Mechanical Ventilation and Lung–Kidney Interactions

Jay L. Koyner and Patrick T. Murray Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois Clin J Am Soc Nephrol 3: 562-570, 2008. doi: 10.2215/CJN.03090707

t was not so long ago that the term “pulmonary-renal Effects of Mechanical Ventilation and ALI syndrome” was synonymous with the combination of im- on Renal Function I mune alveolar hemorrhage and rapidly progressive glo- Hemodynamic Effects of PPV merulonephritis caused by rare conditions such as Goodpas- In 1947, PPV was first shown to effect renal function and ture’s disease and Wegener’s granulomatosis. Recent perfusion (7). Since this first study involving healthy individ- elucidation of the pathobiology of critical illness has led to a uals receiving continuous positive airway pressure, a variety of more basic mechanistic understanding of the complex interplay mechanisms have been shown to alter cardiac output and result between injured organs in patients with multiple organ dys- in changes of renal perfusion and function (8). While a variety function syndrome; this has been aptly called the “slippery of animal and human studies have produced equivocal results, slope of critical illness” (1). Distant organ effects of apparently there are thought to be two main components contributing to isolated injuries to the lungs, gut, and kidneys have all been the decrease in renal perfusion and function caused by PPV, discovered in recent years. In this article, we review the harm- broadly categorized as hemodynamic and neurohormonal (9– ful bidirectional interaction between acute lung injury (ALI) 12). Increased intrathoracic pressure associated with PPV de- and acute kidney injury (AKI), which appears to be a common creases the venous return to the heart (preload) and may result clinical syndrome with routine clinical implications, rather than in decreased cardiac output (10). This may lead to hypotension a rare autoimmune catastrophe. We will review the current and fluid-responsive shock, which is common in the initial understanding of lung–kidney interactions from both perspec- postintubation period when PPV is initiated. The increase in tives, including the renal effects of ALI and mechanical venti- intrathoracic pressure has been shown to correlate with a de- lation, the pulmonary sequelae of AKI, and the emerging evi- crease in renal plasma flow, glomerular filtration rate (GFR) dence of deleterious bidirectional organ cross-talk between and urine output during PPV (9). This aspect of renal hemody- lung and kidney. namics has in part been validated by the canine work per- formed by Qvist et al., who showed that a stable cardiac output Renal Effects of ALI and Mechanical in the setting of PPV is not associated with a decrease in GFR or Ventilation urine output (13). There are other, clinically occult adverse AKI is an independent predictor of mortality in intensive care hemodynamic effects of PPV in the pulmonary, systemic, and unit (ICU) patients (2). Unfortunately, AKI often develops as a renal circulations. PPV has been shown to compress the medi- component of multiorgan system dysfunction in critically ill astinal structures and pulmonary vasculature and may result in patients and may lead to mortality rates in excess of 60%, increased right ventricular afterload. This may result in a de- depending on the setting (2–5). Severe AKI in critically ill creased cardiac output and a decline in renal perfusion inde- patients is typically part of a triad with shock and respiratory pendent of effects on venous return. Similarly, PPV in patients failure requiring positive pressure mechanical ventilation (6). with increased intrathoracic pressure (injured, stiff lungs or The physiologic impact of positive pressure ventilation (PPV) chest wall) or intra-abdominal pressure (morbid obesity, ab- and its effects on renal perfusion and function are well docu- dominal compartment syndrome) may act to decrease renal mented (7). Recent advances in critical care, including the im- blood flow by increasing renal venous pressure (which dimin- plementation of lung-protective ventilatory strategies, have dis- ishes renal perfusion pressure) and by compressing the renal closed the role of inflammatory mediators of ALI and vasculature leading to AKI (14–16). However, because effects specifically ventilator-induced lung injury in the pathogenesis on cardiac output and renal perfusion are insufficient to fully of AKI. explain the mechanism of PPV-induced oliguria and renal dys- function, other mechanisms have been proposed.

Published online ahead of print. Publication date available at www.cjasn.org. Neurohormonal Effects of PPV Address correspondence to: Dr. Patrick T. Murray, Section of Nephrology, MC PPV has been shown to alter a variety of neurohormonal sys- 5100, Room-511, University of Chicago Hospitals, 5841 South Maryland Avenue, Chicago, IL 60637. Phone: 773-834-0374; Fax: 773-702-5818; E-mail: tems, including sympathetic outflow, the renin-angiotensin [email protected] axis, nonosmotic vasopressin (antidiuretic hormone [ADH])

Copyright © 2008 by the American Society of Nephrology ISSN: 1555-9041/302–0562 Clin J Am Soc Nephrol 3: 562-570, 2008 Mechanical Ventilation 563 release and atrial natriuretic peptide (ANP) production. The Inflammatory Mediators and Ventilator-induced Lung and end result of all of these neurohormonal pathways is dimin- Kidney Injury ished renal blood flow, decreased GFR, and fluid retention (salt ALI is the syndrome of respiratory distress characterized by and water) with oliguria. Despite conflicting data, there is some acute onset, severe hypoxemia, and bilateral radiographic in- evidence that fluid retention is caused by PPV-induced produc- filtrates in the absence of left atrial hypertension (30). Acute tion of vasoactive substances. These mediators shift intrarenal respiratory distress syndrome (ARDS) is the most severe form blood flow from the cortex to the medulla, resulting in greater of ALI, an inflammatory condition characterized by injury to fluid retention at any level of renal perfusion (10,17,18). the pulmonary endothelium and epithelium (31). Mounting ADH release in the setting of PPV is likely multifactorial. evidence points to the role of cytokines and chemokines in the While some evidence suggests that decreased atrial stretch due pathogenesis of ARDS (30,32,33). Emerging data further sug- to the absolute or relative intravascular volume depletion as- gest that the pro-inflammatory effects of PPV may be a source sociated with mechanical ventilation plays a role in the in- of AKI, especially in the setting of mechanical ventilation and creased ADH secretion (19), it is clear that there are more lung-injurious ventilator strategies (higher tidal volumes and factors at play (20). Several experimental denervation proce- lower PEEP) (34–37). Douillet et al. showed that mechanical ventilation itself can alter