The effect of continuous versus intermittent renal replacement therapy on the outcome of critically ill patients with acute renal failure (CONVINT): a prospective randomized controlled trial

Patients with ARF requiring RRT treated at the medical intensive care units (ICUs) of the Charité University Hospital, Campus Virchow-Klinikum, Department of Nephrology and Medical Intensive Care, Berlin, Germany, were included in this randomized controlled trial (CONtinuous Vs. INTermittent RRT on the outcome of critically ill patients with ARF trial; CONVINT). CONVINT was performed from January 2002 until October 2007. A single-center prospective randomized controlled open-label trial design applied.

During the recruitment period, adult (>18 years) patients with ARF requiring RRT were eligible for inclusion in CONVINT. Need for RRT was defined as presence of at least one of the following criteria: (a) clinical symptoms of uremia (that is, gastrointestinal symptoms: (for example, nausea, vomiting, diarrhea not explained otherwise; or neurologic symptoms: mental confusion, severe weakness, seizures/coma not explained otherwise; or evidence of pericardial effusion); (b) persisting oliguria (urinary excretion rate <0.5 ml/kg/min for >12 hours), or anuria (anuria for >12 hours or <0.3 ml/kg/h for >24 hours), despite adequate fluid management; (c) fluid overload not responding to diuretic treatment; (d) blood urea nitrogen (BUN) levels >100 mg/dl or creatinine clearance <0.1 ml/ kg of body weight/min; (e) severe metabolic acidosis (pH <7.2) not responding to conventional treatment; and (f) hyperkalemia not responding to conservative treatment.

Patients were excluded when any of the following criteria were met: (a) preexisting chronic renal failure with serum creatinine >3 mg/dl or patients receiving chronic dialysis; (b) kidney-transplant recipients; (c) patients not requiring ICU treatment; (d) denial of written informed consent (patient, legal representative, or legal proxy). The study was approved by the local Ethics Committee (Ethikkommission der Charité-Universitätsmedizin Berlin) and was designed in adherence to the Declaration of Helsinki. Informed consent to participate in the trial was obtained from the patient or legal representative. In case a patient was unable to give informed consent and no legal representative was available, the Ethics Committee approval permitted immediate inclusion of the patient in the trial and to obtain informed consent subsequently, that is, as soon as a legal representative (next of kin without formal rights of representation not sufficient) was installed or the patient regained ability to give informed consent. Data of patients who died before written informed consent was obtained remained in the evaluation. Before randomization, next of kin were always asked if they agreed to including the patient in the study and using the data for future publication. If they declined, or only expressed concerns regarding potential objections the patient himself might have against study participation/publication of data, this patient was not included in the first place.

After assessment of inclusion and exclusion criteria, patients were allocated to the respective study groups (group 1, IHD; group 2, CVVH) at study day 0 (day of randomization; 1). To assure concealment of allocation, an independent external telephone (computer-based) randomization procedure provided by the Department of Biometry and Medical Documentation, University of Ulm, Ulm, Germany, was used (permutated blocks of four).

IHD (AK100/AK200; Gambro, Lund, Sweden) was performed by using polysulfone synthetic membranes. Standard treatment dose was daily IHD with 4 hours of hemodialysis at a blood flow of 200 to 250 ml/min. A dialysate flow at 500 ml/min, volumetric UF-control, water purified by reverse osmosis, and bicarbonate dialysate was used. Postdilutional CVVH (BM11/BM14; Baxter Medical, Deerfield, IL, USA, or Multifiltrate, Fresenius Medical Care, Bad Homburg, Germany) was applied 24 hours daily by using a polysulfone synthetic membrane, blood flow of 200 ml/min, prescribed filtration rate of 35 ml/ kg of body weight/hour, by using bicarbonate-buffered substitution fluids. General treatment target in both groups was absence of any criteria for acute RRT and a target-time-averaged serum urea of 100 to 150 mg/dl every 72 hours (mean pre + post + pre in IHD; not intended as an outcome measure). CVVH membranes were exchanged every 24 hours in patients with severe sepsis/septic shock. In all other patients, membranes were exchanged every 48 hours. As defined in the study protocol, patients in both study groups were allowed to be switched to the respective other RRT modality in cases of significant medical reasons (that is, either in cases of severe RRT-modality-associated complications or whenever the other modality should not be withheld for significant medical reasons). In such cases, switching of the respective RRT modality was performed by the attending ICU physician. Typical reasons for switching of RRT modality were as follows IHD to CVVH: continuous severe hypotension with requirement of advanced inotropic support or impossibility of maintaining fluid homeostasis. CVVH to IHD: patient mobilization, impossibility of maintaining electrolyte/ acid base homeostasis, impossibility of delivering an adequate dialysis dose, impossibility of performing CVVH without anticoagulation in patients with bleeding complications/repeated filter clotting. Number of changes in RRT modality and respective reasons were recorded.

