Prerenal Causes

Prerenal azotemia is a consequence of reduction in renal perfusion without cellular injury. As such, this is a reversible process if the underlying cause is corrected. It may be secondary to decreased blood volume, as occurs with vomiting, dehydration, and hemorrhage, or it may be due to a reduction in the effective arterial blood volume, as in congestive heart failure and cirrhosis. Further, the administration of medications that interfere with the normal autoregulatory ability of the kidney can contribute to prerenal azotemia. In settings of diminished renal perfusion, administration of nonsteroidal antiinflammatory drugs (NSAIDs) or angiotensin-converting enzyme (ACE) inhibitors can precipitate overt prerenal azotemia.³

During prerenal azotemia, the renin-angiotensin-aldosterone system becomes activated secondary to a decrease in renal blood flow accompanied by increased activity of the adrenergic nervous system. Increased levels of angiotensin II and adrenergic activation serve to increase the proximal reabsorption of sodium, whereas aldosterone increases sodium reabsorption in the distal tubule. Together these actions decrease urine sodium concentration to less than 20 mmol/L and fractional excretion of sodium (FE_Na) to less than 1%.⁵

Prerenal azotemia accounts for approximately 70% of community-acquired cases of AKI⁶ and 40% of hospital-acquired cases.⁷ Therefore, prerenal causes should be excluded in all cases of AKI. Therapy of prerenal AKI involves reversing the underlying cause, such as volume replacement or discontinuation of offending agents.

Postrenal Causes

Postrenal AKI occurs when there is bilateral (or unilateral in the case of a single kidney) obstruction of urine flow. Intratubular pressure increases and in turn decreases net glomerular filtration pressure. Obstruction of urine flow is a relatively uncommon cause of AKI and is more common in the community than in the intensive care unit (ICU). Several series have placed the incidence of postrenal AKI at 3% to 25% of all cases of AKI.^8,9,10 Postrenal AKI can be divided into renal and extrarenal causes. Extrarenal causes include prostatic disease, pelvic malignancy, and retroperitoneal disorders. Intrarenal causes include crystal deposition, as occurs in ethylene glycol ingestion, or uric acid nephropathy in tumor lysis syndrome. Cast formation and tubular obstruction also occur in light-chain diseases such as multiple myeloma.

Postrenal causes of AKI should be evaluated with renal ultrasonography and measurement of postvoid residual urine in the bladder (>50 mL is abnormal). It is important to rule out these causes rapidly, because the potential for renal recovery is inversely related to the duration of obstruction.¹¹

Intrarenal Causes

Intrarenal causes of AKI can be classified according to the anatomic location of the injury: glomerulus, tubule, vasculature, or interstitium. Suspicion of glomerulonephritis or vasculitis should be raised in a patient with renal failure who has an active urine sediment with red cells and red cell casts. In contrast, acute interstitial nephritis classically presents with pyuria and white cell casts in the urine; on occasion, hematuria is also present. Most cases of AKI from interstitial nephritis are drug related, commonly due to antibiotics or NSAIDs. Recovery usually occurs with removal of the offending agent and may be hastened by a short course of steroids, such as 60 to 80 mg of prednisone for 10 days. Tubular injury is most often either ischemic or toxic in nature and presents as acute tubular necrosis (ATN). This is the most common form of AKI encountered in the hospital and ICU^10,12,13 and is the focus of this chapter.

In ischemic AKI, there is both tubular and vascular injury. In the tubules, an increase in intracellular calcium after ischemic injury activates the cysteine proteases calpain and caspase. This leads to necrosis and apoptosis as well as relocation of Na⁺/K⁺-ATPase from the basolateral membrane to the cytosol. This relocation interferes with normal vectorial transport of sodium and increases distal delivery of sodium chloride (NaCl). An increase in delivery of NaCl to the macula densa in the distal tubule activates tubuloglomerular feedback and further decreases GFR. Further, ischemia increases production of nitric oxide, which also causes cellular damage and detachment of epithelial cells from the basement membrane. Much of the deleterious action of nitric oxide is mediated through the generation of peroxynitrite from the combination of reactive oxygen species and nitric oxide. Cellular detachment is responsible for cast formation and tubular obstruction. These mechanisms all independently contribute to the decrease in renal function seen in ATN.¹⁴

