Peter H. J. van der Voort

Quantifying bedside-derived imaging of microcirculatory abnormalities in septic patients: a prospective validation study

IntroductionThe introduction of orthogonal polarization spectral (OPS) imaging in clinical research has elucidated new perspectives on the role of microcirculatory flow abnormalities in the pathogenesis of sepsis. Essential to the process of understanding and reproducing these abnormalities is the method of quantification of flow scores.MethodsIn a consensus meeting with collaboraters from six research centres in different fields of experience with microcirculatory OPS imaging, premeditated qualifications for a simple, translucent and reproducible way of flow scoring were defined. Consecutively, a single-centre prospective observational validation study was performed in a group of 12 patients with an abdominal sepsis and a new stoma. Flow images of the microcirculation in vascular beds of the sublingual and stoma region were obtained, processed and analysed in a standardised way. We validated intra-observer and inter-observer reproducibility with kappa cross-tables for both types of microvascular beds.ResultsAgreement and kappa coefficients were >85% and >0.75, respectively, for interrater and intrarater variability in quantification of flow abnormalities during sepsis, in different subsets of microvascular architecture.ConclusionSemi-quantitative analysis of microcirculatory flow, as described, provides a reproducible and transparent tool in clinical research to monitor and evaluate the microcirculation during sepsis.

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.

Relationship between sublingual and intestinal microcirculatory perfusion in patients with abdominal sepsis

Objective:To evaluate the relation between sublingual and intestinal microcirculatory alterations in patients with abdominal sepsis. Design:Prospective observational study. Setting:A 23-bed mixed intensive care unit of a tertiary teaching hospital. Patients:Twenty-three patients with abdominal sepsis and a newly constructed intestinal stoma were included in the study group. Nineteen outpatient healthy individuals with an intestinal stoma and ten nonsepsis patients with a <24-hr-old intestinal stoma were included as controls. Interventions:None. Measurements and Main Results:Orthogonal polarization spectral imaging of the sublingual and intestinal microcirculation was performed on days 1 and 3. In addition, variables of systemic hemodynamics, such as cardiac index, heart rate, blood pressure, central venous pressure, and dosages of vasopressor and inotropic agents, were obtained. On day 1 there was no correlation of the microvascular flow index between the sublingual and intestinal microcirculatory beds (Spearmans rho [rs] = .12; 95% confidence interval, −.51 to .31; p = .59). Furthermore, there was no significant correlation between microcirculatory alterations and variables of systemic circulation (rs ≤ .25). On day 3, however, a correlation between sublingual and intestinal microcirculatory flow appeared to be restored (rs = .74; 95% confidence interval, .28–.92; p = .006), mainly due to a normalization of flow in both regions. Conclusions:On day 1 of abdominal sepsis there is a complete dispersion of flow, not only between hemodynamic compartments of a different order but also between the sublingual and intestinal microcirculation. Over time, both sublingual and intestinal microvascular flow indexes trended to normal values.

Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients

IntroductionThe aim of this study was to investigate whether in-hospital mortality was associated with the administered fraction of oxygen in inspired air (FiO2) and achieved arterial partial pressure of oxygen (PaO2).MethodsThis was a retrospective, observational study on data from the first 24 h after admission from 36,307 consecutive patients admitted to 50 Dutch intensive care units (ICUs) and treated with mechanical ventilation. Oxygenation data from all admission days were analysed in a subset of 3,322 patients in 5 ICUs.ResultsMean PaO2 and FiO2 in the first 24 h after ICU admission were 13.2 kPa (standard deviation (SD) 6.5) and 50% (SD 20%) respectively. Mean PaO2 and FiO2 from all admission days were 12.4 kPa (SD 5.5) and 53% (SD 18). Focusing on oxygenation in the first 24 h of admission, in-hospital mortality was shown to be linearly related to FiO2 value and had a U-shaped relationship with PaO2 (both lower and higher PaO2 values were associated with a higher mortality), independent of each other and of Simplified Acute Physiology Score (SAPS) II, age, admission type, reduced Glasgow Coma Scale (GCS) score, and individual ICU. Focusing on the entire ICU stay, in-hospital mortality was independently associated with mean FiO2 during ICU stay and with the lower two quintiles of mean PaO2 value during ICU stay.ConclusionsActually achieved PaO2 values in ICU patients in The Netherlands are higher than generally recommended in the literature. High FiO2, and both low PaO2 and high PaO2 in the first 24 h after admission are independently associated with in-hospital mortality in ICU patients. Future research should study whether this association is causal or merely a reflection of differences in severity of illness insufficiently corrected for in the multivariate analysis.