the nucleotide and purinoceptor ex- dures (cervical, carotid sinus) in animals have blunted the ADH pression in the kidney (38). They used a 4-way rodent model response, but none has been able to abolish it (20,21). Taken (altering tidal volume and PEEP, as well as the use of a placebo) together with evidence that an increase in urine osmolarity is to show that expression of these stress-responsive molecules is not commonly found as a direct effect of PPV, this suggests that altered even in the presence of lung protective mechanical ADH release is not the primary mechanism responsible for the ventilation strategies (38). Since these extracellular ligands, decrease in urine output during PPV. which help control vascular tone and epithelial/endothelial It should come as no surprise that the renin-angiotensin- permeability, are altered by ventilatory strategy, others have aldosterone axis is affected by PPV. PPV has been shown to looked at the cellular and molecular effects of similar measures. increase renin activity in both animal models and humans Imai et al. used a rabbit model of ALI (acid aspiration) with both (9,21,22). Animal denervation studies have shown that in- injurious and noninjurious ventilator strategies and variable creased sympathetic flow indirectly leads to the increase in oxygen and carbon dioxide levels to demonstrate that injurious renin activity (20). Thus, PPV leads to increased sympathetic ventilator strategies precipitate AKI (34). They demonstrated tone, secondary activation of the renin-angiotensin axis, and that injurious mechanical ventilation strategies induced pro- decreased renal plasma flow, GFR, and urine output. Of course, duction of a variety of inflammatory cytokines (IL-8 and mono- downstream stimulation of aldosterone production is among cyte-chemotactic protein-1, among others). They further dem- the salt-retaining effects of PPV. The limited studies investigat- onstrated that this injurious strategy induced epithelial cell ing catecholamine levels and PPV have not provided a clear apoptosis in both the kidneys and intestines, providing con- correlation between mechanical ventilation and hormone con- crete evidence of distant organ cross-talk initiated by ALI. They centrations (23). then showed that plasma from the injurious strategy rabbits Suppression of ANP release has been proposed as a source of induced apoptosis when it was incubated with fresh, healthy the decreased urine volume and sodium content associated rabbit proximal tubular cells (34). Similarly, limited human with PPV. Using a canine model, Ramamoorthy et al. showed studies suggest that ALI and PPV play a major role in AKI that plasma ANP levels correlated with right atrial filling pres- development. In the ARDS Network tidal volume trial, the low Ͻ sures and decreased with the initiation of PPV (P 0.05) (24). tidal volume group had improved survival and ventilator-free While some animal and human studies have supported these days, along with more days without circulatory, coagulation data, other human studies have refuted it (22,25). Of course, and renal failure (renal: 20 Ϯ 11 versus 18 Ϯ 11 d, P ϭ 0.005) even if ANP suppression does play a role in causing PPV- (37). Furthermore, Ranieri et al. showed in a randomized con- induced sodium retention and oliguria, it may not explain the trolled trial of 44 patients with ARDS that a lung protective reported decrease in GFR caused by PPV. mechanical ventilation strategy (lower tidal volumes and There are no definitive therapeutic trials for the treatment of higher PEEP) induced a lesser systemic and intrapulmonary PPV- and positive end expiratory pressure (PEEP)-induced re- inflammatory response (as measured by serum and bronchoal- nal hypoperfusion and AKI. Several small trials have shown veolar lavage fluid levels of TNF-␣, IL-6, and IL-8) than stan- that fluid administration and the use of vasoactive drugs (do- dard of care ventilation (35). Additionally, they were able to pamine at 5 ␮g/kg per min or fenoldopam) may improve renal show that this same lung protective strategy led to fewer pa- function (24,26,27), but results are not consistently positive (for tients with organ system failure, with a greater decrease in the example, no benefit of dopamine at 2 ␮g/kg per min) (28). It is incidence of renal failure (P Ͻ 0.04) than any other organ unlikely that approaches focused solely on the hemodynamic dysfunction (36). The precise pathways and mediators respon- and neurohormonal mechanisms of ALI-induced AKI will be sible for ventilator-induced injury to the kidneys and other clinically effective in preventing or treating this multifactorial organs have not been elucidated. In addition to a variety of problem, and the development of optimal interventional strat- inflammatory cytokines, the nitric oxide pathway has been egies will require more research into the molecular and cellular implicated in this phenomenon. mechanisms involved (29). Nitric oxide, a vasodilator whose metabolites have been 564 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 562-570, 2008 shown to exert systemic and renal cytotoxic effects via oxida- gested approaches to the management of acidemia and alkale- tive stress mediators, has been shown to play key roles in a mia as follows, with an arterial pH goal: 7.30 Յ pH Յ 7.45: variety of cellular functions, including vascular and epithelial Ͼ permeability and apoptosis (39). It is also well documented that 1. Management of alkalemia (pH 7.45): decrease ventilator nonselective inhibition of nitric oxide synthase (NOS) leads to rate, if possible; Յ Ͻ elevated systemic blood pressure and marked renal vasocon- 2. Management of mild acidemia (7.15 pH 7.30); striction. Using a rodent model of ventilator-induced lung in- a. Increase ventilator rate up to a maximum of 35 or until jury, Choi et al. showed that PPV with injurious high tidal Ͼ Ͻ pH 7.30 or PaCO2 25 mmHg. volumes (20 ml/kg) induced NOS expression in both the lung ϭ Ͻ b. If ventilator rate 35 or PaCO2 25, then bicarbonate and the kidney. At the same time, an increase in systemic infusion may be given. microvascular leak was also seen in both organs. This robust detrimental NOS response was blunted when the animals un- 3. Management of severe acidemia (pH Ͻ 7.15); dergoing PPV were adequately fluid resuscitated, and the im- a. Increase ventilator rate to 35. provement in renal function was amplified using the NOS b. If ventilator rate ϭ 35 and pH Ͻ 7.15 and bicarbonate has inhibitor L-NAME (N-nitro-L-arginine methyl ester). In addi- been considered or infused, then tidal volume may be in- tion to changes in NOS and its metabolites, they showed that creased by 1 ml/kg until pH Ն 7.15 (under these conditions, serum vascular endothelial growth factor levels were increased target plateau pressure may be exceeded). in those animals receiving the lung-injurious ventilation; it is known that nitric oxide