NDT Advance Access originally published online on February 18, 2008
Nephrology Dialysis Transplantation 2008 23(3):820-826; doi:10.1093/ndt/gfn044
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Kidney diseases beyond nephrology: intensive care
1 Department of Pediatric Cardiosurgery, Staff Anesthesiologist, Bambino Gesù Hospital, Rome 2 Department of Nephrology, Dialysis and Transplantation, Head, S.Bortolo Hospital, Vicenza, Italy
Zaccaria Ricci, Piazza S. Onofrio 400100, Rome, Italy. Tel: +39-0644-56115; Fax: +39-0444-993949. E-mail: z.ricci{at}libero.it
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From renal failure to kidney injury |
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Acute kidney injury (AKI) is a complex disorder that occurs in a variety of settings with clinical manifestations ranging from a minimal elevation in serum creatinine to anuric renal failure [1]. It is often under-recognized and associated with severe consequences. Recent epidemiological studies demonstrate the wide variation in aetiologies and risk factors and describe the increased mortality associated with this disease (particularly when dialysis is required) [1–2]. AKI is currently recognized as the preferred nomenclature for the clinical disorder formerly called acute renal failure (ARF). This transition in terminology served to emphasize that the spectrum of disease is much broader than the subset of patients who experience kidney failure requiring dialysis support [3]. This new nomenclature underscores the fact that AKI exists along a continuum, recognizing that an acute decline in kidney function is often secondary to an injury that causes functional and/or structural changes in the kidneys and that the more severe the injury, the more likely the overall outcome will be unfavourable. The Acute Kidney Injury Network (AKIN), formed by members representing key societies in critical care and nephrology along with additional experts in adult and paediatric AKI, participated in a 2-day conference in Amsterdam, the Netherlands, in September 2005. The AKIN defined AKI as ‘an abrupt (within 48 h) reduction in kidney function currently defined as an absolute increase in serum creatinine of
0.3 mg/dl, a percentage increase in serum creatinine of 50% (1.5-fold from baseline) or a reduction in urine output (documented oliguria of <0.5 ml/kg/h for more than 6 h)'. Several specifications were provided by the workgroup to this updated definition and were followed by a new staged classification of AKI severity (Table 1); in synthesis, the time constraint of 48 h for diagnosis was selected based on the evidence that adverse outcomes with small changes in creatinine were observed when the creatinine elevation occurred within 24 to 48 h [4] and to ensure that the process was acute and representative of events within a clinically relevant time period. In the study by Chertow and colleagues [5], the odds ratio for mortality with a change in creatinine of 0.3 mg/dl (25 µmol/l) was 4.1 (confidence interval 3.1–5.5) adjusting for CKD. The authors did not recommend waiting 48 h to diagnose AKI or initiate appropriate measures to treat AKI. Instead, the time period was designed to eliminate situations in which the increase in serum creatinine by 0.3 is very slow, and thus, is not ‘acute’. Furthermore, the need for including urine output as a diagnostic criterion was based on the knowledge that, in critically ill patients, this parameter often heralds renal dysfunction before serum creatinine increases. It was recognized that a urine output reduction of <0.5 ml/kg/h over the span of 6 h is not specific enough to lead confidently to the designation of AKI because the hydration state, use of diuretics and presence of obstruction could influence the urine volume, hence the need to consider the clinical context. Additionally, accurate measurements of urine output may not be easily available in all cases, particularly in patients admitted to non-intensive care unit settings.
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Despite these limitations, it was felt that the use of changes in urine might offer a sensitive and easily discernible means of identifying patients, but its value as an independent criterion for diagnosis of AKI still needs to be validated.
The goal of adopting these explicit diagnostic criteria is to increase the clinical awareness and diagnoses of AKI. It is recognized that there may be an increase in false positives, so that some patients labelled with AKI will not have the condition. There was consensus that adopting the more inclusive criteria is preferable to the current situation, in which AKI is often under-recognized and many people are identified late in the course of their illness and potentially miss the opportunity for prevention or application of strategies to minimize further kidney damage.