In ischemic injury, the vascular endothelium is damaged and displays an exaggerated response to vasoconstrictor stimuli such as angiotensin II and endothelin-1 and a decreased response to vasodilators such as acetylcholine and bradykinin. In addition, there is a loss of autoregulatory capability. This loss of autoregulation in the setting of otherwise minor hemodynamic changes is likely responsible for the fresh ischemic lesions often seen on biopsy when recovery from AKI is delayed.¹⁵

The kidney’s susceptibility to toxic injury can be attributed to its functional properties. The kidneys receive 20% to 25% of the cardiac output, and there is extensive reabsorptive capacity as well as concentrating ability. All these factors contribute to the delivery of large amounts of toxin to the tubular epithelial cells. In addition, there is extensive biotransformation, generating toxic metabolites, and the high energy consumption with marginal oxygen delivery renders the tubules susceptible to toxic injury.¹⁶

An increasingly common form of AKI in the hospital is secondary to the use of contrast media. Nash and colleagues found contrast nephropathy to be the third most common form of AKI in the hospital.⁷ The pathogenesis involves both hemodynamic and toxic effects. Contrast media cause renal vasoconstriction and medullary ischemia as well as direct tubular toxicity.¹⁷ Patients with preexisting renal disease and diabetes are at high risk, as are patients who are volume depleted.

Differentiation of ATN from prerenal azotemia can be aided by evaluating urinary indices (Table 114-1).¹⁸ In established ATN, tubular function is impaired, and tubular sodium reabsorption is hindered. This results in a urine sodium value greater than 40 mmol/L and an FE_Na greater than 2%. Urine concentrating ability is also abnormal, resulting in isosthenuria with urine osmolality less than 350 mOsm/kg H₂O.¹⁹ However, a low FE_Na may be seen in entities causing ATN, such as rhabdomyolysis and myoglobinuria,²⁰ as well as in contrast-mediated AKI²¹ and sepsis.²² In patients with prerenal azotemia who are treated with diuretics that may obscure the FE_Na, fractional excretion of urea (FE_Urea) or urine-to-plasma ratio of creatinine may be more discriminatory. An FE_Urea less than 35% or a urine-to-plasma ratio of creatinine higher than 15 is indicative of prerenal azotemia.²³ However, a subsequent study indicates that in patients with AKI administered diuretics, the distinction between transient and persistent AKI cannot be made accurately by means of FE_Urea because it lacks specificity.²⁴

TABLE 114-1 Laboratory and Microscopic Findings in Prerenal Azotemia and Acute Tubular Necrosis

Data from Esson ML, Schrier RW. Diagnosis and treatment of acute tubular necrosis. Ann Intern Med 2002;137:744-52.

Epidemiology

When the RIFLE criteria (risk, injury, failure, loss, end-stage renal failure) are employed, AKI is a common complication occurring in up to a third of ICU patients and is usually a manifestation of multiorgan failure syndrome.^25–27

The most common cause of intrinsic renal failure is ATN.³ Specific causes of ATN can be classified as hemodynamically mediated AKI, such as in prolonged prerenal azotemia, hypotension, and sepsis; toxic AKI, secondary to antibiotics, chemotherapeutic agents, and contrast media; or postsurgical AKI. In a large prospective analysis by Liano and coworkers, sepsis was the most common cause (35%); postsurgical (25%) and toxic (31%) causes were also common.¹⁰ Many, if not most, patients have a multifactorial cause of AKI (Figure 114-1). Despite ever-improving supportive interventions in the ICU, the mortality rate for AKI has not changed in the last 3 decades, remaining at 40% to 80% depending on the study.²⁸ It has been hypothesized that this continued poor prognosis is due to the changing patient population cared for in the ICU. Today, patients are older with greater comorbidities, and their renal disease most often develops in the setting of multiorgan failure.^10,29 This high incidence of multiorgan failure has made it difficult to discern whether AKI itself causes increased mortality or whether it is a marker of severely ill patients. Several recent studies have found that AKI does in fact contribute to excess mortality in the setting of contrast nephropathy and cardiac surgery.^30,31 In those patients who do survive, there is significant morbidity, with about 33% requiring long-term renal replacement therapy (RRT) and 28% requiring long-term institutionalization.³² As explained later, increasing RIFLE severity grades correspond with increasing mortality in patients. Hoste et al. reported that patients with a maximum score of RISK had a mortality rate of 8.8%, compared to 11.4% for INJURY and 26.3% for FAILURE. On the other hand, patients who had no evidence of AKI had a mortality rate of 5.5%.³³

Figure 114-1 Pathophysiology of ischemic acute kidney injury (AKI). Interacting microvascular and tubular events contribute to the physiology of ischemic acute renal failure. PGE2, prostaglandin E2.