increases vascular permeability via Unfortunately, details of the frequency and extent to which extracellular signal-regulated kinases 1 and 2 and vascular these guidelines were applied in this landmark trial have not endothelial growth factor (40). Thus, it appears that increased been published. While the available data do not permit an vascular permeability and associated cytokine release are con- analysis of any impact of the use and dose of buffer therapy on tributors to the development of AKI in the setting of PPV. In outcomes, we can infer from the original report that severe summary, the decreased morbidity and mortality of patients acidemia was not commonly encountered. The day 1 pH values with ALI achieved with lung-protective strategies for mechan- for those receiving low tidal volumes were (mean Ϯ SD) 7.38 Ϯ Ϯ ical ventilation are mediated not only by amelioration of ven- 0.08 (with PaCO2 40 10 mmHg), whereas those for the normal Ϯ Ϯ tilator-induced lung injury and inflammation, but also by di- tidal volume group were 7.41 0.07 (with PaCO2 35 8 minished crosstalk and injury to distant organs, including the mmHg). With the pH rising over the course of the next 7 d, kidneys. there was not an apparent need to use bicarbonate therapy during the course of this trial. Nonetheless, the approach to pH management used in this trial seems sensible and was associ- Effects of Permissive Hypercapnia ated with improved outcomes. We suggest that this approach Permissive hypercapnia is a commonly accepted mechanical should be used in clinical practice pending further research in ventilation practice, in which tidal volumes and alveolar ven- this area. Of course, this approach is intended for patients with tilation are reduced to decrease ventilator-induced lung injury ALI, not those with exacerbations of chronically hypercapnic while treating ALI. Although it has been assumed that the pulmonary diseases such as chronic obstructive pulmonary beneficial effects of this lung-protective ventilatory strategy are disease. Many such patients have chronic respiratory acidosis the result of decreased stretch, lower pressure, and less me- with compensatory metabolic alkalosis; bicarbonate should be chanical trauma to injured lung, emerging data suggest an used to maintain their plasma bicarbonate concentration at independent lung-protective effect of permissive hypercapnia. their chronic, pre-exacerbation level (if known), to facilitate Although there are no universally accepted guidelines to guide liberation from mechanical ventilation when superimposed the approach to mechanical ventilation in patients with ALI/ acute respiratory failure has resolved. ARDS, many physicians use the approach that was successful Permissive hypercapnia has a variety of effects, some harm- in the original ARDS Network trial of lower tidal volume ful, others beneficial. In both animal models and human stud- ventilation (37). This approach requires use of a tidal volume of ies, modest hypercapnia has been shown to have reproducible 6 ml/kg of ideal body weight and aims to keep static/plateau hemodynamic effects that are well tolerated and reversible Յ airway pressure 30 cmH2O, requiring permissive hypercap- (41–44). In both canine and human studies, these effects have nia as needed to avoid ventilator-induced lung injury. Yet included a decrease in systemic vascular resistance, and in- despite the use of this approach in clinical practice and in creased cardiac output despite a decrease in cardiac contractil- subsequent ARDS Network trials, the approach to permissive ity (42–44), although these findings are not consistent in all hypercapnia and associated acidosis remains an area of clinical studies (45). One human study evaluated the effects of buffer uncertainty and practice variation. Intensivists, consulting therapy for hypercapnic acidosis. Weber et al. investigated the nephrologists, and other practitioners commonly grapple with use of tromethamine, a buffer that does not generate CO2 questions such as: “How much acidosis is too much acidosis?” (unlike bicarbonate) for this purpose (44). In this human study, and “When should I consider buffering with bicarbonate or they found that tromethamine raised cardiac contractility and renal replacement therapy?” The original ARDS Network low mean arterial pressure (44). Hypercapnia also raises pulmonary tidal volume trial protocol included arterial pH goals and sug- vascular resistance, which is potentially harmful in patients Clin J Am Soc Nephrol 3: 562-570, 2008 Mechanical Ventilation 565 with right ventricular dysfunction, including those with pul- favorably influence the course of ALI, associated ventilator- monary hypertension caused by ARDS (46,47). Hypercapnic induce lung injury, and organ cross-talk between the injured pulmonary vasodilation may also have unfavorable effects on lung and other organs, leading to a protective effect against the ventilation-perfusion matching and result in increased in- development of AKI. Of course, these experimental data raise trapulmonary shunt with worsening oxygenation in ARDS (46). obvious concerns regarding potentially deleterious effects of On the other hand, hypercapnic acidosis also causes a right- the common practice of using sodium bicarbonate infusions or ward shift of the oxygen-hemoglobin dissociation curve and bicarbonate-buffered renal replacement therapy to provide improves tissue oxygen delivery in shock. Thus, although hy- compensation for respiratory acidosis in mechanically venti- percapnic acidosis may cause or aggravate myocardial depres- lated patients with ALI. However, there is no clinical confirma- sion in critically ill patients, it is generally well tolerated, and tion of the putative protective effects of hypercapnic acidosis in buffer therapy should probably be reserved for patients with ALI patients ventilated with low tidal volumes, so the current severe acidemia (pH Ͻ7.15). Caution should be exercised in the approach to acid-base management of these complex patients use of permissive hypercapnia in patients with pulmonary continues to include buffer therapy when severe acidosis de- hypertension and right heart failure, in whom associated pul- velops. We suggest that the guideline for pH management used monary vasoconstriction may have significant adverse hemo- in the ARDS Network low tidal volume trial is an appropriate dynamic effects. Finally, it must be remembered that the use of approach. permissive hypercapnia is contraindicated in patients with raised intracranial pressure (e.g., cerebral edema) because of Pathophysiologic Effects of AKI on associated cerebral vasodilation and increased pressure. Pulmonary Function What are the beneficial effects of hypercapnic acidosis? Re- AKI in the ICU setting is frequently associated with ALI and cent analysis of the ARDS Network tidal volume study data- more specifically ARDS, and the mortality rate of this group