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Normotensive ischaemic ARF |
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In a recent review published in the New England Journal of Medicine, Abuel describes the concept of ‘normotensive ischaemic ARF’ [6]. The author classifies ischaemic ARF in prerenal azotaemia and acute tubular necrosis, and states that they account for more than half of the cases of renal failure seen in hospitalized patients. In many patients with ARF, the contribution of ischaemia may be initially unrecognized. These patients may experience low-perfusion states (volume depletion, fluid loss to the third space and congestive heart failure) although their blood pressure may remain within the normal range (with systolic blood pressure over 90 to 100 mmHg). In such cases, involved mechanisms responsible for progressive renal injury may be unobserved temporary drops in blood pressure; otherwise normotensive renal failure can occur as a result of renal susceptibility to modest reductions in arterial pressure even when such reductions remain within the ‘normal’ range of perfusion pressure. Among the factors included by Abuelo in the pathogenesis of normotensive ischaemic ARF, altered glomerular haemodynamics and a reduced glomerular filtration rate are emphasized. Failure of afferent arteriole resistance to decrease can occur when a patient is receiving nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors, which reduce the synthesis of vasodilatory prostaglandins in the kidneys. When this occurs, angiotensin II, norepinephrine, vasopressine and other vasoconstrictors released in low-perfusion states may act, unopposed, on the afferent arterioles, further decreasing glomerular capillary pressure. Sepsis, hypercalcaemia, severe liver failure, calcineurin inhibitors and radiocontrast agents may also affect, through different mediators, afferent arteriolar resistance. In addition, sepsis and contrast agents may have direct toxic effects on the tubules. Slightly decreased renal perfusion may also cause a significant drop in glomerular filtration rate when angiotensin II does not raise efferent resistance in patients who are receiving angiotensin-receptor blockers or angiotensin-converting enzyme (ACE) inhibitors. Normotensive renal failure may also occur in low-cardiac output/low-perfusion states in the presence of increased levels of vasoconstrictive substances that efficiently maintain, and occasionally increase, the measured blood pressure. Hypercalcaemia may increase afferent glomerular arteriolar resistance and may lead to marked hypovolaemia because it may increase renal fluid losses. Hypercalcaemia-induced systemic vasoconstriction, again, may paradoxically maintain or increase blood pressure.
This extensive review may miss one interesting point recently addressed by several authors: septic ARF. This is the most frequent and lethal cause of kidney failure in the intensive care unit (ICU) [7] and its complex, poorly understood pathogenesis would have deserved a dedicated section of the review to be fully described. Recent animal models have questioned that during hyperdynamic states of sepsis, renal ischaemia is involved, whereas septic kidney injury often occurs in ‘normotensive’ patients [8]. In particular, there is no evidence that acute tubular necrosis is the histopathological substrate of septic AKI; there is no evidence that urine tests can help in the diagnosis of septic AKI (as anecdotically suggested by Abuelo), nor is there any evidence that any proposed differentiation in different forms of AKI can lead to different treatments or different outcomes [9]. In conclusion, it must be said that the finding of both high and low renal blood flows in studies of experimental septic ARF calls into question, but does not rule out, the role of ischaemia in the pathogenesis of this condition; few data on this issue are available and good studies are still being awaited.