Baseline demographics (including hospital/ICU admission day), baseline laboratory data (including baseline blood-gas analyses, urinary output), concomitant diagnoses, and reasons for ARF were recorded. For assessment of clinical disease severity over time, the following clinical scoring systems were used: Sepsis-related Organ Failure Assessment (SOFA) [18], and Therapeutic Intervention Scoring System (TISS)-28 [19]. Acute Physiology And Chronic Health Evaluation (APACHE) II score [20] and Simplified Acute Physiology Score (SAPS)-2 [21] were recorded at baseline. Data on respective RRT treatments, changes in RRT modality, necessity for mechanical ventilation or vasopressor support, routine laboratory data (daily until study day 10 and at days 15, 21), and outcome-related data were recorded daily. Patients were followed up until 14 days after RRT, withdrawal of consent, or death. Follow-up was performed by using electronic hospital data-management systems or telephone follow-up.

The primary outcome measure of CONVINT was survival at 14 days after end of RRT. Secondary outcome measures included 14-day-, 30-day-, all cause intrahospital mortality, days until death (on ICU), days in ICU/hospital, days on RRT/dialysis-free days, total days on vasopressors/mechanical ventilation, and course of disease severity (that is, clinical scores).

The initial power calculation aimed at inclusion of n = 200 patients per arm (the OR of failure (that is, primary end point) between the study groups can be given as the probability (true logOR is between estimated logOR ± 0.45) is at least 0.95, under the assumption that failure rates of the therapies may vary within 40% to 80%. No hypothesis of superiority of one of the methods studied, nor equality between the methods, was initially anticipated. Thus, estimation of effects was the focal point. CONVINT was terminated after inclusion of n = 252 patients in October 2007 after substantial treatment-protocol changes due to replacement of respective RRT equipment provided by the university hospital (change in contract; machines provided by different supplier; please also refer to Discussion section). Data from two of the 252 included patients were lost to follow-up and could not be included in the final analysis. One patient/proxy per study group withdrew consent (data until withdrawal entered the analysis). With a sample size of 125 patients per group, a precision of log OR ± 0.50 is achieved.

As defined in the study protocol, the sample for the statistical analysis consists of the intention-to treat (ITT) population. Patients were evaluated in the group to which they had been randomly allocated. An explorative PP analysis was performed. Subgroup analyses of patients with need for advanced inotropic support (norepinephrine dose of >0.3 μg/kg/min at any time during the study interval; overall sample group) was performed to identify potential outcome differences between the study groups. Switches from one RRT modality to the other were evaluated as a secondary end point. Statistical methods included Student paired and unpaired t test and χ² test, as appropriate. Kaplan-Meier survival estimates were constructed for illustrative purposes. Data were checked for normal distribution by using the Kolmogorov-Smirnov test. Results are reported as means ± standard deviations (SD), if not indicated otherwise. Significance was assigned when P < 0.05. Statistical analyses were performed by using MedCalc 12.0.1 software (MedCalc Software, Mariakerke, Belgium).

Data from n = 128 patients (group 1, IHD) and n = 122 (group 2, CVVH) patients were analyzed (Figure 1). At baseline, no statistically significant differences between the study groups were noted regarding demographics, days on ICU until study inclusion, disease severity (as assessed by APACHE II, SOFA, SAPS-2, and TISS-28 scores), key physiological and hemodynamic indices (except diastolic blood pressure), renal function, and acid/base balance (Table 1). Concomitant illness was recorded in both study groups. The number of patients with advanced vascular disease, congestive heart failure, chronic obstructive pulmonary disease, and metabolic disease (including diabetes) was not different between the two study groups (Table 1). Major reasons for development of ARF were severe sepsis/septic shock (both groups >65% of study patients at baseline) or cardiogenic shock (please also refer to Table 1). At baseline, >80% of study patients in both groups required both mechanical ventilation and vasopressor support (Table 1) and thus suffered from multiple organ failure. Main underlying cause for developing severe sepsis/septic shock was pneumonia (n = 33 patients in group 1 versus n = 25 patients in group 2, n.s.). Moreover, 22 patients were initially diagnosed with Acute Respiratory Distress Syndrome (ARDS) (group 1, n = 10; group 2, n = 12; P = n.s.). Peritonitis was present in n = 5 (group 1) versus n = 5 (group 2) patients (P = n.s.). In addition, n = 9 (group 1) versus n = 8 patients (group 2) were diagnosed with severe pancreatitis. At baseline, no difference in vasopressor need or need for mechanical ventilation was noted (Table 1).