is base suggested an intrinsic benefit from hypercapnia itself, approximately 80% (54,55). Despite this high mortality and the independent of the reduction of minute ventilation and airway clear clinical link, few studies have examined the role of the pressures (48). Kregenow et al. (48) showed that the adjusted kidney in the pathogenesis and development of ALI. There are odds ratio for 28-d mortality rate associated with hypercapnic both experimental animal data and limited human study re- Ͻ Ͼ acidosis (defined as pH 7.35 and a PaCO2 45 mmHg) was sults that describe effects of AKI and the use of renal replace- 0.14 (95% confidence interval, 0.03–0.070; P ϭ 0.016) for those ment therapy (RRT) on pulmonary function, including the de- receiving high tidal volumes (12 ml/kg; the injurious ventila- velopment of ALI as a consequence of AKI, and the effects of tion strategy), after controlling for severity of lung injury and RRT on the management and outcomes of patients with ALI comorbidities. Those who received the lung protective strategy combined with renal failure. (6 ml/kg) had an adjusted ratio of 1.18 (P ϭ not significant), suggesting that hypercapnic acidosis was not of additional Pulmonary Effects of AKI benefit in those ventilated with lower, lung-protective tidal Many of the effects of AKI are difficult to identify and quantify volumes. The observed decrease in mortality for those with independently, but experimental data are increasingly elucidat- respiratory acidosis in the high tidal volume arm of the trial is ing the subclinical effects of AKI on distant organ function (56). consistent with other emerging data suggesting an independent It is obvious that problems such as refractory hyperkalemia, protective effect of hypercapnic acidosis in the setting of ALI pulmonary edema, or uremic manifestations such as pericardi- (49–51), and in experimental ischemic-reperfusion injury and tis are related to AKI when they develop acutely in the appro- shock (46,52,53). Several studies have shown that hypercapnic priate setting. Other uremic manifestations may have several acidosis attenuates experimental ALI and ventilator-induced explanations (encephalopathy, acidosis) or may be occult lung injury (49,50). Similarly, in isolated perfused animal causes of other complications (bleeding diathesis and gastroin- hearts, hypercapnic acidosis has been shown to have a dose- testinal bleed, leukocyte dysfunction with immunosuppression dependent protective effect against myocardial ischemia-reper- and nosocomial infection). In addition to the emerging data that fusion injury (53). Similar degrees of metabolic acidosis do not appear to confirm an independent role of AKI in increasing offer the same level of protection from ischemia-reperfusion mortality in the ICU, it is also clinically obvious that AKI is a injury as respiratory acidosis (53). The protective effect of hy- cause of significant morbidity and severely complicates ICU percapnic acidosis may result from the inactivation of calcium management (57). channels (leading to regional vasodilation), a reduction in cel- It is becoming increasingly clear that the inflammatory re- lular oxygen demand (49), or anti-inflammatory effects (50–52). sponse and cytokine cascade that occur in the setting of AKI Hypercapnia can decrease the conversion rate of inhibitor of play a significant role in the development of ALI. Rabb et al. (58) nuclear factor kappa B (I-␬B) to nuclear factor kappa B (NF-␬B), have investigated the mechanisms of the link of AKI and ALI. and accordingly decrease the release of cytokines (IL-8 and They demonstrated, in a 4-way rodent model (unilateral isch- ICAM-1) that are implicated in the pathogenesis of ALI and emic injury, bilateral ischemic injury, bilateral nephrectomy AKI (51). Similarly, hypercapnia and associated intracellular and sham/placebo), that ischemic AKI leads to alteration in acidosis decrease the release of other cytokines (TNF-␣ and pulmonary gene/protein expression (58). Specifically, bilateral IL-1) by inhibition of toll-like receptors (50,52). In summary, ischemic AKI down-regulates the pulmonary expression of all through a variety of mechanisms, permissive hypercapnia may of the following: epithelial sodium channel (eNaC), Na/K 566 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 562-570, 2008

ATPase, and aquaporin-5. It should be noted that unilateral cluding TNF-␣ and pro-inflammatory chemokines) differed be- ischemic injury did not lead to alteration of the pulmonary tween animal models of lung injury, indicating that distinct expression of these proteins, in contrast to bilateral renal isch- inflammatory mediator profiles were involved in the different emia or nephrectomy. Thus, the observed increase of lung injury mechanisms (32). Finally, the phenomenon of distant permeability is likely mediated by a systemic effect of AKI, organ injury resulting in ALI is not unique to renal ischemia, as rather than the dose-dependent effect of the “reperfusion prod- gut ischemia has been shown to alter systemic cytokine levels ucts” of ischemic renal injury (58). Subsequently, a variety of (specifically IL-18) and cause inflammatory ALI (65). Specifi- animal models have shown that pulmonary expression of these cally, a rodent model of gut ischemia/reperfusion induces a proteins (eNaC, Na/K ATPase, and aquaporins) play impor- rapid increase of systemic IL-18, peaking at 1-h postreperfu- tant roles in the salt and water/fluid handling and permeability sion, paralleled by similar inflammation in lung tissue. The of alveolar epithelium, and dysregulation of these mechanisms pulmonary inflammation associated with gut ischemia/reper- may result in the development of ARDS in humans (59–61). fusion can be augmented by the exogenous administration of In mice, Hoke et al. used a similar experimental protocol IL-18 (65). This research is all the more intriguing when one (sham, unilateral renal ischemia, bilateral renal ischemia, and considers that urinary IL-18 has been shown to be an early bilateral nephrectomy) and demonstrated that AKI leads to diagnostic marker for AKI (and mortality) in patients with altered pulmonary cytokine expression (62). Similar to the ARDS (66) and after cardiac surgery (67). above studies, they showed that bilateral ischemic injury and bilateral nephrectomy were associated with statistically signif- icant increases (compared with unilateral injury and sham) in Effects of Fluid Management and Renal several serum cytokine levels (IL-1␤, IL-6, and IL-12). Of note, Replacement Therapy on Pulmonary there were several other cytokines that increased in the setting Function and ALI of bilateral injury or bilateral nephrectomy, but not both, com- Fluid balance impacts pulmonary edemagenesis and oxygen- pared with the same controls (granulocyte macrophage colony- ation in patients with cardiac dysfunction, ALI, renal failure, or stimulating