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RIFLE in the general ICU |
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The first multilevel classification system for AKI was proposed by the Acute Dialysis Quality Initiative workgroup in 2004 [10]; the classification was identified by the acronym RIFLE (Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease). Several studies have been published in order to validate it in clinical practice and to verify if outcome progressively worsened with the severity of AKI. Some of these studies specifically concerned the population of the general ICU. We recently reviewed 13 studies where patient level data on mortality were available for Risk, Injury and Failure patients, as well as those without AKI (non-AKI), in order to analyse the pooled estimate of risk ratio (RR) for mortality for patients with Risk, Injury or Failure levels compared with non-AKI patients [11]. Over 71 000 patients were included in the analysis of published reports. With respect to non-AKI, there appeared to be a stepwise increase in RR for death going from Risk (RR: 2.40) to Injury (RR: 4.15) to Failure (6.37, P < 0.0001 for all). Among the reviwed studies, we may report the one from Osterman and Chang [12] who performed a retrospective analysis of a database of 41 972 patients admitted to 22 ICUs in UK and Germany between 1989 and 1999. The authors found that AKI as defined by RIFLE occurred in 35.8% of patients: 17.2% R, 11% I and 7.6% F. Patients with Risk, Injury and Failure had a hospital mortality of 20.9%, 45.6% and 56.8%, respectively, compared to 8.4% among non-AKI patients. Independent risk factors for hospital mortality were age, Acute Physiology and Chronic Health Evaluation (APACHE) II score on admission to ICU, presence of preexisting end-stage disease, mechanical ventilation, RIFLE class, maximum number of failed organs, admission after emergency surgery and non-surgical admission. Interestingly, RRT was not an independent risk factor for hospital mortality. The authors concluded that there was an association between AKI and hospital outcome, but associated organ failure, nonsurgical admission and admission after emergency surgery had a greater impact on prognosis than severity of AKI. Abosaif and colleagues [13] retrospectively applied the RIFLE classification of AKI in order to evaluate its sensitivity and specificity to predict renal and patient outcomes in 183 critically ill patients with AKI. The RIFLE-F group showed the worst parameters with regard to APACHE II score, pH, lowest and highest mean arterial pressures and Glasgow Coma Scale. Mortality rate in the ICU (60 days, 74.4%) and 6-month mortality rate (86%) were significantly greater in the RIFLE-F group compared with all groups. The authors concluded that RIFLE classification might improve the ability of other scoring systems in predicting outcome of ICU patients with AKI. Cruz and co-workers [14] conducted the first prospective multicentre study in order to estimate the AKI incidence in critically ill patients in 19 ICUs in northeastern Italy. Of 2164 ICU patients who were admitted during the study period, 234 (10.8%) developed AKI while 3.3% were treated with RRT. Of the AKI patients, 19% were classified as Risk, 35% as Injury and 46% as Failure. Preexisting kidney disease was present in 36.8%. The most common causes of AKI were prerenal causes (38.9%) and sepsis (25.6%). At diagnosis of AKI, median serum creatinine and urine output were 2.0 mg/dl and 1100 ml/day, respectively. Overall ICU mortality in the cohort was between 30 and 42%, and was highest among those in RIFLE class F (mortality 20% in R, 29.3% in I and 49.5% in F). Independent risk factors for mortality included RIFLE class, sepsis and need for RRT, whereas a postsurgical cause of AKI, exposure to nephrotoxins, higher serum creatinine and higher urine output were associated with lower mortality risk. Hoste and co-workers [15] performed a retrospective single-centre study on 5383 patients in seven ICUs admitted during a 1-year period. AKI occurred in 67% of ICU admissions, and 28, 27 and 12% reached a maximum RIFLE class of Risk, Injury and Failure, respectively. Interestingly, among the patients that reached a level of R, 56% progressed to either I or F. Patients with maximum RIFLE class R, I and F had hospital mortality rates of 8.8%, 11.4% and 26.3%, respectively, in contrast to 5.5% in non-AKI patients. RIFLE classes were still associated with hospital mortality after adjusting for multiple covariates (baseline severity of illness, case mix, race, gender and age). Their findings showed that patients with RIFLE-R are indeed at significant risk of progression to more severe AKI. Patients with RIFLE class I or F incur a significantly increased length of stay and an increased risk of in-hospital mortality compared with those who do not progress past class R or those who never develop AKI.