(Adapted from Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of ischemic acute renal failure. J Am Soc Nephrol 2003;14:2199-210.)

The risk of developing AKI in the ICU was evaluated by de Mendonca and associates, who found that seven characteristics, if present on admission, were associated with a high risk of developing AKI (Table 114-2).²⁹ Several other studies addressed risk factors for mortality in the setting of AKI.^7,10,12,34 As indicated in Table 114-3, the risk of death in those with AKI is increased by the presence of nonrenal organ failure; more severe renal dysfunction, as indicated by oliguria; sepsis; advanced age; and male gender. Liano and colleagues found that as the number of organ failures increased, mortality increased.¹⁰ With two organ failures, mortality was 53%; this increased to 80% with three organ failures and 100% with five organ failures.

TABLE 114-2 Risk Factors for Developing Acute Kidney Injury

Adapted from de Mendonca A et al. Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score. Intensive Care Med 2000;26:915-21.

TABLE 114-3 Risk Factors for Mortality in Acute Kidney Injury

To further stratify the probability of death in critically ill patients, several severity-of-illness scoring systems have been developed. These indices help compare patients enrolled in clinical trials and better utilize finite resources to help those patients with the best chance of recovery. In large populations, these scoring indices have been successful in predicting outcome³⁵; however, they do not discriminate well in patients with AKI.³⁶ The renal parameters used in these scores consist of blood urea nitrogen (BUN), serum creatinine, and total urine output per day. With the latest version of the Acute Physiology and Chronic Health Evaluation (APACHE III), oliguric AKI constitutes just 12.7% of the maximal score, thereby underestimating the effect of AKI on mortality.³⁷ Further, there is no correction for patients with AKI and a low serum creatinine, who also have a poor outcome, probably reflective of poor nutritional status.³⁷ An attempt has therefore been made to develop more disease-specific indices, such as Liano and colleagues’ individual severity index, the Cleveland Clinic Foundation severity score, and the Project to Improve Care in Acute Renal Disease index. The majority of these indices were developed at single centers, and few have been validated outside the original institution. Also, the patient populations to which the indices were applied have differed, such as using all AKI patients or only dialyzed patients. Thus, there is no completely generalizable, validated bedside predictor for mortality in AKI patients.

Definition

Acute renal failure (ARF) has traditionally been defined as an abrupt decrease in GFR with resultant retention of urea and other nitrogenous waste products along with dysregulation of body fluids and electrolytes. However, this is only a qualitative definition and not very helpful clinically, where a quantitative definition is required. Until recently, no agreement existed about how to best define, characterize, and study acute renal failure. This lack of a standard definition has been a major hindrance to the progress of clinical and basic research in this field. The term acute kidney injury was proposed by the Acute Kidney Injury Network (AKIN) as an alternative to ARF in order to encompass the entire range of failure based on recent data showing that a small change in serum creatinine influences outcome. The Acute Dialysis Quality Initiative (ADQI) was created to develop consensus and evidence-based guidelines for treatment and prevention of acute renal failure, with the goal of comparing studies and advancing research.³⁸ The ADQI group proposed a consensus categorized definition—the RIFLE criteria³⁹—which were validated and shown to correlate with hospital mortality and patient outcomes in several populations in large international databases. Subsequently, AKIN proposed a revision of the RIFLE criteria^40,41,42 to better account for small changes in serum creatinine not captured by RIFLE. The following modifications were made (Table 114-4):

Existing evidence supports the validity of both RIFLE and AKIN criteria to identify groups of hospitalized patients with increased risk of death and/or need for RRT.^39,40,46 Staging of AKI is relevant because with increased stage of AKI, the risk of death increases. Moreover, there is now mounting evidence of long-term risk of subsequent development of cardiovascular disease or chronic kidney disease and mortality even after resolution of AKI.⁴⁷ Lo et al. recently studied the long-term sequelae of AKI in a retrospective analysis of the large Kaiser Permanente database using the years 1996-2003.⁴⁸ This paper explored AKI and its correlation with long-term kidney disease and mortality in comparison with enrollees of the same healthcare organization who did not develop AKI and served as controls. Compared with controls, patients who suffered dialysis-dependent AKI during their hospitalization had a 28-fold increased risk of developing stage 4 or 5 CKD. There was also a more than twofold long-term risk of death in this group.