factor, IL-10, and keratinocyte-derived chemo- other causes of pulmonary edema. Retrospective studies have kines) (62). Thus, both models for the acute absence of renal shown that a negative fluid balance in patients with ALI and function displayed similar but uniquely different patterns of pulmonary capillary leak increased the number of ventilator- cytokine expression. Using a similar but not identical protocol, free days (68,69). It is thought to be that decreased pulmonary Hassoun et al. demonstrated that the global gene profiles from capillary hydrostatic pressure and alveolar fluid flux leads to murine lungs exposed to AKI caused by ischemia-reperfusion improved patient oxygenation and lung compliance (70). Pro- or bilateral nephrectomy differed significantly (63). Finally, spective data from a randomized controlled trial of 101 subjects using the bilateral nephrectomy model, Hoke et al. prophylac- found shorter duration of mechanical ventilation and ICU stay tically administered the anti-inflammatory agent IL-10; they in patients with ALI managed with negative fluid balance found prophylaxis with IL-10 decreased the intensity of the titrated according to extravascular lung water measurements inflammatory cascade induced by nephrectomy (62). (71). More recently, Mangialardi et al. found that hypoproteine- Similarly, a rodent ischemia model was used to show that the mia and decreased oncotic pressures worsened patient out- administration of ␣-melanocyte stimulating hormone immedi- comes in the setting of ARDS (72). They subsequently demon- ately before reperfusion (and following ischemic injury) re- strated that the use of a loop diuretic to achieve negative fluid duced both kidney and lung injury. In addition, this prevented balance and improve oxygenation is more effective with the the activation of kidney and lung transcription factors and concomitant use of intravenous albumin; this combination in- decreased the expression of stress response genes (TNF-␣ and creases total plasma protein levels and oncotic pressure more lung intracellular adhesion molecule-1) (64). It is thought that than the diuretic alone (73,74). However, neither of these pro- ␣-melanocyte stimulating hormone acts by inhibition of the spective, randomized, double-blind, placebo-controlled trials activation of transcription factors and stress response genes. was adequately powered (n ϭ 37 and 40) to detect an effect on This emerging data warrants further investigation of the use of patient mortality; nor were they able to show a significant IL-10 and other anti-inflammatory agents as potential therapeu- change in ventilator-free days. The FACTT trial, which is dis- tic options for early AKI. cussed elsewhere in this edition of CJASN, used a 2 ϫ 2 Emerging data continue to underscore the complexity of factorial design to combine two trials in 1000 patients with ALI kidney–lung interaction in AKI. Kim et al. determined in a receiving low tidal volume mechanical ventilation. The second rodent model that ALI following ischemia-reperfusion is dis- of these trials compared the effects of a fluid conservative versus tinct from ALI caused by experimental sepsis (32). Although fluid liberal algorithm (75). Although the fluid conservative both the sepsis and ischemia models lead to increased pulmo- strategy did not improve mortality, the number of ventilator nary vascular permeability and pulmonary histology consistent free-days was significantly increased (75). Details of this trial with ARDS, they were distinct in that the ischemia-induced are discussed by Liu and Matthay in this supplement, but is AKI was associated with lower levels of pulmonary inflamma- should be noted that renal failure requiring dialysis was an tory cell infiltration, and each animal model had significantly exclusion criterion in this trial, and the fluid management al- different expression of a variety of heat-shock proteins. Fur- gorithm and trial protocol participation was suspended if dial- thermore, pulmonary expression of a variety of cytokines (in- ysis-requiring AKI developed following enrollment. Clin J Am Soc Nephrol 3: 562-570, 2008 Mechanical Ventilation 567

Meanwhile, the correct approach to the use of RRT to control when interpreting these data as the study was uncontrolled, it azotemia is increasingly guided by randomized, controlled dos- was conducted in patients with refractory late septic shock, and ing trials (76–78). However, the correct approach to use of RRT only 55% of the study subjects had ALI. Other recent studies to control fluid balance or buffer permissive hypercapnic respi- investigating the role of RRT specifically in ARDS have had ratory respiratory acidosis is not guided by high-level evidence. mixed results, in part because of study design limitations. As discussed above, emerging experimental evidence suggests Ronco et al. retrospectively reviewed 80 cases of septic shock that respiratory acidosis may have protective effects in ALI, associated with ARDS (86). They compared 40 individuals who and buffering with bicarbonate may be harmful, but such cor- received early isovolemic hemofiltration with 40 individuals rection is commonly made with continuous RRT in patients who received conventional therapy. They found that hemofil- with combined ALI and AKI (48,50,52). Of course, support with tration improved oxygenation (as measured by partial pressure renal replacement therapy has many potentially beneficial ef- of oxygen in arterial blood (Pao2)/(fraction of inspired oxygen Ͻ fects with patients with combined AKI and ALI. By extrapola- (Fio2)) (P 0.05) and hemodynamic status (as measured by tion from the literature describing beneficial effects of negative mean arterial pressure and pressor dose) (P Ͻ 0.05). In addition, fluid balance in ALI, the use of intermittent or continuous RRT the subjects receiving the early hemofiltration had shorter ICU to control fluid balance should have benefit in this patient stays (P Ͻ 0.002) and improved 28-d survival (55% versus population. However, there is a lack of clinical trial data to 27.5%, P Ͻ 0.05) (86). Some of these findings were supported by support this assumption. Most trials of RRT to treat patients a smaller uncontrolled, prospective study of 10 children with with ALI have focused on approaches to treat inflammation ARDS associated with cancer therapy. In this trial, only 4 of the rather than achieve negative fluid balance. 