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Markers and biomarkers of AKI |
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If AKI has been defined and detected by measuring surrogates of kidney function such as serum creatinine and urine output, these markers are acknowledged as insensitive and non-specific for both acute changes to kidney function and kidney injury. They also increase late in the injury process. As a consequence, they may not detect an acute insult or potentially ongoing injury to the kidney. Alternative markers such as urinary analysis and novel biomarkers have been extensively reviewed and examined in the last 2 years.
As far as the specific setting of experimental septic AKI is concerned, urinary analysis is often used to diagnose and classify renal injury. The scientific basis for such use has been systematically evaluated by Bagshaw and co-workers [16]; the authors found 27 experimental studies describing urinary biochemistry, derived indices and microscopy in septic AKI. The methods for induction of sepsis and models were variable. The urinary sodium, fractional excretion of sodium and urine osmolality were reported in only 4 (15%), 21 (78%) and 7 (26%) studies, respectively. The fractional excretion of sodium exhibited a decrease, no change, or an increase from baseline in 11 (52%), 5 (24%) and 5 (24%) studies, respectively. The urine osmolality decreased from baseline in all endotoxin-induced models but showed an early transient increase in six (22%) studies of cecal-ligation perforation. Proteinuria or urinary enzymuria was reported in only seven (26%) studies. Urinary microscopy was described in one study. Only 10 studies (37%) simultaneously reported on histopathology. In all these studies, histology either was normal or showed minor ultrastructural changes on electron microscopy. The authors suggest that no conclusions are possible on how several urinary tests perform in diagnosing or classifying AKI or in predicting the presence of acute tubular necrosis in experimental sepsis. In light of such review, additional research seems necessary to define the diagnostic and prognostic value of urinalysis in experimental sepsis. The same group also performed a review on urinary biochemistry in human septic AKI [17]. The scientific basis in patients with septic AKI of urine biochemistry and microscopy of urine has not been assessed systematically although widely published. A systematic review of all studies describing urinary biochemistry, indices and microscopy in patients with septic AKI was performed. Urinary biochemistry or derived indices were reported in 24 articles (89%), and microscopy in 7 articles (26%). The majority were small single-centre reports and had serious limitations. For example, only 52% of patients were septic and only 54% of patients had AKI, many studies failed to include a control group, time from diagnosis of sepsis or AKI to the measurement of urinary tests was variable, and there were numerous potential confounders. Urinary sodium, fractional excretion of sodium, urinary-plasma creatinine ratio, urinary osmolality, urinary-plasma osmolality ratio and serum urea-creatinine ratio showed variable and inconsistent results. Low-molecular-weight proteinuria was described in only 22% of the articles. A few reports of urinary microscopy described muddy-brown/epithelial cell casts and renal tubular cells in patients with septic AKI, whereas others described normal urinary sediment. According to these findings, the scientific basis for the use of urinary biochemistry, indices and microscopy in patients with septic AKI is weak. More research is required to describe their accuracy, pattern and time course in patients with septic AKI. A promising future seems to be reserved for urinary biomarkers [18]. A review of 14 articles on the value of urinary biomarkers in the specific setting of septic AKI showed that most studies were small, singlecentre and included mixed medical/surgical adult populations. Retrieved articles included data on low-molecular-weight proteins (β2-microglobulin, 
1-microglobulin, adenosine deaminase-binding protein, retinol-binding protein, cystatin C and renal tubular epithelial antigen-1), enzymes (N-acetyl-β-glucosaminidase, alanine-aminopeptidase, alkaline phosphatase; lactate dehydrogenase, /
-glutathione-S-transferase and 
-glutamyl transpeptidase), cytokines (platelet activating factor (PAF), interleukin-18 (IL-18)) and other biomarkers (kidney injury molecule-1 and Na/H exchanger isoform- 3 (NHE3)). Increased PAF, IL-18 and NHE3 were detected early in septic AKI and predicted kidney failure. Several additional biomarkers were evident early in AKI; however, their diagnostic value in sepsis remains unknown. In one study, IL-18 excretion was higher in septic than in non-septic AKI. IL-18 also predicted deterioration in kidney function, with increased values preceding clinically significant kidney failure by 24–48 h. Detection of cystatin C, 1-microglobulin and IL-18 predicted the need for renal replacement therapy (RRT). The authors conclude that there is promising evidence that selected biomarkers may aid in the early detection of AKI in sepsis and may have value for predicting subsequent deterioration in kidney function. Additional prospective studies are needed to accurately describe their diagnostic and prognostic value in septic AKI.