Routine use of the confusion assessment method for the intensive care unit : a multicenter study

RATIONALE Delirium is often unrecognized in ICU patients and associated with poor outcome. Screening for ICU delirium is recommended by several medical organizations to improve early diagnosis and treatment. The Confusion Assessment Method for the ICU (CAM-ICU) has high sensitivity and specificity for delirium when administered by research nurses. However, test characteristics of the CAM-ICU as performed in routine practice are unclear. OBJECTIVES To investigate the diagnostic value of the CAM-ICU in daily practice. METHODS Teams of three delirium experts including psychiatrists, geriatricians, and neurologists visited 10 ICUs twice. Based on cognitive examination, inspection of medical files, and Diagnostic and Statistic Manual of Mental Disorders, 4th edition, Text Revision criteria for delirium, the expert teams classified patients as awake and not delirious, delirious, or comatose. This served as a gold standard to which the CAM-ICU as performed by the bedside ICU-nurses was compared. Assessors were unaware of each others conclusions. MEASUREMENTS AND MAIN RESULTS Fifteen delirium experts assessed 282 patients of whom 101 (36%) were comatose and excluded. In the remaining 181 (64%) patients, the CAM-ICU had a sensitivity of 47% (95% confidence interval [CI], 35%-58%); specificity of 98% (95% CI, 93%-100%); positive predictive value of 95% (95% CI, 80%-99%); and negative predictive value of 72% (95% CI, 64%-79%). The positive likelihood ratio was 24.7 (95% CI, 6.1-100) and the negative likelihood ratio was 0.5 (95% CI, 0.4-0.8). CONCLUSIONS Specificity of the CAM-ICU as performed in routine practice seems to be high but sensitivity is low. This hampers early detection of delirium by the CAM-ICU.

Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: a double blind randomized controlled trial.

Objective:To study the potential beneficial role of furosemide in resolving renal failure after hemofiltration in mechanically ventilated critically ill patients. Design:Single-center randomized, double blind, placebo-controlled study. Setting:A 13-bed mixed intensive care unit (ICU) in a teaching hospital. Patients:Patients who had been treated with continuous venovenous hemofiltration were included. Interventions:After the end of continuous venovenous hemofiltration, the urine of the first 4 hours was collected for measuring creatinine clearance. Patients were subsequently randomized for furosemide (0.5 mg/kg/hr) or placebo by continuous infusion. To prevent hypovolemia, the rate of fluid infusion was adapted every hour and was set as the urinary production of the previous hour. Measurements and Main Results:End points were renal recovery (creatinine clearance more than 30 mL/min or stable serum creatinine without renal replacement therapy) in the ICU and in the hospital. Seventy-two patients were included and 71 were eligible for the analysis. The 36 furosemide-treated patients had a significantly increased urinary volume compared with the 35 placebo-treated patients (median 247 mL/hr (interquartile range [IQR] 774 mL/hr) vs. 117 mL/hr (IQR 158 mL/hr), p = 0.003) and greater sodium excretion (median 73 mmol/L (IQR 48) vs. 37 (IQR 48) mmol/L, p = 0.001). In the furosemide group 25 patients and in the placebo group 27 patients showed recovery of renal function at ICU discharge (p = 0.46). Two patients of the furosemide group needed long-term dialysis dependency (p = 0.23). Conclusion:Furosemide by continuous infusion in the recovery phase of hemofiltration-dependent acute kidney failure did increase urinary volume and sodium excretion but did not lead to a shorter duration of renal failure or more frequent renal recovery.

Laxation of critically ill patients with lactulose or polyethylene glycol: a two-center randomized, double-blind, placebo-controlled trial