10 children had AKI, but all underwent early continuous veno- Continuous hemofiltration with a negative or zero net fluid venous hemodiafiltration to achieve a negative or zero fluid balance has a hypothesized therapeutic benefit in patients with balance. Ninety percent of the subjects achieved resolution of ALI because of its ability to remove inflammatory and humoral their ARDS, with 8 of the 10 patients alive at the 18-mo fol- mediators of AKI (and ALI) from the circulation. In addition, low-up (87). On the other hand, Hoste et al. (84) conducted a patients could derive some therapeutic benefit (improved oxy- retrospective study of 37 patients with AKI and ALI, all of genation/gas exchange) from fluid removal resulting in de- whom underwent continuous venovenous hemodiafiltration. crease pulmonary vascular congestion (lower cardiac filling They found no benefit when comparing hemodynamics (e.g., pressures) if the prescribed therapy maintains even fluid bal- mean arterial pressure, central venous pressure), mechanical ance (i.e., prevents positive fluid balance) or achieves negative ventilation requirements (e.g.,Fio2, PEEP), or gas exchange fluid balance. Several animal models (porcine and canine) have (e.g., partial pressure of oxygen in arterial blood, partial pres- reported success in reducing pulmonary edema via these afore- sure of carbon dioxide in arterial blood) parameters from 24 h mentioned mechanisms (79–82). The models used in these before RRT initiation with those from the first 24 h after initi- studies have varied but include oleic acid-induced ALI (80), ation. Unfortunately, this retrospective study did not deliver endotoxin-induced ALI (79,81), and experimental models of optimal RRT with blood flow rates being set at 100 ml/min and pancreatitis (82). Some of these studies have documented suc- dialysate flow at 1.0 L/h. It is clear that additional prospective cess both clinically as well as via reduced plasma levels of a trials are required to determine the optimal approach to deliv- variety of inflammatory markers, including IL-6 and NF-␬B ery of RRT in the treatment of patients with AKI and ALI (84). (80,82). Similarly, Bellomo et al. showed, in a placebo controlled study of canine endotoxemia/septic shock (independent of Conclusion ALI) that intensive continuous veno-venous hemofiltration It is evident that there is a close relationship between the AKI (CVVH), was able to reduce the serum concentration of endo- and ALI. Increasing evidence points to cross-talk between these thelin-1 and blunt the hypotension (as measured by mean two distant organs and shows that injury to one organ may arterial pressure) associated with sepsis (83). initiate and aggravate injury to the other. Recent data show that Unfortunately human trials, using modern continuous RRT, the kidneys play an important role in the production and have yielded conflicting results. Several studies performed in elimination of mediators of inflammation and ALI. Conversely, the late 1980s and 1990s had conflicting results regarding gas exposure to the inflammatory milieu of ALI and associated exchange and outcomes of patients with ALI receiving RRT ventilator-induced lung injury may precipitate the onset of (84), but some more recent trials have been encouraging. AKI. While there have been recent advances in approaches to Honore et al. conducted a prospective interventional trial to limit ventilator-induced lung injury and decrease the duration examine the effects of short-term, high-volume hemofiltration of mechanical ventilatory support, the net effect of these ad- on 20 patients with septic shock (85). It should be noted that this vances on the incidence and severity of AKI in critically ill trial consisted of an initial 4-h period during which 35 L of patients remains to be determined. Close collaboration between ultrafiltrate was removed and replaced and a net zero fluid intensivists and nephrologists is required to optimize manage- balance was achieved; the patients then went on to receive 96 h ment and improve outcomes of this new “pulmonary-renal of CVVH. This study found that patients who met a preset list syndrome.” of clinical and timed parameters (e.g., mixed venous oxygen saturation, cardiac index) after the initial 4-h period were more Disclosures likely to have improved outcomes. Caution should be used None. 568 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 562-570, 2008

References 19. Gauer OH, Henry JP, Sieker HO, Wendt WE: The effect of 1. Breen D, Bihari D: Acute renal failure as a part of multiple negative pressure breathing on urine flow. J Clin Invest 33: organ failure: the slippery slope of critical illness. Kidney 287–296, 1954 Int Suppl 66[Suppl]: S25–S33, 1998 20. Fewell JE, Bond GC: Renal denervation eliminates the renal 2. Chertow G, Levy E, Hammermeister K, Grover F, Daley J: response to continuous positive-pressure ventilation. Proc Independent association between acute renal failure and Soc Exp Biol Med 161: 574–578, 1979 mortality following cardiac surgery. Am J Med 104: 343– 21. Bark H, Le Roith D, Nyska M, Glick SM: Elevations in 348, 1998 plasma ADH levels during PEEP ventilation in the dog: 3. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, mechanisms involved. Am J Physiol 239: E474–E81, 1980 Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney 22. Andrivet P, Adnot S, Sanker S, Chabrier PE, Macquin- N, Tolwani A, Ronco C: Acute renal failure in critically ill Mavier I, Braquet P, Brun-Buisson C: Hormonal interac- patients: a multinational, multicenter study. JAMA 294: tions and renal function during mechanical ventilation and ANF infusion in humans. J Appl Physiol 70: 287–292, 1991 813–818, 2005 23. Farge D, De la Coussaye JE, Beloucif S, Fratacci MD, Payen 4. Star RA: Treatment of acute renal failure. Kidney Int 54: DM: Interactions between hemodynamic and hormonal 1817–1831, 1998 modifications during PEEP-induced antidiuresis and anti- 5. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, natriuresis. Chest 107: 1095–1100, 1995 Druml W, Bauer P, Hiesmayr M: Minimal changes of se- 24. Ramamoorthy C, Rooney MW, Dries DJ, Mathru M: Ag- rum creatinine predict prognosis in patients after cardio- gressive hydration during continuous positive-pressure thoracic surgery: a prospective cohort study. JAmSoc ventilation restores atrial transmural pressure, plasma Nephrol 15: 1597–1605, 2004 atrial natriuretic peptide concentrations, and renal func- 6. Murray P, Pinsky MR: Renal effect of critical illness, In tion. Crit Care Med 20: 1014–1019, 1992 Intensive Care Unit Nephrology, edited by Murray P, Brady 25. Sata T, Yoshitake J: Increased release of alpha-atrial natri- B, Hall R, London, Taylor & Francis, 2005, pp 47–67 uretic peptide during controlled mechanical ventilation 7. Drury DR, Henry JP, Goodman J: The effects of continuous with positive end-expiratory pressure in humans. J Anesth pressure breathing on kidney function. J Clin Invest 26: 2: 119–123, 1988 945–951, 1947 26. Pannu N, Mehta RL: Mechanical ventilation and renal 8. Pannu N, Mehta RL: Effect of mechanical ventilation on the function: an area for concern? Am J Kidney Dis 39: 616–624, kidney. Best Pract Res Clin Anaesthesiol 18: 189–203, 2004 2002 9. Annat G, Viale JP, Bui Xuan B, Hadj Aissa O, Benzoni D, 27. Poinsot O, Romand JA, Favre H, Suter PM: Fenoldopam Vincent M, Gharib C, Motin J: Effect of PEEP ventilation on improves renal hemodynamics