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AKI outcomes in the last 10 years |
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The overall incidence of AKI or mortality after cardiac surgery is low, but mortality in patients with AKI remains high. Effects of change in comorbid diseases, intraoperative factors or postoperative complications on trends in the incidence of AKI and associated mortality after cardiac surgery were analysed by Thakar and colleagues [19]. A total of 33 217 cardiac surgeries were considered; AKI was defined as a composite outcome of a
50% decrease in postoperative glomerular filtration rate or requirement of dialysis (AKI-D). Between the first and second halves of the study period (1993–2002), the incidence of AKI increased from 5.1 to 6.6%, but the associated mortality rate decreased from 32 to 23%. Similarly, the incidence of AKI-D also increased from 1.5 to 2.0%, with a decrease in associated mortality from 61 to 49%. In a risk-adjusted model, mortality in patients with AKI significantly decreased over time. Patients with AKI-D and with other organ system failures did not show improvement in survival over time, except for patients with a preoperative history of congestive heart failure which were significantly associated with a decrease in mortality risk over time. The incidence of AKI after cardiac surgery, regardless of its definition, increased over time. The increasing frequency of major risk factors of AKI is one of the likely contributors to the increasing incidence of AKI. Conversely, postoperative mortality in patients with AKI decreased over time. Patients developing AKI showed a significant decrease in mortality. Persistent high mortality in patients with postoperative multiorgan system failure along with severe AKI-D remains a therapeutic challenge.
Based on similar observations, Swaminathan and colleagues tested the hypothesis that the diagnosis of AKI associated with coronary artery bypass graft surgery is increasing in the United States [20]. Patients admitted for coronary artery bypass graft surgery from 1988 to 2003 comprised the study population; those diagnosed with AKI formed the subset of interest. The authors adjusted the results for risk factors and comorbidities, in order to identify the relationship between year of surgery, diagnosis of AKI and mortality. The incidence of AKI diagnosis increased significantly during the study period from 1.1 to 4.1% (P < 0001). The proportion of AKI cases that required dialysis decreased from 15.8 to 8.7% (P < 0001). Despite an increase in comorbid disease burden, mortality in the AKI subgroup declined from 39.5 to 17.9% (P < 0001). The percentage of AKI survivors with chronic care requirements after discharge increased from 35.5 to 64.5% (P < 0001). These findings may be partly attributable to less restrictive criteria for diagnosis; although the need for dialysis is a relatively common level of disease for AKI diagnosis, use of alternate criteria to define this disorder has become more common, perhaps contributing to higher diagnosis rates and earlier therapeutic intervention and potentially improved outcome. Another Australian survey from data of all adult admissions to 20 Australian intensive care units (ICUs) for 24 h, from 1 January 1996 to 31 December 2005, assessed the trends in incidence and mortality for ICU admissions associated with early AKI [21]. The authors analysed 91 254 patient admissions with 4754 cases of AKI, for an estimated crude cumulative incidence of 5.2%. The incidence of AKI increased during the study period, with an estimated annual increment of 2.8%. The crude hospital mortality was significantly higher for patients with AKI than those without (42.7% versus 13.4%). There was also a decrease in AKI crude mortality (annual percentage change, –3.4%) which, however, was not seen in patients without AKI. After covariate adjustment, AKI remained associated with a higher mortality (odds ratio, 1.23; 95% confidence interval, 1.14–1.32; P < 0.001), but there was a declining trend in the odds ratio for hospital mortality. Such retrospective studies, and many other observational studies, suggest that critically ill patients with AKI are increasingly older, have more comorbid disease, are more probably septic and have greater severity of illness and organ failure [22]. Nevertheless, the authors explain this trend with likely improvements in the overall care of critically ill patients or