The time course of clinical and laboratory data is shown in Table 2. Time until dialysis, days on RRT, dialysis-free days (all n.s.; Tables 1 and 3), as well as course of urinary output, serum creatinine, and serum urea concentrations were not different between the two groups. No differences were noted in serum creatinine at hospital discharge or total fluid balance (Table 3). In the IHD group, the mean blood-flow rate was 222.9 ± 30.4 ml/min, and mean dialysate flow rate was 491.4 ± 6.23 ml/min. Mean duration of IHD was 215.4 ± 82.3 min/session. In the CVVH group, mean applied dose (that is, filtration rate was 30.9 ± 7.0 ml/kg body weight/hour (88% of prescribed dose). Mean blood flow rate in the CVVH group was 188.7 ± 29.4 ml/min. Mean daily ultrafiltration rates were 1.24 ± 0.9 kg (IHD group) and 1.25 ± 1.2 kg (CVVH group) (P = 0.87), respectively (means ± SD are given). Anticoagulation was used in 72.8% (IHD) and 74.4% (CVVH) of sessions (unfractionated heparin used in 99.4% versus 97.8% of sessions, respectively). Hirudine derivates or citrate/calcium were used in the remaining cases. Mean dose of unfractionated heparin was 682.8 ± 357 i.U./hour (IHD group) versus 781.6 ± 497 i.U./hour (CVVH group) (P = 0.0001).

In group 2, switching of modality was mostly indicated because of repeated filter clotting (27%), metabolic reasons (for example, progressive lactic acidosis; 18%), bleeding/discontinuation of anticoagulation required (11%), severe thrombocytopenia (5%), or because of desired mobilization/clinical improvement of study patients.

Disease severity was assessed over time by using SOFA and TISS-28 scoring systems, revealing no differences between the study groups (Table 2). Cumulative catecholamine need and total days on vasopressors were not different between the two study groups (data not shown). Key hemodynamic variables (that is, heart rate, mean arterial pressure, and central venous pressure) did not differ between the study groups at randomization, baseline, and during follow-up (Tables 1 and 2). Need for mechanical ventilation was assessed in both study groups. Initial need for mechanical ventilation (Table 1), total days on mechanical ventilation (Table 3), and paO₂/FiO₂ (data not shown) did not differ between the study groups. During follow-up, other physiological variables including blood pH, urinary output, temperature, and C-reactive protein were also not different (Table 2).

Survival at 14 days after RRT, 14-day-, 30-day- and all-cause intrahospital mortality rates were not different between the study groups in both the ITT and PP populations (all n.s.; survival rates of the ITT population given in Table 3). The univariate OR (for patients in IHD group) for survival at 14 days after end of RRT was 0.84 (95% CI, 0.49 to 1.41; P = 0.5). OR (for patients in IHD group) for 14-day mortality was 1.27 (95% CI, 0.76 to −2.12; P = 0.36). Missing data (survival at 14 days after RRT) in nine (IHD group) versus eight (CVVH group) patients (that is, 7.0%, n.s.). OR (IHD group) for 28-day mortality was 1.37 (95% CI, 0.82 to 2.27; P = 0.22). For patients randomized to receive IHD, the OR for 30-day mortality was 1.32 (95% CI, 0.80 to 2.19; P = 0.27), and for all-cause intrahospital mortality, 1.26 (95% CI, 0.76 to 2.10; P = 0.37). In the CVVH study group, the survival rate at 14 days after RRT was 4.4% higher, and mortality rates were not significantly reduced by 5.8% (14-day mortality), 7.9% (28-day mortality), 7.0% (30-day mortality), and 5.7% (all-cause intrahospital mortality).

Moreover, we investigated whether higher norepinephrine need (defined as >0.3 μg/kg/min at any time during the study interval) was associated with different outcomes in the respective study groups. It was noted that, in this subgroup with higher catecholamine need (n = 47 in group 1 versus n = 40 in group 2), survival at 14 days after RRT (36.2% versus 37.5%; P = 0.9), 14-day-, 30-day-, and all-cause mortality rates (65.9% versus 60.0%; P = 0.92) were also not different between the study groups. To illustrate survival characteristics, Kaplan-Meier survival estimates were constructed for the total study population (Figure 2) and the subpopulation receiving a higher vasopressor dose (Figure 3).