impaired by positive end- renal function, plasma renin, aldosterone, neurophysins expiratory pressure. Anesthesiology 79: 680–684, 1993 and urinary ADH, and prostaglandins. Anesthesiology 58: 28. Kim YJ, Shin CS, Kim JL, Kim JS, Chi HS, Lee EW: Does 136–141, 1983 low dose dopamine attenuate the decrease of renal func- 10. Priebe HJ, Heimann JC, Hedley-Whyte J: Mechanisms of tion in the treatment of patients under controlled mechan- renal dysfunction during positive end-expiratory pressure ical ventilation with positive end expiratory pressure? Yon- ventilation. J Appl Physiol 50: 643–649, 1981 sei Med J 39: 189–195, 1998 11. Mullins RJ, Dawe EJ, Lucas CE, Ledgerwood AM, Banks 29. Kuiper JW, Groeneveld AB, Slutsky AS, Plotz FB: Mechan- SM: Mechanisms of impaired renal function with PEEP. ical ventilation and acute renal failure. Crit Care Med 33: J Surg Res 37: 189–196, 1984 1408–1415, 2005 12. Kaukinen S, Eerola R: Positive end expiratory pressure 30. Meyer NJ, Garcia JGN: Wading into the genomic pool to ventilation, renal function and renin. Ann Clin Res 11: unravel acute lung injury genetics. Proc Am Thorac Soc 4: 58–62, 1979 69–76, 2007 13. Qvist J, Pontoppidan H, Wilson RS, Lowenstein E, Laver 31. Ware LB, Matthay MA: The acute respiratory distress syn- MB: Hemodynamic responses to mechanical ventilation drome. N Engl J Med 342: 1334–1349, 2000 with PEEP: the effect of hypervolemia. Anesthesiology 42: 32. Kim do J, Park SH, Sheen MR, Jeon US, Kim SW, Koh ES, 45–55, 1975 Woo SK: Comparison of experimental lung injury from 14. Doty JM, Saggi BH, Blocher CR, Fakhry I, Gehr T, Sica D, acute renal failure with injury due to sepsis. Respiration 73: Sugerman HJ: Effects of increased renal parenchymal pres- 815–824, 2006 sure on renal function. J Trauma 48: 874–877, 2000 33. Cohen J: The immunopathogenesis of sepsis. Nature 420: 15. Sugerman HJ: Effects of increased intra-abdominal pres- 885–891, 2002 sure in severe obesity. Surg Clin North Am 81: 1063–1075, 34. Imai Y, Parodo J, Kajikawa O, de Perrot M, Fischer S, 2001 Edwards V, Cutz E, Liu M, Keshavjee S, Martin TR, Mar- 16. Shear W, Rosner MH: Acute kidney dysfunction secondary shall JC, Ranieri VM, Slutsky AS: Injurious mechanical to the abdominal compartment syndrome. J Nephrol 19: ventilation and end-organ epithelial cell apoptosis and 556–565, 2006 organ dysfunction in an experimental model of acute re- 17. Moore ES, Galvez MB, Paton JB, Fisher DE, Behrman RE: spiratory distress syndrome. JAMA 289: 2104–2112, 2003 Effects of positive pressure ventilation on intrarenal blood 35. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, flow in infant primates. Pediatr Res 8: 792–796, 1974 Brienza A, Bruno F, Slutsky AS: Effect of mechanical ven- 18. Hall SV, Johnson EE, Hedley-Whyte J: Renal hemodynam- tilation on inflammatory mediators in patients with acute ics and function with continuous positive-pressure venti- respiratory distress syndrome: a randomized controlled lation in dogs. Anesthesiology 41: 452–461, 1974 trial. JAMA 282: 54–61, 1999 Clin J Am Soc Nephrol 3: 562-570, 2008 Mechanical Ventilation 569

36. Ranieri VM, Giunta F, Suter PM, Slutsky AS: Mechanical a key regulator of synovial inflammation. Arthritis Rheum ventilation as a mediator of multisystem organ failure in 44: 1897–1907, 2001 acute respiratory distress syndrome. JAMA 284: 43–44, 52. Coakley RJ, Taggart C, Greene C, McElvaney NG, O’Neill 2000 SJ: Ambient pCO2 modulates intracellular pH, intracellu- 37. ARDSNet: Ventilation with lower tidal volumes as com- lar oxidant generation, and interleukin-8 secretion in hu- pared with traditional tidal volumes for acute lung injury man neutrophils. J Leukoc Biol 71: 603–610, 2002 and the acute respiratory distress syndrome: the Acute 53. Nomura F, Aoki M, Forbess JM, Mayer JE Jr: Effects of Respiratory Distress Syndrome Network. N Engl J Med 342: hypercarbic acidotic reperfusion on recovery of myocar- 1301–1308, 2000 dial function after cardioplegic ischemia in neonatal lambs. 38. Douillet CD, Robinson WP 3rd, Zarzaur BL, Lazarowski Circulation 90: II321–II327, 1994 ER, Boucher RC, Rich PB: Mechanical ventilation alters 54. Chertow GM, Christiansen CL, Cleary PD, Munro C, Laza- airway nucleotides and purinoceptors in lung and ex- rus JM: Prognostic stratification in critically ill patients trapulmonary organs. Am J Respir Cell Mol Biol 32: 52–58, with acute renal failure requiring dialysis. Arch Intern Med 2005 155: 1505–1511, 1995 39. Moncada S, Higgs A: The L-arginine-nitric oxide pathway. 55. Rabb H, Chamoun F, Hotchkiss J: Molecular mechanisms N Engl J Med 329: 2002–2012, 1993 underlying combined kidney-lung dysfunction during 40. Choi WI, Quinn DA, Park KM, Moufarrej RK, Jafari B, acute renal failure. Contrib Nephrol 132: 41–52, 2001 Syrkina O, Bonventre JV, Hales CA: Systemic microvascu- 56. Kelly KJ: Distant effects of experimental renal ischemia/ lar leak in an in vivo rat model of ventilator-induced lung reperfusion injury. J Am Soc Nephrol 14: 1549–1558, 2003 injury. Am J Respir Crit Care Med 167: 1627–1632, 2003 57. Vieira JM Jr, Castro I, Curvello-Neto A, Demarzo S, Caruso 41. Feihl F, Perret C: Permissive hypercapnia: how permissive P, Pastore L, Jr., Imanishe MH, Abdulkader RC, Deheinze- should we be? Am J Respir Crit Care Med 150: 1722–1737, lin D: Effect of acute kidney injury on weaning from me- 1994 chanical ventilation in critically ill patients. Crit Care Med 42. Thorens JB, Jolliet P, Ritz M, Chevrolet JC: Effects of rapid 35: 184–191, 2007 permissive hypercapnia on hemodynamics, gas exchange, 58. Rabb H, Wang Z, Nemoto T, Hotchkiss J, Yokota N, So- leimani M: Acute renal failure leads to dysregulation of and oxygen transport and consumption during mechanical lung salt and water channels. Kidney Int 63: 600–606, 2003 ventilation for the acute respiratory distress syndrome. 59. Ma T, Fukuda N, Song Y, Matthay MA, Verkman AS: Lung Intensive Care Med 22: 182–191, 1996 fluid transport in aquaporin-5 knockout mice. J Clin Invest 43. Walley KR, Lewis TH, Wood LD: Acute respiratory acido- 105: 93–100, 2000 sis decreases left ventricular contractility but increases car- 60. Hummler E, Barker P, Beermann F, Gatzy J, Verdumo C, diac output in dogs. Circ Res 67: 628–635, 1990 Boucher R, Rossier BC: Role of the epithelial sodium chan- 44. Weber T, Tschernich H, Sitzwohl C, Ullrich R, Germann P, nel in lung liquid clearance. Chest 111[Suppl]: 113S, 1997 Zimpfer M, Sladen RN, Huemer G: Tromethamine buffer 61. Hummler E, Barker P, Gatzy J, Beermann F, Verdumo C, modifies the depressant effect of permissive hypercapnia Schmidt A, Boucher R, Rossier BC: Early death due to on myocardial contractility in patients with acute respira- defective neonatal lung liquid clearance in alpha-ENaC- tory distress syndrome. Am J Respir Crit Care Med 162: deficient mice. Nat Genet 12: 325–328, 1996 1361–1365, 2000 62. Hoke TS, Douglas IS, Klein CL, He Z, Fang W, Thurman 45. McIntyre