Given the difficulties of measuring function as an index of injury, there has been a search for identifying kidney injury markers of critically ill patients. This approach would be optimal because it could identify patients early in the course of AKI who would benefit from intervention. Several biomarkers have been proposed and are currently being investigated.^49–51 These biomarkers include:

Further studies are required to establish any of these or other potential biomarkers as practical diagnostic tools in the early clinical diagnosis of AKI. Such tools should facilitate timely and aggressive therapeutic interventions. Currently, urine sediment (i.e., epithelial cells) and urine indices (i.e., FE_Na) are early and sensitive harbingers of ATN.

Treatment

In light of its dismal outcome, it is imperative that therapies to prevent or ameliorate AKI be developed. To that end, several trials for both prevention and treatment of AKI have been conducted with multiple agents.

With the increasing use of contrast agents in diagnostic and therapeutic procedures, prevention of contrast-mediated nephropathy has been studied extensively. Intravenous fluids have long been used to prevent contrast nephropathy, but in patients with chronic renal insufficiency, the incidence is still high. Therefore, multiple other agents have been studied. Solomon and coworkers found that both furosemide and mannitol when given with saline produced a worse outcome than saline alone in patients with chronic renal insufficiency.⁵⁸ Dopamine⁵⁹ and atrial natriuretic peptide⁶⁰ have also failed to reduce contrast nephropathy. Two agents, acetylcysteine⁶¹ and fenoldopam,⁶² were found to decrease the incidence of contrast nephropathy in high-risk patients, but these findings were not verified in a study by Allaqaband and associates.⁶³ In that trial, acetylcysteine and fenoldopam offered no additional benefit in patients with chronic renal insufficiency undergoing cardiovascular procedures. Landoni et al. recently performed a meta-analysis of 16 randomized trials of fenoldopam versus placebo or dopamine in 1290 patients who were in a variety of ICU or perioperative settings. They found that fenoldopam reduced the need for renal replacement and mortality in patients with AKI. However, because of the small size and heterogeneity of the studies included, a large multicenter appropriately powered trial will be needed to better define the role of fenoldopam in AKI.⁶⁴ Currently, our recommendation for preventing contrast nephropathy in high-risk patients (Table 114-5) is adequate hydration, preferably with isotonic sodium bicarbonate,^65,66,67 administration of 1200 mg acetylcysteine orally twice daily the day before and day of the procedure (given its tolerability and relative low cost), and the use of low-osmolar⁶⁸ or iso-osmolar⁶⁹ contrast media.

TABLE 114-5 Risk Factors for Contrast Nephropathy

Dopamine has long been used to treat AKI. The renal effects of dopamine include an increase in GFR and an increase in sodium and water excretion. Clinically, the first response is an increase in diuresis.⁷⁰ These responses occur in patients with normal renal function, but it is unknown whether they are also seen in those with AKI. In patients with early renal dysfunction (serum creatinine > 1.8 mg/dL or urine output < 0.5 mL/kg/h), dopamine did not alter peak serum creatinine or the need for RRT.⁷¹ This was confirmed in a meta-analysis to determine whether progression of AKI, need for RRT, or mortality were affected by dopamine.⁷²

Aside from its lack of efficacy in AKI, dopamine has deleterious side effects. It hastened the onset of gut ischemia in an experimental model,⁷³ and clinically it worsened contrast nephropathy.⁷⁴ In cardiac surgery patients, dopamine was independently associated with an increased risk of postoperative atrial fibrillation.⁷⁵ Higher doses may increase mortality,⁷⁶ perhaps by worsening myocardial ischemia.⁷⁷ Therefore, low-dose dopamine currently has no role in the treatment or prevention of AKI.