Objective: To study whether lactulose or polyethylene glycol is effective to promote defecation in critically ill patients, whether either of the two is superior, and whether the use of enteral laxatives is related to clinical outcome. Design: Double‐blind, placebo‐controlled, randomized study. Setting: Two tertiary intensive care units. Patients: Three hundred and eight consecutive patients with multiple organ failure were included when receiving mechanical ventilation and intravenous circulatory support and when defecation did not occur on day 3 after admission. Interventions: Thrice daily administration of lactulose, polyethylene glycol, or placebo until defecation occurred, to a maximum of 4 days. Measurements and Main Results: The number of patients with defecation during the study period was 32 of 103 (31%) for placebo, 76 of 110 (69%) for lactulose, and 70 of 95 (74%) for polyethylene glycol (p = .001 for lactulose and polyethylene glycol vs. placebo). Lactulose and polyethylene glycol‐treated patients produced stools after a median of 36 and 44 hrs, respectively, compared with 75 hrs for the placebo group (p = .001 for lactulose and polyethylene glycol vs. placebo). Length of stay in the intensive care unit was a median of 156 hrs for the lactulose group, 190 hrs for the polyethylene glycol group, and 196 hrs for the placebo group (p = .001). Intestinal pseudoobstruction or Ogilvies syndrome occurred in 4.1% of patients in the placebo group, 5.5% of patients in the lactulose group, and 1.0% of patients in the polyethylene glycol group. There was no difference in hospital mortality. Administration of morphine was associated with a longer time before first defecation, except in the polyethylene glycol group. For all groups, defecation within 6 days after admission was associated with a shorter length of stay. Conclusions: Both lactulose and polyethylene glycol are more effective in promoting defecation than placebo. Patients receiving polyethylene glycol had a slightly lower incidence of acute intestinal pseudoobstruction, whereas length of stay was shorter in lactulose‐treated patients. Morphine administration was associated with delayed defecation except in the polyethylene glycol‐treated group. Irrespective of study medication, early defecation was associated with a shorter length of stay.

Albumin-adjusted calcium is not suitable for diagnosis of hyper- and hypocalcemia in the critically ill.

ObjectiveTo evaluate whether calcium adjusted for albumin can be used to monitor calcium homeostasis in critically ill patients. DesignProspective single-single center observational study. SettingClinical laboratory and critical care unit of a regional teaching hospital. PatientsFifty-three paired samples were from 36 patients requiring intensive care treatment. InterventionsNone. Measurements and Main ResultsTotal calcium, albumin-adjusted calcium, and ionized calcium were measured in critically ill patients during an 8-wk period. Calcium was adjusted for albumin using the formula that is most frequently used in The Netherlands. Using ionized calcium as the gold standard, albumin-adjusted calcium overestimated hypercalcemia and totally missed hypocalcemia. The same seemed to be true for other formulas used for albumin or protein adjustment of calcium concentrations. ConclusionsAlbumin-adjusted calcium cannot be used in an intensive care setting to monitor reliably the calcium levels in critically ill patients and should be replaced by measurement of ionized calcium.

A systematic review of implementation strategies for assessment, prevention, and management of ICU delirium and their effect on clinical outcomes

IntroductionDespite recommendations from professional societies and patient safety organizations, the majority of ICU patients worldwide are not routinely monitored for delirium, thus preventing timely prevention and management. The purpose of this systematic review is to summarize what types of implementation strategies have been tested to improve ICU clinicians’ ability to effectively assess, prevent and treat delirium and to evaluate the effect of these strategies on clinical outcomes.MethodWe searched PubMed, Embase, PsychINFO, Cochrane and CINAHL (January 2000 and April 2014) for studies on implementation strategies that included delirium-oriented interventions in adult ICU patients. Studies were suitable for inclusion if implementation strategies’ efficacy, in terms of a clinical outcome, or process outcome was described.ResultsWe included 21 studies, all including process measures, while 9 reported both process measures and clinical outcomes. Some individual strategies such as “audit and feedback” and “tailored interventions” may be important to establish clinical outcome improvements, but otherwise robust data on effectiveness of specific implementation strategies were scarce. Successful implementation interventions were frequently reported to change process measures, such as improvements in adherence to delirium screening with up to 92%, but relating process measures to outcome changes was generally not possible. In meta-analyses, reduced mortality and ICU length of stay reduction were statistically more likely with implementation programs that employed more (six or more) rather than less implementation strategies and when a framework was used that either integrated current evidence on pain, agitation and delirium management (PAD) or when a strategy of early awakening, breathing, delirium screening and early exercise (ABCDE bundle) was employed. Using implementation strategies aimed at organizational change, next to behavioral change, was also associated with reduced mortality.ConclusionOur findings may indicate that multi-component implementation programs with a higher number of strategies targeting ICU delirium assessment, prevention and treatment and integrated within PAD or ABCDE bundle have the potential to improve clinical outcomes. However, prospective confirmation of these findings is needed to inform the most effective implementation practice with regard to integrated delirium management and such research should clearly delineate effective practice change from improvements in clinical outcomes.

International study on microcirculatory shock occurrence in acutely ill patients

Objectives:Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. The prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables. Design:Multicenter observational point prevalence study. Setting:The Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide. Patients:A heterogeneous ICU population consisting of 501 patients. Interventions:None. Measurements and Main Results:Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10–21), a Sequential Organ Failure Assessment score of 5 (2–8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67–4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963–0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11–3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28–3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. In reference to microvascular flow index, a significant interaction was observed with tachycardia. In patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30–8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients. Conclusions:In a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.