Detlef Kindgen-Milles

Delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury

IntroductionThe optimal dialysis dose for the treatment of acute kidney injury (AKI) is controversial. We sought to evaluate the relationship between renal replacement therapy (RRT) dose and outcome.MethodsWe performed a prospective multicentre observational study in 30 intensive care units (ICUs) in eight countries from June 2005 to December 2007. Delivered RRT dose was calculated in patients treated exclusively with either continuous RRT (CRRT) or intermittent RRT (IRRT) during their ICU stay. Dose was categorised into more-intensive (CRRT ≥ 35 ml/kg/hour, IRRT ≥ 6 sessions/week) or less-intensive (CRRT < 35 ml/kg/hour, IRRT < 6 sessions/week). The main outcome measures were ICU mortality, ICU length of stay and duration of mechanical ventilation.ResultsOf 15,200 critically ill patients admitted during the study period, 553 AKI patients were treated with RRT, including 338 who received CRRT only and 87 who received IRRT only. For CRRT, the median delivered dose was 27.1 ml/kg/hour (interquartile range (IQR) = 22.1 to 33.9). For IRRT, the median dose was 7 sessions/week (IQR = 5 to 7). Only 22% of CRRT patients and 64% of IRRT patients received a more-intensive dose. Crude ICU mortality among CRRT patients were 60.8% vs. 52.5% (more-intensive vs. less-intensive groups, respectively). In IRRT, this was 23.6 vs. 19.4%, respectively. On multivariable analysis, there was no significant association between RRT dose and ICU mortality (Odds ratio (OR) more-intensive vs. less-intensive: CRRT OR = 1.21, 95% confidence interval (CI) = 0.66 to 2.21; IRRT OR = 1.50, 95% CI = 0.48 to 4.67). Among survivors, shorter ICU stay and duration of mechanical ventilation were observed in the more-intensive RRT groups (more-intensive vs. less-intensive for all: CRRT (median): 15 (IQR = 8 to 26) vs. 19.5 (IQR = 12 to 33.5) ICU days, P = 0.063; 7 (IQR = 4 to 17) vs. 14 (IQR = 5 to 24) ventilation days, P = 0.031; IRRT: 8 (IQR = 5.5 to 14) vs. 18 (IQR = 13 to 35) ICU days, P = 0.008; 2.5 (IQR = 0 to 10) vs. 12 (IQR = 3 to 24) ventilation days, P = 0.026).ConclusionsAfter adjustment for multiple variables, these data provide no evidence for a survival benefit afforded by higher dose RRT. However, more-intensive RRT was associated with a favourable effect on ICU stay and duration of mechanical ventilation among survivors. This result warrants further exploration.Trial RegistrationCochrane Renal Group (CRG110600093).

Prophylactic Nasal Continuous Positive Airway Pressure Following Cardiac Surgery Protects From Postoperative Pulmonary Complications: A Prospective, Randomized, Controlled Trial in 500 Patients

BACKGROUND Continuous positive airway pressure is a noninvasive respiratory support technique that may prevent pulmonary complications following cardiac surgery. This study was conducted to determine the efficacy of prophylactic nasal continuous positive airway pressure (nCPAP) compared with standard treatment. The primary end points were pulmonary adverse effects defined as hypoxemia (Pao(2)/fraction of inspired oxygen [Fio(2)] <100), pneumonia, and reintubation. The secondary end point was the readmission rate to the ICU or intermediate care unit (IMCU). METHODS We prospectively randomized 500 patients scheduled for elective cardiac surgery. Following extubation either in the operating room (early) or in the ICU (late), patients were allocated to standard treatment (control) including 10 min of intermittent nCPAP at 10 cm H(2)O every 4 h or prophylactic nCPAP (study) at an airway pressure of 10 cm H(2)O for at least 6 h. RESULTS Prophylactic nCPAP significantly improved arterial oxygenation (Pao(2)/Fio(2)) without altering heart rate and mean arterial BP. Pulmonary complications including hypoxemia (defined as Pao(2)/Fio(2) <100), pneumonia, and reintubation rate were reduced in study patients compared to controls (12 of 232 patients vs 25 of 236 patients, respectively; p = 0.03). The readmission rate to the ICU or IMCU was significantly lower in nCPAP-treated patients (7 of 232 patients vs 14 of 236 patients, respectively; p = 0.03). CONCLUSIONS The long-term administration of prophylactic nCPAP following cardiac surgery improved arterial oxygenation, reduced the incidence of pulmonary complications including pneumonia and reintubation rate, and reduced readmission rate to the ICU or IMCU. Thus noninvasive respiratory support with nCPAP is a useful tool to reduce pulmonary morbidity following elective cardiac surgery.

