Durk F. Zandstra

Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial

ObjectiveTo study the effects of the initiation time of continuous venovenous hemofiltration and of the ultrafiltrate rate in patients with circulatory and respiratory insufficiency developing early oliguric acute renal failure. The primary end points were mortality at 28 days and recovery of renal function. DesignA randomized, controlled, two-center study. SettingThe closed-format multidisciplinary intensive care units of a university hospital (30 beds) and a teaching hospital (18 beds). Patients and InterventionsA total of 106 ventilated severely ill patients who were oliguric despite massive fluid resuscitation, inotropic support, and high-dose intravenous diuretics were randomized into three groups. Thirty-five patients were treated with early high-volume hemofiltration (72–96 L per 24 hrs), 35 patients with early low-volume hemofiltration (24–36 L per 24 hrs), and 36 patients with late low-volume hemofiltration (24–36 L per 24 hrs). ResultsMedian ultrafiltrate rate was 48.2 (42.3–58.7) mL·kg−1·hr−1 in early high-volume hemofiltration, 20.1 (17.5–22.0) mL·kg−1·hr−1 in early low-volume hemofiltration, and 19.0 (16.6–21.1) mL·kg−1·hr−1 in late low-volume hemofiltration. Survival at day 28 was 74.3% in early high-volume hemofiltration, 68.8% in early low-volume hemofiltration, and 75.0% in late low-volume hemofiltration (p = .80). On average, hemofiltration started 7 hrs after inclusion in the early groups and 42 hrs after inclusion in the late group. All hospital survivors had recovery of renal function at hospital discharge, except for one patient in the early low-volume hemofiltration group. Median duration of renal failure in hospital survivors was 4.3 (1.4–7.8) days in early high-volume hemofiltration, 3.2 (2.4–5.4) days in early low-volume hemofiltration, and 5.6 (3.1–8.5) days in late low-volume hemofiltration (p = .25). ConclusionsIn the present study of critically ill patients with oliguric acute renal failure, survival at 28 days and recovery of renal function were not improved using high ultrafiltrate volumes or early initiation of hemofiltration.

Nitroglycerin in septic shock after intravascular volume resuscitation

In patients with septic shock, oxygen consumption is increased, but oxygen delivery and extraction is impaired, partly because of microcirculatory shutdown and shunting. Orthogonal polarisation spectral (OPS) imaging allows visualisation of the microcirculation. We used this technique to assess microcirculatory flow in septic-shock patients who had a mean arterial blood pressure of more than 60 mm Hg and central venous pressure greater than 12 mm Hg. The infusion of 0.5 mg of nitroglycerin intravenously then resulted in a marked increase in microvascular flow on OPS imaging. Improved recruitment of the microcirculation could be a new resuscitation endpoint in septic shock.

Glucose variability is associated with intensive care unit mortality.

Objective:Mounting evidence suggests a role for glucose variability in predicting intensive care unit (ICU) mortality. We investigated the association between glucose variability and intensive care unit and in-hospital deaths across several ranges of mean glucose. Design:Retrospective cohort study. Setting:An 18-bed medical/surgical ICU in a teaching hospital. Patients:All patients admitted to the ICU from January 2004 through December 2007. Interventions:None. Measurements and Main Results:Two measures of variability, mean absolute glucose change per hour and sd, were calculated as measures of glucose variability from 5728 patients and were related to ICU and in-hospital death using logistic regression analysis. Mortality rates and adjusted odds ratios for ICU death per mean absolute glucose change per hour quartile across quartiles of mean glucose were calculated. Patients were treated with a computerized insulin algorithm (target glucose 72–126 mg/dL). Mean age was 65 ± 13 yrs, 34% were female, and 6.3% of patients died in the ICU. The odds ratios for ICU death were higher for quartiles of mean absolute glucose change per hour compared with quartiles of mean glucose or sd. The highest odds ratio for ICU death was found in patients with the highest mean absolute glucose change per hour in the upper glucose quartile: odds ratio 12.4 (95% confidence interval, 3.2–47.9; p < .001). Mortality rates were lowest in the lowest mean absolute glucose change per hour quartiles. Conclusions:High glucose variability is firmly associated with ICU and in-hospital death. High glucose variability combined with high mean glucose values is associated with highest ICU mortality. In patients treated with strict glycemic control, low glucose variability seemed protective, even when mean glucose levels remained elevated.