by specific interventions or therapies for AKI (significative results are reported in the subgroup of trauma patients). In another review, however, Dr Bellomo claimed that the crude mortality of AKI has not changed in the last 30 years [23]. Nevertheless, this author considered that patients with AKI treated in hospitals 30 years ago were mostly treated outside the ICU, did not require or receive mechanical ventilation or vasopressor drugs, were 20–30 years younger in age and their outcome was typically assessed retrospectively and in academic centres only. Their outcome cannot be meaningful compared with prospective data from multinational and multicentre assessment of patients who are all critically ill, treated in an ICU and typically receiving mechanical ventilation and vasopressor therapy. Despite the much greater illness severity for patients treated today, the mortality of AKI has not increased and has perhaps slightly decreased while the duration of treatment has clearly decreased in terms of need for dialysis, time in ICU and in hospital, and the techniques of artificial renal support have also changed markedly. It is likely, hence, that the 50–60% crude mortality associated with AKI will remain unchanged in the next decade or more; therapeutic capabilities improve and the healthcare system will progressively admit and treat sicker and sicker patients with AKI. Comparisons that do not take into account this continuing adjustment and do not appreciate the continuing change in illness severity will present a misleading picture of the achievements associated with improvement in technology and medications [23].
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Fluid resuscitation: effects on outcome |
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 TopFrom renal failure to...Normotensive ischaemic ARFRIFLE in the general...Markers and biomarkers of...AKI outcomes in the... Fluid resuscitation: effects on... Continuous renal replacement...References |
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In all critically ill patients, volume replacement is a crucial point of hypovolaemia management and optimal therapy should avoid development of multiple organ and kidney failure by assuring stable circulatory parameters and organ perfusion while reducing excessive interstitial fluid overload. The choice of fluid is still a matter of controversy. Most crystalloids consist of a non-physiological mixture of electrolytes, and in patients who had large amounts of saline (NS) infused, ‘hyperchloraemic acidosis’ frequently occurs [24]. Colloids have been shown to have some benefits with respect to crystalloids for correcting intravascular volume deficits and for improving systemic and microcirculatory haemodynamics. However, the recent saline versus albumin (SAFE) double-blind randomized controlled trial in 6997 patients (3497 were assigned to receive albumin and 3500 to receive saline) showed that there is no advantage to resuscitation with albumin as compared to normal saline [25]. In a post hoc subgroup analysis of patients with severe sepsis, there was a trend towards decreased mortality in the albumin group. There were no differences between groups in mortality for patients with ARDS. Nonetheless, colloids are often preferred for correcting hypovolaemia [26]. Almost all colloids [albumin, hydroxyethylstarch (HES) and gelatins] are prepared in nonphysiological solutions and can be defined as ‘unbalanced colloids’. The use of large amounts of these colloids may be associated with unwanted electrolyte or acid–base disturbances [27]. Results from human studies suggested that fluid-related derangements in acid–base status may have adverse effects when large amounts of crystalloids are infused [27]. In order to achieve the target of a total balanced fluid resuscitation, balanced colloids are needed aside from balanced, plasma-adapted crystalloids. A first generation high-molecular-weight HES [mean molecular weight (Mw), 650 kD] with a high molar substitution (MS: 0.7) has been dissolved in a physiologically balanced solution (Hextend). Subsequently, a more rapidly degradable third generation HES with a lower Mw (130 kD), lower MS (0.4) and lower C2/C6 ratio has been developed to improve safety and is prepared in a balanced, plasma-adapted solution. When used in a plasma-adapted volume replacement strategy (balanced crystalloid plus balanced HES) and given in high doses (