A safe citrate anticoagulation protocol with variable treatment efficacy and excellent control of the acid-base status.

Objective:Citrate anticoagulation is an excellent alternative to heparin anticoagulation for critically ill patients requiring continuous renal replacement therapy. In this article, we provide a safe and an easy-to-handle citrate anticoagulation protocol with variable treatment doses and excellent control of the acid–base status. Design:Prospective observational study. Setting:University hospital. Patients:One hundred sixty-two patients with acute renal failure requiring renal replacement therapy were enrolled in the study. Intervention:A continuous venovenous hemodialysis-based citrate anticoagulation protocol using a 4% trisodium solution, a specially designed dialysate fluid, and a continuous calcium infusion were used. The study period was 6 days. Hemofilters were changed routinely after 72 hours of treatment. The patients were grouped according to body weight, with patients below 60 kg body weight in group 1, patients with at least 60 kg and up to 90 kg body weight in group 2, and patients with a body weight of above 90 kg in group 3. Dialysate flow was adapted according to body size and matched approximately 2 L/hr for a patient with average body size. Blood flow, citrate flow, and calcium flow were adjusted according to the dialysate flow used. Measurements and Main Results:Median filter run time was 61.5 hours (interquartile range: 34.5–81.1 hours). Only 5% of all hemofilters had to be changed because of clotting. The prescribed treatment dose was achieved in all patients. Acid–base and electrolyte control were excellent in all groups. In the rare cases of metabolic disarrangement during citrate anticoagulation, acid–base values were rapidly corrected by modifying either the dialysate flow or alternatively the blood flow rate. Eight patients (5%) developed signs of citrate accumulation indicated by an increase of the total calcium >3 mmol/L or a need for high calcium substitution. Conclusions:We provide a safe and an easy-to-handle citrate anticoagulation protocol that allows an excellent acid–base and electrolyte control in critically ill patients with acute renal failure. The protocol can be adapted to patients’ need, allowing a wide spectrum of treatment doses.

Assessment of microvascular oxygen saturation in gastric mucosa in volunteers breathing continuous positive airway pressure

OBJECTIVE Adequate oxygenation of the gastrointestinal mucosa to preserve its barrier function is a basic objective in the prevention of multiple organ failure. Sustaining a positive airway pressure during the entire respiratory cycle remains a cornerstone in the therapeutic regimen to improve systemic oxygenation. Whereas increased systemic oxygenation during breathing continuous positive airway pressure has been shown, the impact of continuous positive airway pressure on regional oxygenation in the gastrointestinal tract has not yet been evaluated. We hypothesized that continuous positive airway pressure decreases microvascular oxygen saturation in gastric mucosa. DESIGN Prospective, randomized study. SETTING University department of anesthesiology. PARTICIPANTS Twelve healthy volunteers. INTERVENTIONS Incremental increases of continuous positive airway pressure (0, 5, and 10 cm H(2)O) and subsequent release of continuous positive airway pressure. MEASUREMENTS AND MAIN RESULTS We continuously measured microvascular oxygen saturation in gastric mucosa by reflectance spectrophotometry. Systemic oxygen saturation, end-tidal Pco(2), respiratory rate, heart rate, and arterial blood pressure were obtained noninvasively. In every volunteer, microvascular oxygen saturation in gastric mucosa was reduced corresponding to the level of continuous positive airway pressure, although systemic variables, especially systemic oxygen saturation, did not change. Continuous positive airway pressure reduced microvascular oxygen saturation in gastric mucosa from 59 +/- 7% (baseline with 0 cm H(2)O continuous positive airway pressure, mean +/- sd) to 54 +/- 8% (p <.05) during 5 cm H(2)O continuous positive airway pressure and to 50 +/- 9% (p <.05) during 10 cm H(2)O continuous positive airway pressure, returning to 59 +/- 7% during spontaneous breathing with 0 cm H(2)O continuous positive airway pressure. End-tidal Pco(2), respiratory rate, as well as hemodynamic variables, remained stable. CONCLUSIONS Reflectance spectrophotometry meticulously monitored changes in microvascular oxygen saturation in gastric mucosa during breathing continuous positive airway pressure. Microvascular oxygen saturation in gastric mucosa decreased with increasing levels of continuous positive airway pressure despite steady systemic variables. These results suggest that the impact of altering airway pressures on splanchnic oxygenation is not mirrored necessarily by concomitant changes in systemic circulation. Moreover, if these findings also apply to critically ill patients, monitoring microvascular oxygen saturation in gastric mucosa would be useful to further optimize the setting of ventilation variables.