Citrate anticoagulation for continuous venovenous hemofiltration.

Objective:Continuous venovenous hemofiltration (CVVH) is applied in critically ill patients with acute renal failure for renal replacement. Heparins used to prevent circuit clotting may cause bleeding. Regional anticoagulation with citrate reduces bleeding, but has metabolic risks. The aim was to compare the safety and efficacy of the two. Design:Randomized, nonblinded, controlled single-center trial. Setting:General intensive care unit of a teaching hospital. Patients:Adult critically ill patients needing CVVH for acute renal failure and without an increased bleeding risk. Interventions:Regional anticoagulation with citrate or systemic anticoagulation with the low-molecular weight heparin nadroparin. Measurements and Main Results:End points were adverse events necessitating discontinuation of study anticoagulant, transfusion, metabolic and clinical outcomes, and circuit survival. Of the 215 randomized patients, 200 received CVVH per protocol (97 citrate and 103 nadroparin). Adverse events required discontinuation of citrate in two patients (accumulation and clotting) of nadroparin in 20 (bleeding and thrombocytopenia) (p < 0.001). Bleeding occurred in 6 vs. 16 patients (p = 0.08). The median number of red blood cell units transfused per CVVH day was 0.27 (interquartile range, 0.0–0.63) for citrate, 0.36 (interquartile range, 0–0.83) for nadroparin (p = 0.31). Citrate conferred less metabolic alkalosis (p = 0.001) and lower plasma calcium (p < 0.001). Circuit survival was similar. Three-month mortality on intention-to-treat was 48% (citrate) and 63% (nadroparin) (p = 0.03), per protocol 45% and 62% (p = 0.02). Citrate reduced mortality in surgical patients (p = 0.007), sepsis (p = 0.01), higher Sepsis-Related Organ Failure Assessment score (p = 0.006), and lower age (p = 0.009). Conclusions:The efficacy of citrate and nadroparin anticoagulation for CVVH was similar, however, citrate was safer. Unexpectedly, citrate reduced mortality. Less bleeding could only partly explain this benefit, less clotting could not. Post hoc citrate appeared particularly beneficial after surgery, in sepsis and severe multiple organ failure, suggesting interference with inflammation.

Bench-to-bedside review: Sepsis is a disease of the microcirculation

Microcirculatory perfusion is disturbed in sepsis. Recent research has shown that maintaining systemic blood pressure is associated with inadequate perfusion of the microcirculation in sepsis. Microcirculatory perfusion is regulated by an intricate interplay of many neuroendocrine and paracrine pathways, which makes blood flow though this microvascular network a heterogeneous process. Owing to an increased microcirculatory resistance, a maldistribution of blood flow occurs with a decreased systemic vascular resistance due to shunting phenomena. Therapy in shock is aimed at the optimization of cardiac function, arterial hemoglobin saturation and tissue perfusion. This will mean the correction of hypovolemia and the restoration of an evenly distributed microcirculatory flow and adequate oxygen transport. A practical clinical score for the definition of shock is proposed and a novel technique for bedside visualization of the capillary network is discussed, including its possible implications for the treatment of septic shock patients with vasodilators to open the microcirculation.