Diuretics are also frequently used in patients with AKI, especially in an attempt to convert oliguric into nonoliguric AKI, given the improved prognosis of the latter.^78–80 Loop diuretics, most commonly furosemide, inhibit Na⁺/K⁺-ATPase in the thick ascending loop of Henle and therefore decrease the active reabsorption of sodium. Theoretically, this has some potential benefits, such as decreasing energy expenditure and increasing flow rate to flush out tubular casts. In the experimental setting, loop diuretics can be protective if administered before the insult. However, even when patients are successfully converted to nonoliguria, there is no reduction in the need for RRT or mortality.^81,82 Cantarovich and colleagues studied the role of high-dose loop diuretics in a placebo-controlled clinical trial of 388 dialysis-requiring AKI patients. Despite the increase in urine output, there were no differences between the two groups in terms of patient survival, renal recovery rates, number of dialysis sessions required, or time on dialysis. In addition, cardiac surgery patients and patients with contrast nephropathy who were treated with furosemide had a worse outcome.^83,84 A study by Mehta and coworkers found an increased mortality in AKI patients treated with diuretics.⁸⁵ It is unclear why this occurred, but the authors speculated about a possible nephrotoxic effect of diuretics or a delay in the initiation of RRT because of increased urine output. However, the increased mortality occurred in patients who were not diuretic responsive, likely because of more severe AKI. These patients already had a worse prognosis, and whether diuretics may have worsened the outcome is unknown. Ho et al. recently conducted a comprehensive systematic review of the use of furosemide in AKI.⁸⁶ They have shown that furosemide is not associated with any significant clinical benefits in the prevention or treatment of ARF in adults. High doses may be associated with an increased risk of ototoxicity. Although the use of loop diuretics in early or established AKI facilitates management of fluid balance, hyperkalemia, and hypercalcemia, and is indicated for these clinical purposes, any putative role in prevention or amelioration of AKI course is unproven. Therefore, if diuretics are temporarily employed for such indications, care must be taken to avoid delaying initiation of dialysis if clinically necessary.

Atrial natriuretic peptide is a hormone secreted by the cardiac atria that increases GFR and glomerular filtration pressure by dilating the afferent arteriole and constricting the efferent arteriole.⁸⁷ It also decreases tubular reabsorption of sodium and chloride,⁸⁸ redistributes medullary blood flow,⁸⁹ disrupts tubuloglomerular feedback,⁹⁰ and reverses endothelin-induced vasoconstriction.⁹¹ Mentzer and colleagues studied the perioperative effects of nesiritide (BNP type) in 303 patients with left ventricular dysfunction who were undergoing coronary artery bypass graft.⁹² They demonstrated short-term benefits of nesiritide on perioperative renal function as assessed by an attenuated increase in levels of serum creatinine, a reduction in calculated GFR loss, and a greater urine output 24 hours after surgery. This trial and other reports that have studied administration of natriuretic peptides during cardiac surgery were recently reviewed by Murray, who emphasized that in addition to such surrogate renal endpoints, future studies must demonstrate beneficial effects on overall survival and/or dialysis-free survival.⁹³ Pending further studies, atrial natriuretic peptide cannot be recommended for prevention or therapy of ATN.

Hemodynamic Management

Intravascular volume is critical in maintaining hemodynamic stability, tissue oxygenation, and organ function.⁹⁴ In critically ill patients, it is increasingly being recognized that accurate assessment of volume status and appropriate use of fluid replacement may lead to better outcomes. In a study by Rivers and associates, it was shown that early goal-directed therapy (EGDT) based on optimizing the mixed control venous oxygen saturation in the first 6 hours resulted in decreased mortality in septic patients.⁹⁵ Subsequent studies have replicated those results,^96,97 and one of them showed a significantly improved prevention of AKI in patients randomized to EGDT compared to the standard care group.⁹⁸ However, supranormal levels of cardiac index or mixed venous oxygen saturation did not decrease mortality.⁹⁹ In addition, studies have shown increased mortality in patients with positive fluid balance and acute respiratory distress syndrome (ARDS).^100–102

We have coined the term pseudo- or pre-ARDS to focus on a common and clinically important situation in ICUs. Just as prolonged prerenal azotemia may eventually lead to ischemic ATN, prolonged pseudo- or pre-ARDS may lead to ARDS in association with evidence of pulmonary capillary damage and stiff lungs, as diagnosed clinically by a decrease in pulmonary compliance. Thus, pseudo- or pre-ARDS describes a clinical syndrome of noncardiogenic pulmonary edema in the absence of evidence of decreased pulmonary compliance. Although many clinicians group these clinical entities together as ARDS—independent of pulmonary compliance—we believe that from a pathophysiologic, prognostic, and therapeutic viewpoint, these clinical entities may be substantially different.