2500 ml of HES within 24 h), this had better effects with regard to electrolyte concentrations and base excess compared with a non-balanced strategy including normal saline and a non-balanced HES [27]. HES is thought to alter coagulation and platelet function leading to increased bleeding tendency. Coagulation may be affected by both the physico-chemical characteristics of the HES preparation and the electrolyte composition of the solvent. In a prospective, randomized, double-blinded study in 90 patients undergoing major non-cardiac surgery, the use of HES prepared in normal saline (Hetastarch 1300 ml) resulted in significantly more impaired thrombelastographic data than HES prepared in a balanced solution (Hextend 1450 ml) [27]. However, balanced colloidal volume replacement relevance for patient outcome is unclear as outcome data (mortality) in patients are lacking. At present, only limited data are available and it is plausible that such strategy would potentially affect organ function and morbidity rather than patient mortality, and large controlled studies such as the SAFE trial will be needed in order to show definitive results. |
Continuous renal replacement therapy: effects on outcome |
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Recently, the Beginning Ending renal Support Therapy (BEST) study group reported the results of a prospective observational study on a worldwide large cohort of 54 centres and over 1260 patients being treated with RRT for ARF: 1006 (82.6%) were initially treated with continuous RRT (CRRT), 212 with intermittent RRT (IRRT) (17.4%) and a minority consisting of very few patients applied peritoneal dialysis (PD) [7]. Uchino and co-workers reported that very few units deliver the intensive CRRT regimen of 35 ml/kg/h: median unadjusted CRRT dose was 2000 ml/h and the corrected dose was 20.4 ml/h/kg. Only 11.7% of patients were treated with a corrected dose of >35 ml/kg/h [28]. No effect on survival seemed to be evident in this observational study.
However, Saudan and co-workers [29] enrolled 371 patients with AKI (102 to CVVH and 104 to continuous veno-venous haemodiafiltration—CVVHDF) prescribed 25 ml/h/kg ultrafiltration in the CVVH group and 24 ml/ h/kg in the CVVHDF group; patients on CVVHDF were prescribed an adjunctive mean dialysis dose of 18 ml/h/kg. The CVVHDF patients had significantly higher mean urea and creatinine reduction ratios 48 h after the initiation of continuous RRT than did the CVVH patients (50% versus 40%, P <0.009, and 46% versus 38%, P <0.014, respectively). Survival rates at 28 and 90 days were higher with CVVHDF than with CVVH. The main limit of such a study, like previous trials, is underpower; furthermore, it confounds the effects of dose and technique by adding dialysis to filtration. Nonetheless, other recent non-randomized reports found beneficial effects from intensive RRT doses. Piccinni and co-workers evaluated the effects of early short-term, isovolaemic haemofiltration (EIHF) at 45 ml/kg/h, on physiological and clinical outcomes in patients with septic shock in a retrospective study, before and after a change of unit protocol that occurred over a period of 8 years [30]. In the pre-EIHF period, 40 patients who received conventional renal replacement therapy were analysed. In the post-EIHF period, 40 patients who received EIHF at 45 ml/kg/h of plasma-water exchange over 6 h, followed by conventional CVVH, were considered. The two groups were comparable for age and gender and had an adequately high baseline APACHE II score (about 27). Delivered haemofiltration dose was >85% of prescription in all patients. The PaO2/FIO2 ratio increased from 117 ± 59 to 240 ± 50 in EIHF while it changed from 125 ± 55 to 160 ± 50 in the control group (P < 0.05). In EIHF patients, mean arterial pressure increased (95 ± 10 versus 60 ± 12 mmHg; P < 0.05), and norepinephrine dose decreased (0.20 ± 2 versus 0.02 ± 0.2 mcg/kg/min; P < 0.05). Among EIHF patients, 28 (70%) were successfully weaned from the ventilator compared with 15 (37%) in the control group (P < 0.01). Similarly, 28-day survival was 55% compared with 27.5% (P < 0.05). The length of stay in the ICU was 9 ± 5 days compared with 16 ± 4 days (P < 0.002). The study is limited by the retrospective nature and by the limited sample size, but it points the light on extrarenal (pulmonary and cardiovascular) effects of intensive CRRT prescription. These results need to be confirmed by prospective and adequately powered studies.