Use of a Computerized Guideline for Glucose Regulation in the Intensive Care Unit Improved Both Guideline Adherence and Glucose Regulation

OBJECTIVE To measure the impact of a computerized guideline for glucose regulation in an ICU. DESIGN A randomized, controlled trial with an off-on-off design. METHODS We implemented a glucose regulation guideline in an intensive care unit in paper form during the first study period. During the second period, the guideline was randomly applied in either paper or computerized form. In the third period, the guideline was available only in paper form. MEASUREMENTS AND RESULTS We analyzed data for 484 patients. During the intervention period, the control group included 54 patients and the computerized intervention group included 66 patients. The two guideline-related outcome measures consisted of compliance with: (a) glucose measurement timing recommendations and (b) insulin dose advice. We measured clinical impact as the proportion of time that glucose levels fell within target range. In the first (paper-based) study period, 29.0% of samples occurred with optimal timing; during the second period, this increased to 35.5% for paper-based and to 40.2% for computerized protocols. The third study period timeliness scores reverted to the first period rates. Late (suboptimal) sampling occurred for 66% of glucose measurements in the first study period, for 42% of paper-based and 28% of computer-based protocol samples in the second period, and for 50.0% of samples in the third study period. In the first study period, insulin-dosing guideline compliance was 56.3%; in the second period, it was 64.2% for paper-based and 77.3% for computer-based protocols, and it fell to 42.4% in the third period. For the second study period, the time that a patients glucose values fell within target range improved for both the control (52.9%) and the computerized groups (54.2%) compared with the first study period (44.3%) and the third period (42.3%). CONCLUSION Implementing a computerized version of a guideline significantly improved timeliness of measurements and glucose level regulation for critically ill patients compared with implementing a paper-based version of the guideline.

Outcome of critically ill patients treated with intermittent high-volume haemofiltration: a prospective cohort analysis.

Objective: To evaluate intervention and outcome in critically ill patients treated with high-volume haemofiltration (HV-HF). Design: Prospective cohort analysis. Setting: 18-bed closed format general intensive care unit (ICU) of a teaching hospital. Patients: 30-month cohort of ICU patients treated with HV-HF. Interventions: Intermittent high-volume venovenous haemofiltration. Endpoints: Observed and predicted mortality in prospectively stratified prognostic groups. Measurements and results: Clinical and filtration data, Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II and the Madrid Acute Renal Failure (ARF) score and predicted mortality. A total of 306 patients were haemofiltrated (140 medical, 166 surgical), 52 % were oliguric. Mean APACHE II score was 31 (SD 8) and mean SAPS II score 60 (SD 16). Mean ultrafiltrate rate was 63 ml/min (SD 20). A median total of 160 litres (90 % range 49 to 453) were filtrated per patient, material costs were 565 ECU (90 % range 199 to 1514). ICU mortality was 33 %, hospital mortality 40 % [95 % confidence interval (CI) 34 to 45], predicted mortality by the ARF score 67 % (CI 66 to 69). Non-cardiac surgery mortality was 47 % (CI 39 to 54), 73 % (CI 70 to 76) predicted by APACHE II and 67 % (CI 64 to 70) by SAPS II. Observed mortality was significantly lower than predicted in all prognostic groups. The standardised mortality ratio (SMR) was no higher than the SMR in the overall ICU population. Conclusions: Mortality in HV-HF patients was lower than that predicted by illness severity scores, as was the case in all patients in our ICU. Treatment with HV-HF appears to be safe and feasible. The efficacy of HV-HF should be tested in randomised, controlled trials of suitable power.

Hypoglycemia is associated with intensive care unit mortality.