Both pseudo-ARDS and ARDS are frequently associated with sepsis. Sepsis is a vasodilated state in which systemic vascular resistance decreases and cardiac output increases. Studies in renal experimental animals have shown that vasodilatation with an arterial vasodilator such as minoxidil is associated with an increased albumin distribution space and a failure of interstitial hydrostatic pressure to rise during saline administration.¹⁰³ These changes in interstitial Starling forces favor an increase in interstitial fluid volume during saline infusion. We frequently consult on ventilated ICU patients with AKI who have a 20-L positive fluid balance that has not been recognized in a quantitative sense because the pulmonary capillary wedge pressures are not considered elevated (<18 mm Hg). Excess saline fluid has been administered to resuscitate these vasodilated septic patients, leading to pulmonary edema, hypoxia, and ventilatory support. In the early stages, the majority of these patients do not have decreased pulmonary compliance (i.e., stiff lungs). However, these septic ICU patients with renal failure on prolonged respiratory support ultimately have a mortality as high as 80%. Patient mortality has been reported to begin increasing after 48 hours on a respirator. The potential barotrauma, oxygen toxicity, and pulmonary infections that may occur with prolonged ventilatory support frequently lead to stiff lungs and what virtually all authorities would term bona fide ARDS.

We believe that not distinguishing clinically between pseudo-ARDS and ARDS may be detrimental to ICU patients. Marked improvement in the pulmonary edema of pseudo-ARDS by diuresis or ultrafiltration may allow much earlier extubation and removal of ventilatory support before the development of pulmonary capillary damage and stiff lungs (i.e., ARDS). With ARDS and prolonged ventilatory support, a very high mortality occurs, particularly in the presence of renal failure and thus multiorgan failure. Recently, Bouchard and colleagues have reported results of a prospective multicenter observational study of 618 patients that aimed to determine whether fluid overload (>10% increase in body weight) in critically ill patients with AKI is associated with increased mortality. After adjustment for severity of illness, the study has shown that fluid overload was independently associated with mortality in those AKI patients who did and did not receive dialysis therapy.¹⁰⁴ A randomized study by the ARDS clinical trials network demonstrated that pulmonary function in critically ill patients was worse in those treated with a liberal fluid management strategy (to achieve a mean central venous pressure [CVP] of ∼12 mm Hg) than in those who were treated with a conservative strategy (to achieve a mean CVP ∼8 mm Hg).¹⁰⁵ Moreover, fewer patients in the conservative strategy group required dialysis than in the liberal strategy group. Several pediatric studies comprising more than 400 children have demonstrated an association between worsening fluid overload (higher than 10% to 20%) and mortality.^106–108 Thus, there are reasons to believe that fluid overload is not just a marker but rather a pathologic factor in the high mortality of critically ill patients with AKI. Prospective randomized clinical trials will be needed to confirm this possibility. Until such studies are available, however, we recommend the avoidance of fluid overload in patients with AKI on the basis of knowledge of body weight changes and cumulative fluid balance for these patients.¹⁰⁹

To aid in appropriate hemodynamic support, invasive monitoring has been used to guide therapy. Techniques such as the pulmonary artery catheter rely on measurement of filling pressures (e.g., CVP, pulmonary artery occlusion pressure) to estimate preload responsiveness. In critically ill patients, the relation between filling pressures and ventricular end-diastolic volume (preload) is often obscured by changes in ventricular compliance or changes in the pericardium or thorax.¹¹⁰ In addition, the pulmonary artery catheter has been linked to a worse outcome in patients.^111,112 A positive response to fluid challenge can be predicted in mechanically ventilated patients by analyzing respiratory variations in pulse pressure. It has been shown that a change in pulse pressure greater than 15% during a single breath is more accurate in predicting an increase in cardiac output in response to volume loading than either right atrial pressure or wedge pressure.^113,114

Fluid management in critical illness is aimed at improving organ perfusion. However, in inflammatory states such as sepsis, there may be major fluid shifts resulting in tissue edema despite intravascular depletion. Aside from the inflammatory cascade, vasodilatation itself can result in an increase in interstitial fluid volume, likely secondary to albumin escape from the vasculature.¹¹⁵ There are currently no clinical methods to detect the presence of capillary leak, apart from fluid administration having no effect on intravascular volume.¹¹⁰ Therefore, if only transient improvements in hemodynamics occur with fluid administration, or if there is a continuing need for fluid, it is likely the patient will best be served by a change to vasopressor agents.