RC Jr, Haenel JB, Moore FA, Read RR, Burch JM, JM, Tao Y, Dursun B, Voelkel NF, Edelstein CL, Faubel S: Moore EE: Cardiopulmonary effects of permissive hyper- Acute renal failure after bilateral nephrectomy is associ- capnia in the management of adult respiratory distress ated with cytokine-mediated pulmonary injury. JAmSoc syndrome. J Trauma 37: 433–438, 1994 Nephrol 18: 155–164, 2007 46. Hickling KG, Joyce C: Permissive hypercapnia in ARDS 63. Hassoun HT, Grigoryev DN, Lie ML, Liu M, Cheadle C, and its effect on tissue oxygenation. Acta Anaesthesiol Scand Tuder RM, Rabb H: Ischemic acute kidney injury induces a Suppl 107: 201–208, 1995 distant organ functional and genomic response distin- 47. Rose CE Jr, Van Benthuysen K, Jackson JT, Tucker CE, guishable from bilateral nephrectomy. Am J Physiol Renal Kaiser DL, Grover RF, Weil JV: Right ventricular perfor- Physiol 293: F30–F40, 2007 mance during increased afterload impaired by hypercap- 64. Deng J, Hu X, Yuen PS, Star RA: Alpha-melanocyte-stim- nic acidosis in conscious dogs. Circ Res 52: 76–84, 1983 ulating hormone inhibits lung injury after renal ischemia/ 48. Kregenow DA, Rubenfeld GD, Hudson LD, Swenson ER: reperfusion. Am J Respir Crit Care Med 169: 749–756, 2004 Hypercapnic acidosis and mortality in acute lung injury. 65. Yang YJ, Shen Y, Chen SH, Ge XR: Role of interleukin 18 in Crit Care Med 34: 1–7, 2006 acute lung inflammation induced by gut ischemia reperfu- 49. Kavanagh BP, Laffey JG: Hypercapnia: permissive and sion. World J Gastroenterol 11: 4524–4529, 2005 therapeutic. Minerva Anestesiol 72: 567–576, 2006 66. Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL: 50. Laffey JG, Tanaka M, Engelberts D, Luo X, Yuan S, Urine IL-18 is an early diagnostic marker for acute kidney Tanswell AK, Post M, Lindsay T, Kavanagh BP: Therapeu- injury and predicts mortality in the intensive care unit. tic hypercapnia reduces pulmonary and systemic injury J Am Soc Nephrol 16: 3046–3052, 2005 following in vivo lung reperfusion. Am J Respir Crit Care 67. Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Med 162: 2287–2294, 2000 Q, Kelly C, Dent C, Devarajan P, Edelstein CL: Urinary 51. Tak PP, Gerlag DM, Aupperle KR, van de Geest DA, IL-18 is an early predictive biomarker of acute kidney Overbeek M, Bennett BL, Boyle DL, Manning AM, Fire- injury after cardiac surgery. Kidney Int 70: 199–203, 2006 stein GS: Inhibitor of nuclear factor kappaB kinase beta is 68. Alsous F, Khamiees M, DeGirolamo A, Amoateng-Adje- 570 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 562-570, 2008

pong Y, Manthous CA: Negative fluid balance predicts Kocher F: The consequences of continuous haemofiltration survival in patients with septic shock: a retrospective pilot on lung mechanics and extravascular lung water in a por- study. Chest 117: 1749–1754, 2000 cine endotoxic shock model. Intensive Care Med 17: 293–298, 69. Schuster DP: The case for and against fluid restriction and 1991 occlusion pressure reduction in adult respiratory distress 80. Su X, Bai C, Hong Q, Zhu D, He L, Wu J, Ding F, Fang X, syndrome. New Horiz 1: 478–488, 1993 Matthay MA: Effect of continuous hemofiltration on he- 70. Lewis CA, Martin GS: Understanding and managing fluid modynamics, lung inflammation and pulmonary edema in balance in patients with acute lung injury. Curr Opin Crit a canine model of acute lung injury. Intensive Care Med 29: Care 10: 13–17, 2004 2034–2042, 2003 71. Mitchell JP, Schuller D, Calandrino FS, Schuster DP: Im- 81. Ullrich R, Roeder G, Lorber C, Quezado ZM, Kneifel W, proved outcome based on fluid management in critically ill Gasser H, Schlag G, Redl H, Germann P: Continuous veno- patients requiring pulmonary artery catheterization. Am venous hemofiltration improves arterial oxygenation in Rev Respir Dis 145: 990–998, 1992 endotoxin-induced lung injury in pigs. Anesthesiology 95: 72. Mangialardi RJ, Martin GS, Bernard GR, Wheeler AP, 428–436, 2001 Christman BW, Dupont WD, Higgins SB, Swindell BB: 82. Yan XW, Li WQ, Wang H, Zhang ZH, Li N, Li JS: Effects of Hypoproteinemia predicts acute respiratory distress syn- high-volume continuous hemofiltration on experimental drome development, weight gain, and death in patients pancreatitis associated lung injury in pigs. Int J Artif Organs with sepsis. Ibuprofen in Sepsis Study Group. Crit Care 29: 293–302, 2006 Med 28: 3137–3145, 2000 83. Bellomo R, Kellum JA, Gandhi CR, Pinsky MR, Ondulik B: 73. Martin GS, Mangialardi RJ, Wheeler AP, Dupont WD, The effect of intensive plasma water exchange by hemofil- Morris JA, Bernard GR: Albumin and furosemide therapy tration on hemodynamics and soluble mediators in canine in hypoproteinemic patients with acute lung injury. Crit endotoxemia. Am J Respir Crit Care Med 161: 1429–1436, Care Med 30: 2175–2182, 2002 2000 74. Martin GS, Moss M, Wheeler AP, Mealer M, Morris JA, 84. Hoste EA, Vanholder RC, Lameire NH, Roosens CD, De- Bernard GR: A randomized, controlled trial of furosemide cruyenaere JM, Blot SI, Colardyn FA: No early respiratory with or without albumin in hypoproteinemic patients with benefit with CVVHDF in patients with acute renal failure acute lung injury. Crit Care Med 33: 1681–1687, 2005 and acute lung injury. Nephrol Dial Transplant 17: 2153– 75. Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, 2158, 2002 Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Hara- 85. Honore PM, Jamez J, Wauthier M, Lee PA, Dugernier T, bin AL: Comparison of two fluid-management strategies in Pirenne B, Hanique G, Matson JR: Prospective evaluation acute lung injury. N Engl J Med 354: 2564–2575, 2006 of short-term, high-volume isovolemic hemofiltration on 76. Ronco C, Bellomo R, Homel P, Brendolan A, Dan M, Pic- the hemodynamic course and outcome in patients with cinni P, La Greca G: Effects of different doses in continuous intractable circulatory failure resulting from septic shock. veno-venous haemofiltration on outcomes of acute renal Crit Care Med 28: 3581–3587, 2000 failure: a prospective randomised trial. Lancet 356: 26–30, 86. Piccinni P, Dan M, Barbacini S, Carraro R, Lieta E, Marafon 2000 S, Zamperetti N, Brendolan A, D’Intini V, Tetta C, Bellomo 77. Schiffl H, Lang SM, Fischer R: Daily hemodialysis and the R, Ronco C: Early isovolaemic haemofiltration in oliguric outcome of acute renal failure. N Engl J Med 346: 305–310, patients with septic shock. Intensive Care Med 32: 80–86, 2002 2006 78. Palevsky PM, O’Connor T, Zhang JH, Star RA, Smith MW: 87. DiCarlo JV, Alexander SR, Agarwal R, Schiffman JD: Con- Design of the VA/NIH Acute Renal Failure Trial Network tinuous veno-venous hemofiltration may improve survival (ATN) Study: intensive versus conventional renal support from acute respiratory distress syndrome after bone mar- in acute renal failure. Clin Trials 2: 423–435, 2005 row transplantation or chemotherapy. J Pediatr Hematol 79. Stein B, Pfenninger E, Grunert A, Schmitz JE, Deller A, Oncol 25: 801–805, 2003