Objective:The implementation of intensive insulin therapy in the intensive care unit is accompanied by an increase in hypoglycemia. We studied the relation between hypoglycemia on intensive care unit mortality, because the evidence on this subject is conflicting. Design:Retrospective database cohort study. Setting:An 18-bed medical/surgical intensive care unit in a teaching hospital (Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, The Netherlands). Patients:A total of 5961 patients admitted to from 2004 to 2007 were analyzed. Readmissions and patients with a withholding care policy or with hypoglycemia on the first glucose measurement were excluded. Patients were treated with a computerized insulin algorithm (target glucose range, 72-126 mg/dL). Interventions:None. Measurements and Main Results:All first episodes of hypoglycemia (glucose ≤45 mg/dL) were derived from 154,015 glucose values. Using Poisson regression, the incidence rates for intensive care unit death and incidence rate ratio comparing exposure and nonexposure to hypoglycemia were calculated. Patients were considered to be exposed to hypoglycemia from the event until the end of intensive care unit admittance. We corrected for severity of disease using the daily Sequential Organ Failure Assessment score. Age, sex, cardiothoracic surgery, sepsis, and diabetes mellitus were also included as possible confounders. Two hundred eighty-eight (4.8%) patients experienced at least one episode of hypoglycemia. Median age was 68 yrs (range, 58-75 yrs), 66% were male, and 6.4% died in the intensive care unit. The incidence rate of death in patients exposed to hypoglycemia was 40 per 1000 intensive care unit days compared with 17 per 1000 intensive care unit days in patients without exposure. The adjusted incidence rate ratio for intensive care unit death was 2.1 (95% confidence interval, 1.6-2.8; p < .001). Conclusions:Hypoglycemia is related to intensive care unit mortality, also when adjusted for a daily adjudicated measure of disease severity, indicating the possibility of a causal relationship.

The use of intensive care information systems alters outcome prediction

ObjectiveTo study the effect of using an Intensive Care Information System (ICIS) on severity scores and prognostic indices: Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II), and Mortality Probability Models II (MPMII).DesignProspective pilot study.SettingA 20-bed medical-surgical intensive care unit (ICU) in a teaching hospital.Patients50 consecutive adult patients admitted to the ICU on a bed equipped with an ICIS.InterventionsNone.Measurements and resultsIn each patient all the physiologic variables, as required by the severity scores, were both manually charted and recorded by ICIS. ICIS registration resulted in the extraction of more abnormal values for all physiologic variables (except temperature): p<0.05. Higher severity scores and mortality prediction were achieved by using ICIS charting: predicted mortality increased by 15 % for APACHE II compared to manual charting, 25 % for SAPS II, and 24% for MPM0. ICIS charting resulted in higher severity scores and mortality prediction for 29 of the 50 patients using APACHE II with a mean increase in mortality prediction in this subgroup of 27 %. In the case of SAPS II, ICIS charting resulted in higher scores in 23 of the 50 patients and in the case of MPM0 in 13 patients, the mean increase in mortality in these subgroups being 64 and 148 %, respectively.ConclusionsThe use of ICIS charting to acquire the most abnormal physiologic values for severity scores and the derived prognostic indices results in a higher mortality prediction. Comparison of groups of patients and/or ICUs based on severity scores is impossible without standardization of data collection. The mortality prediction models have to be revalidated for the use of ICIS charting. While awaiting this, we suggest that every patient record in local regional, national, or international ICU databases should be marked as being recorded by manual or by ICIS charting.

Disseminated tuberculosis, pulmonary aspergillosis and cutaneous herpes simplex infection in a patient with infliximab and methotrexate

Case presentationDespite chemoprophylaxis with isoniazid a 58-year-old Creole patient with mild rheumatoid arthritis developed disseminated tuberculosis, pulmonary aspergillosis and cutaneous herpes simplex infection during treatment with infliximab and methotrexate.TreatmentThe patient received antituberculous drugs (ethambutol, isoniazid, pyrazinamide, rifampicin), amphotericin B, flucytosine, and valaciclovir, along with prolonged intensive care treatment and mechanical ventilation.ConclusionsThe present case confirms that isoniazid prophylaxis (300 mg once daily, during 6 months) does not protect against the reactivation and dissemination of latent tuberculosis. It also shows that combined treatment with infliximab and methotrexate may induce severe immunosuppression with prolonged leukocytopenia and depressed cellular immunity, leading to multiple opportunistic infections. Extensive diagnostic testing, early start of antimicrobial therapy and enteral immunonutrition, and further infection prevention with selective decontamination of the digestive tract may have been the key to a good clinical outcome.