleagues have found similar differences between delivered and prescribed delivery in CRRT. In 110 patients the delivered CRRT dose was 68% of the prescribed dose.[524] As opposed to IHD, no treatments were interrupted due to hemodynamic instability, but the authors attributed the low delivery of therapy to recurrent clotting of the CRRT system. Because SLEDD is low flow and of shorter duration, prescribed therapy may be easier to obtain. Significant evidence is lacking, but one recent abstract evaluated delivered versus prescribed Kt/V in 9 patients and found no significant difference between prescribed and delivered dose.[525]

In addition, factors that effect therapy delivery are also machine related. Newer generation of CRRT machines now can increase rates of hemofiltration, dialysis, and hemodiafiltration. The amount and type of clearance delivered in any of these modalities is also influenced by blood flow rate. Increasing blood flow leads to decreased filtration fraction in post-dilution CVVH. Filtration Fraction is equivalent to replacement rate (Qr) divided by plasma flow rate (Qp):

Filtration Fraction=Qr/Qp

Increasing the blood flow in pre-dilution CVVH decreases the dilution fraction. Dilution fraction is equivalent to the flow of blood water (Qbw) divided by the sum of Qbw and replacement rate.

Dilution Fraction=Qbw/(Qbw+Qr)

Thus, increasing blood flow allows for increased clearances achievable in pre- or post-filter CVVH therapies.[526]

Recently an increasing body of evidence suggests that increasing the intensity and therapy dose of RRT in AKI influences outcome.[527] Dosing of intermittent dialysis has rendered some conflicting reports. An early study (1980's) of 34 ICU patients by Gillum and co-workers compared daily intensive therapy versus non-intensive therapy. In this small number of patients there was no difference in survival.[528]

Paganini and colleagues[529] reviewed the outcomes of 844 patients with AKI requiring RRT in the ICU between 1988 and 1994. He described no difference in survival in the most critically ill or those with low severity of illness scores based on dose of dialysis. However in the majority of the patients, those with an intermediate severity of illness score, there was a significant improvement in survival with higher delivery of intermittent dialysis (Kt/V>1.0).

Schiffl and colleagues[518] prospectively compared alternate day to daily dialysis in the ICU. They described a decrease in mortality from 46% to 28% in the patients who received daily dialysis when compared to the alternate day group. They also described a reduction in sepsis and increased rate of renal function recovery in the daily group.

Similarly studies in CRRT also suggest a benefit to increasing the delivery of therapy. Storck and co-workers[530] compared survival in a non-randomized prospective study of CAVH versus CVVH. Survival was significantly higher in the CVVH group and correlated with increasing volumes of ultrafiltration delivered (7.5 liters per day in the CAVH group and 15.5 liters per day in the CVVH group).

More recently, Ronco and colleagues[531] reported the results of a randomized study comparing the dose of therapy in CVVH. Using a lactate-based post filter CVVH system, the differences in outcome in 420 ICU AKI patients randomized to receive replacement fluid rates of 20 cc/kg/hr, 35 cc/kg/hr, and 45 cc/kg/hr. Delivered ultrafiltration rates were 31, 56, and 68 liters per day. Survival was found to be significantly higher in the 35 cc/kg/hr and 45 cc/kg/hr groups (57% and 58%) when compared to the group of patients receiving 20 cc/kg/hr (survival of 41%, p < 0.001). Although not primary endpoints, this study noted prolonged time to death with the higher therapies, BUN at time of initiation was significantly lower in survivors versus non-survivors, and there was a tendency toward improved survival in the septic patients with 45 cc/kg/hr (although the number of septic patients was too small to be significant).

Comparisons of modalities of RRT on AKI are few. Numerous historical control studies have suggested that CRRT may be superior to IHD. However, the data comparing CRRT to IHD is limited. Swartz did compare IHD to CRRT survival in 349 patients in the ICU at the University of Michigan. The study was not randomized and clearly comorbidities were higher in the group receiving CRRT. After adjusting for comorbidities, no difference in survival was seen.[532] Mehta and colleagues performed a prospective randomized multicenter trial comparing CRRT to IHD in 166 patients. Survival was actually higher in the group receiving IHD (58.5% survival in IHD versus 40.5% in CRRT). This study excluded hemodynamically unstable patients and unfortunately the randomization was flawed because the patients in the CRRT group had significantly higher APACHE III scores and a greater percentage of liver failure.[533] Kellum and colleagues have tried to reconcile the differences in an excellent meta-analysis of studies comparing CRRT to IHD. Overall there was no difference in therapy, but when adjusting for studies with relative risk of death and sufficient quality relative risk of death was substantially lower in CRRT. However, the authors concluded that given the quality of studies, there was insufficient evidence to make strong conclusions.[534]

Although studies in the late 1970's and early 1980's demonstrated efficacy of PD when compared to intermittent hemodialysis, these were not randomized nor do they represent current methods of extracorporeal therapy.[521] Phu and associates studied 70 adult patients with AKI from malaria (48 patients) or sepsis (22 patients) in Vietnam. The patients receiving PD had a mortality rate of 47% compared to 15% in the CVVH (p<0.005). Peritoneal dialysis was performed with 2-liter exchanges and only 30-minute dwell times—thus limiting clearance significantly. The patients receiving CVVH were prescribed clearances of only 25 liters per day. The study suggests that peritoneal dialysis is inferior to CVVH in the management of AKI associated with malaria or sepsis.[522]

Acute kidney injury in the ICU requiring RRT is associated with significant mortality and morbidity. Over time etiology of death has changed from that due to complications of uremia to that of complications of co-morbidities. RRT must be prescribed based on the individual patient needs, supporting the patient and allowing for time and other therapies to improve patient recovery. For the time being, local preferences and expertise in general determine the delivery of RRT. In the future, ability to achieve goals of toxin clearance, fluid stabilization, control of electrolyte, and acid base derangements may dictate type, frequency, and duration of extracorporeal therapies.


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