Regional Citrate Anticoagulation for High Volume Continuous Venovenous Hemodialysis in Surgical Patients With High Bleeding Risk

Acute kidney injury requiring renal replacement therapy occurs in up to 10% of all intensive care unit patients. Those who are hemodynamically unstable are often treated with continuous renal replacement therapy requiring continuous anticoagulation of the extracorporeal circuit. This is usually achieved by infusion of unfractionated heparin, which subsequently increases the risk of bleeding. To avoid systemic anticoagulation for continuous renal replacement therapy, regional anticoagulation with citrate has been introduced. We studied safety and efficacy of regional citrate anticoagulation for continuous venovenous hemodialysis in surgical patients requiring high dialysis doses. This was an observational prospective study in a 40‐bed surgical intensive care unit at a university hospital. During a 12‐month study period, all consecutive critically ill patients with high risk of bleeding requiring continuous renal replacement therapy continuous renal replacement therapy were treated with citrate anticoagulation for continuous venovenous hemodialysis. Prescribed dialysis dose was 45 mL/kg per h with a 10% increase for expected downtime. We studied filter lifetime, delivered dialysis dose, control of acid–base status, bleeding episodes, and adverse effects, that is, citrate intolerance. The total number of filters analyzed in 75 patients was 100. Mean (± standard deviation) filter running time was 78 ± 25 h. Fifty‐one circuits had to be renewed because of extended filter running time (96 ± 18 h), 33 discontinued for reasons not related to renal replacement therapy (62 ± 19 h), and 13 due to filter clotting (58 ± 18 h). The mean dialysis dose during the first 72 h was 49 ± 14 mL/kg per h. Overall, acid–base status after 72 h was well controlled in 62% of patients, metabolic alkalosis (pH > 7.45) occurred in 29%, and metabolic acidosis (pH < 7.35) in 9%. In one patient, treatment was stopped because of citrate accumulation. Citrate intoxication or overt bleeding episodes were not observed. Regional citrate anticoagulation for continuous venovenous hemodialysis is a safe and effective method to deliver a high dialysis dose in critically ill patients with a high risk of bleeding. Filter patency was excellent, acid–base status was well controlled, and clinically relevant adverse effects were not observed. Therefore, citrate anticoagulated continuous venovenous hemodialysis is a useful treatment option for patients with acute kidney injury requiring high dialysis doses and at risk of bleeding.

Effects of prostaglandin E2 on the intensity of bradykinin-evoked pain from skin and veins of humans.

Prostaglandin E2 increases bradykinin-induced spike activity from polymodal nociceptors of the skin and deep tissues in animals, suggesting sensitization of these receptors. To see whether these neurophysiological observations in animals correspond with increased pain intensity in humans, and whether also vascular nociceptors are sensitized, we studied in humans the effects of prostaglandin E2 on the intensity of pain evoked by bradykinin via the nociceptive systems of skin and veins. In seven healthy subjects, bradykinin was injected into the skin and into a vascularly isolated hand vein segment, prior to and after local application of prostaglandin E2. Subsequent pain intensity was recorded continuously with an electronically controlled visual analogue scale. Prostaglandin E2 alone never elicited pain, but without exception increased the intensity of bradykinin-induced pain in a concentration-related manner at concentrations from 10(-9) to 10(-6) M, both in skin and veins. Thus, bradykinin is more painful after pretreatment with prostaglandin E2, suggesting sensitization of nociceptors of the skin, but also of hand veins in humans.

Treatment of Severe Hypercalcemia Using Continuous Renal Replacement Therapy With Regional Citrate Anticoagulation

We report a patient with severe hypercalcemia and acute kidney failure, in whom citrate anticoagulation was used not only for anticoagulation but also to correct ionized hypercalcemia (1.77 mmol/L). In this patient, after a complicated surgical procedure, septic shock led to acute kidney failure. We started continuous venovenous hemodialysis with citrate anticoagulation. By almost stopping the calcium substitution during the first hours, elevated systemic ionized calcium decreased into the normal range within 8 hours. Although calcium substitution was then increased, serum ionized calcium decreased to a nadir of 0.86 mmol/L and then stabilized within the normal range within the next 24 hours. To correct the imbalance in systemic ionized calcium concentration, the calcium substitution was varied over a wide range of 0.1–3.0 mmol/L of generated effluent. The time delay between adjustment in calcium infusion rate and the first detectable change in ionized calcium level was below 4 hours. However, the full response to a change of the calcium substitution was found after 8–12 hours.