When volume replacement is indicated, there is controversy over the optimal type of fluid. Crystalloids are the most common form of volume replacement, but their effect on plasma volume is limited. Each liter of fluid administered increases plasma volume 200 mL, but the intravascular half-life is only 20 to 30 minutes.⁹⁴

Colloidal substances such as albumin, dextran, and hydroxyethyl starches, because they are macromolecules, are better retained within the intravascular space and have a greater effect on plasma volume. Albumin has been used for decades, but it is expensive and may cause an increase in mortality, according to the Cochrane Injuries Group.¹¹⁶ Nevertheless, a randomized controlled trial was conducted to compare human albumin with crystalloid in ICU patients (Saline versus Albumin Fluid Evaluation [SAFE] study). It indicated that albumin is safe, albeit no more effective than saline for fluid resuscitation. SAFE demonstrated no difference in renal outcomes, at least based on duration of RRT.¹¹⁷ Dextran cannot be recommended for plasma volume expansion because of serious side effects such as coagulation abnormalities¹¹⁸ and AKI.¹¹⁹

Hydroxyethyl starches (HESs) are polymers of amylopectin that vary in molecular weight and number of substitutions of hydroxyethyl groups. As molecular weight and number of substitutions increase, side effects also increase. HES 200/0.5 is a compound with a middle molecular weight and low substitution number. It has been studied in a number of situations such as perioperative volume replacement, cardiac surgery, trauma, and sepsis.^120–122 A recent trial compared a “modern” HES preparation with a low-molecular-weight and low-molar substitution and a human albumin solution, given in cardiac surgery patients with preoperative compromised kidney function, showed that this type of HES solution had no negative influence on kidney integrity.¹²³ In another study (Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis [VISEP]), severely septic patients were randomly assigned to receive either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer’s lactate for fluid resuscitation. HES appeared to be harmful, leading to higher rate and longer duration of AKI, and its toxicity increased with accumulating doses.¹²⁴ Aside from coagulation disorders, all hyperoncotic colloids may induce a pathologic entity known as osmotic nephrosis with potential impairment of kidney function.¹²⁵ A systematic review of randomized controlled trials (RCTs) on the use of HES for fluid management in patients with sepsis (totaling 1062 patients) showed an almost twofold increased risk of AKI with HES compared with crystalloids.¹²⁶ Lastly, a recent comprehensive Cochrane review concluded there is no evidence from RCTs that resuscitation with colloids instead of crystalloids reduces the risk of death in patients with trauma, burns, or following surgery.¹²⁷ There is even evidence that colloids may be associated with a higher incidence of AKI. Given the relative efficacy and safety of crystalloids, it is prudent to utilize them in fluid resuscitation and limit colloid use to the framework of clinical trials.

In sepsis and septic shock, there is hypotension despite normal or increased cardiac output.¹²⁸ The hypotension in sepsis is often unresponsive to fluid and requires administration of vasopressor agents. Because these agents cause vasoconstriction, there has been concern about their use in AKI. Norepinephrine causes a reduction in renal blood flow in healthy animals and humans.¹²⁹ The ultimate effect of norepinephrine on renal blood flow, however, depends on the resulting increase in blood pressure and vascular resistance. Norepinephrine increases blood pressure via an α₁-mediated increase in systemic vascular resistance and a β₁-mediated increase in cardiac output. The increase in resistance can potentially decrease cardiac output by increasing afterload. In the kidney, the effect on renal vascular resistance depends on the increase in systemic pressure, with a decreased renal sympathetic tone causing vasodilatation as well as an autoregulatory vasoconstriction secondary to increased perfusion pressure and α₁-mediated renal vasoconstriction.¹³⁰ In a nonrandomized study, it was demonstrated that norepinephrine increased arterial blood pressure, urine output, and GFR.¹³¹ A large randomized trial comparing dopamine to norepinephrine as initial vasopressor in patients with septic shock showed no significant differences between groups with regard to renal function or mortality, though norepinephrine was associated with less tachycardia in the first hours and was superior with regard to survival in cardiogenic shock patients (De Backer et al., in press).

Vasopressin is a hormone secreted by the posterior pituitary; it increases systemic vascular resistance by activating V_1a receptors on vascular smooth muscle. During septic shock, there is a biphasic response, with early high levels of endogenous vasopressin followed by a decrease.¹³² The renal effects of vasopressin are complex and involve an interplay between V₁ and V₂ receptors that regulates the antidiuretic function of vasopressin.¹³²