Recently, a meta-analysis on 15 studies including 1550 patients reported, confirming previous results, that CRRT did not differ from IRRT with respect to in-hospital mortality (RR 1.01, 95% CI 0.92–1.12), ICU mortality (RR 1.06, 95% CI 0.90–1.26), number of surviving patients not requiring RRT (RR 0.99, 95% CI 0.92–1.07), haemodynamic instability (RR 0.48, 95% CI 0.10–2.28) or hypotension (RR 0.92, 95% CI 0.72–1.16) and need for escalation of pressor therapy (RR 0.53, 95% CI 0.26–1.08) [31]. Interestingly, patients on CRRT were likely to have significantly higher mean arterial pressure; considering that typically more haemodynamically unstable patients are treated by CRRT rather than by IRRT, this notion confirms the haemodynamic tolerability of such form of dialysis and, possibly, the fact that haemodynamic parameters improve during the course of the treatment. The authors obviously also found a higher risk of clotting for CRRT filters (RR, 95% CI 8.50 CI 1.14–63.33). Although these data may still not be definitive, the best evidence to date still supports the use of at least 35 ml/h/kg for CVVH, CVVHDF or 1.2 Kt/V daily intermittent haemodialysis [32]. Furthermore, the design of future trials should include, as the primary outcome, other parameters than mortality; another report from the BEST study group showed that patients treated first with CRRT required vasopressor drugs and mechanical ventilation more frequently, compared to those receiving IRRT [33]. Unadjusted hospital survival was lower (35.8% versus 51.9%, P < 0.0001). However, unadjusted dialysis independence at hospital discharge was higher after CRRT (85.5% versus 66.2%, P < 0.0001). Multivariable logistic regression showed that choice of CRRT was not an independent predictor of hospital survival or dialysis-free hospital survival. However, the choice of CRRT was a predictor of dialysis independence at hospital discharge among survivors (OR: 3.333, 95% CI 1.845–6.024, P < 0.0001). The choice of CRRT as initial therapy probably is not a predictor of hospital survival or dialysis-free hospital survival, but is an independent predictor of renal recovery among survivors [33]. Similar results were presented by other authors. In his randomized controlled trial, Mehta reported that initial CRRT was associated with a significantly higher rate of complete renal recovery than IRRT in the subgroup of surviving patients who received an adequate trial of therapy without crossover (CRRT: 92.3% versus IRRT: 59.4%, P < 0.01) [34]. Bell and the Swedish Intensive Care Nephrology Group [35] showed that within 1102 patients surviving 90 days after inclusion in the cohort, 944 (85.7%) were treated with CRRT and 158 (14.3%) were treated with IHD. Seventy-eight patients (8.3%; confidence interval, CI 6.6–10.2) never recovered their renal function in the CRRT group. The proportion was significantly higher among IHD patients, where 26 subjects or 16.5% (CI 11.0–23.2) developed need for chronic dialysis. Again, analysing a smaller cohort, Jacka and co-workers reviewed the records of 116 patients undergoing RRT and realized that renal recovery was significantly more frequent among patients initially treated with CRRT (21/24 versus 5/14, P = 0.0003) [36].
Conflict of interest statement. None declared.
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References |
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[Abstract/Free Full Text]
Accepted in revised form: 22. 1.08
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