Study protocol: the DOse REsponse Multicentre International collaborative initiative (DO-RE-MI)

IntroductionCurrent practices for renal replacement therapy in intensive care units (ICUs) remain poorly defined. The DOse REsponse Multicentre International collaborative initiative (DO-RE-MI) will address the issue of how the different modes of renal replacement therapy are currently chosen and performed. Here, we describe the study protocol, which was approved by the Scientific and Steering Committees.MethodsDO-RE-MI is an observational, multicentre study conducted in ICUs. The primary end-point will be the delivered dose of dialysis, which will be compared with ICU mortality, 28-day mortality, hospital mortality, ICU length of stay and number of days of mechanical ventilation. The secondary end-point will be the haemodynamic response to renal replacement therapy, expressed as percentage reduction in noradrenaline (norepinephrine) requirement. Based on the the sample analysis calculation, at least 162 patients must be recruited. Anonymized patient data will be entered online in electronic case report forms and uploaded to an internet website. Each participating centre will have 2 months to become acquainted with the electronic case report forms. After this period official recruitment will begin. Patient data belong to the respective centre, which may use the database for its own needs. However, all centres have agreed to participate in a joint effort to achieve the sample size needed for statistical analysis.ConclusionThe study will hopefully help to collect useful information on the current practice of renal replacement therapy in ICUs. It will also provide a centre-based collection of data that will be useful for monitoring all aspects of extracorporeal support, such as incidence, frequency, and duration.

Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial

IntroductionCritically ill patients often require renal replacement therapy accompanied by thrombocytopenia. Thrombocytopenia during heparin anticoagulation may be due to heparin-induced thrombocytopenia with need for alternative anticoagulation. Therefore, we compared argatroban and lepirudin in critically ill surgical patients.MethodsFollowing institutional review board approval and written informed consent, critically ill surgical patients more than or equal to 18 years with suspected heparin-induced thrombocytopenia, were randomly assigned to receive double-blind argatroban or lepirudin anticoagulation targeting an activated Partial Thromboplastin Time (aPTT) of 1.5 to 2 times baseline. In patients requiring continuous renal replacement therapy we compared the life-time of hemodialysis filters. We evaluated in all patients the incidence of bleeding and thrombembolic events.ResultsWe identified 66 patients with suspected heparin-induced thrombocytopenia, including 28 requiring renal replacement therapy. Mean filter lifetimes did not differ between groups (argatroban 32 ± 25 hours (n = 12) versus lepirudin 27 ± 21 hours (n = 16), mean difference 5 hours, 95% CI −13 to 23, P = 0.227). Among all 66 patients, relevant bleeding occurred in four argatroban- versus eleven lepirudin-patients (OR 3.9, 95% CI 1.1 to 14.0, P = 0.040). In the argatroban-group, three thromboembolic events occurred compared to two in the lepirudin group (OR 0.7, 95% CI 0.1 to 4.4, P = 0.639). The incidence of confirmed heparin-induced thrombocytopenia was 23% (n = 15) in our study population.ConclusionsThis first randomized controlled double-blind trial comparing two direct thrombin inhibitors showed comparable effectiveness for renal replacement therapy, but suggests fewer bleeds in surgical patients with argatroban anticoagulation.Trial registrationClinical Trials.gov NCT00798525. Registered 25 November 2008

Pain and inflammation evoked in human skin by bradykinin receptor antagonists

We showed the intrinsic effects of the bradykinin (BK) receptor antagonists, NPC 567 (D-Arg-[Hyp3,D-Phe7]BK) and NPC 349 (D-Arg-[Hyp3,Thi5,8,D-Phe-7]BK), in the skin of humans. NPC 567 and NPC 349 caused dose-dependent pain, wheal, and flare on intracutaneous injection. After bradykinin, only the pain, but not the wheal and flare reactions were dose-dependent. The intravenous application of antihistamines (dimetidinmaleate and ranitidine) had little effect on pain intensity and reduced both wheal and flare response to the antagonists but not to bradykinin. We conclude that NPC 567 and NPC 349 have pain-evoking and histamine-releasing properties in the skin of humans which may limit their therapeutic and experimental use.