Evert de Jonge

Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints.

BACKGROUND Excessive bleeding may complicate cardiac surgery, and is associated with increased morbidity and mortality. Pharmacological strategies to decrease perioperative bleeding have been investigated in a large number of controlled trials, most of which have shown a decrease in blood loss. However, most studies lacked sufficient power to detect a beneficial effect on clinically more relevant outcomes. We did a meta-analysis of all randomised, controlled trials of the three most frequently used pharmacological strategies to decrease perioperative blood loss (aprotinin, lysine analogues [aminocaproic acid and tranexamic acid], and desmopressin). METHODS Studies were included if they reported at least one clinically relevant outcome (mortality, rethoracotomy, proportion of patients receiving a transfusion, or perioperative myocardial infarction) in addition to perioperative blood loss. In addition, a separate meta-analysis was done for studies concerning complicated cardiac surgery. FINDINGS We identified 72 trials (8409 patients) that met the inclusion criteria. Treatment with aprotinin decreased mortality almost two-fold (odds ratio 0.55 [95% CI 0.34-0.90]) compared with placebo. Treatment with aprotinin and with lysine analogues decreased the frequency of surgical re-exploration (0.37 [0.25-0.55], and 0.44 [0.22-0.90], respectively). These two treatments also significantly decreased the proportion of patients receiving any allogeneic blood transfusion. By contrast, the use of desmopressin resulted in a small decrease in perioperative blood loss, but was not associated with a beneficial effect on other clinical outcomes. Aprotinin and lysine analogues did not increase the risk of perioperative myocardial infarction; however, desmopressin was associated with a 2.4-fold increase in the risk of this complication. Studies in patients undergoing complicated cardiac surgery showed similar results. INTERPRETATION Pharmacological strategies that decrease perioperative blood loss in cardiac surgery, in particular aprotinin and lysine analogues, also decrease mortality, the need for rethoracotomy, and the proportion of patients receiving a blood transfusion.

Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial

BACKGROUND Selective decontamination of the digestive tract (SDD) is an infection-prevention regimen used in critically ill patients. We assessed the effects of SDD on intensive-care-unit (ICU) and hospital mortality, and on the acquisition of resistant bacteria in adult patients admitted to intensive care. METHODS We did a prospective, controlled, randomised, unblinded clinical trial. 934 patients admitted to a surgical and medical ICU were randomly assigned oral and enteral polymyxin E, tobramycin, and amphotericin B combined with an initial 4-day course of intravenous cefotaxime (SDD group n=466), or standard treatment (controls n=468). Primary endpoints were ICU and hospital mortality and the acquisition of resistant bacteria. FINDINGS In the SDD group 69 (15%) patients died in the ICU compared with 107 (23%) in the control group (p=0.002). Hospital mortality was lower in the SDD groups than in the control group (113 [24%] vs 146 [31%], p=0.02). During their stay in intensive care, colonisation with gram-negative bacteria resistant to ceftazidime, ciprofloxacin, imipenem, polymyxin E, or tobramycin occurred in 61 (16%) of 378 SDD patients and in 104 (26%) of 395 patients in the control group (p=0.001). Colonisation with vancomycin-resistant enterococcus occurred in five (1%) SDD patients and in four (1%) controls (p=1.0). No patient in either group was colonised with meticillin-resistant Staphylococcus aureus. INTERPRETATION In a setting with low prevalence of vancomycin-resistant enterococcus and meticillin-resistant S aureus, SDD can decrease ICU and hospital mortality and colonisation with resistant gram-negative aerobic bacteria.

Effects of different plasma substitutes on blood coagulation : A comparative review

Objective To compare the effects of different colloid plasma substitutes on blood coagulation and postoperative blood loss. Data Sources Relevant studies were obtained from the medical literature. Study Selection Articles were selected that provided data on the effects of colloids on hemostasis and postoperative blood loss in humans. Studies comparing different colloids were looked for using MEDLINE and by searching through the references of studies as they were collected. Data Synthesis Articles were reviewed and relevant data were extracted and partly presented in comparative tables. Conclusions Dextran, gelatin, and hydroxyethyl starch (HES) all can induce a specific decrease of von Willebrand factor and factor VIII:c. Blood coagulation is most impaired by dextran and high molecular weight HES, both associated with increased postoperative blood loss. The effects of HES on blood coagulation have been shown to depend on its molecular weight and rate of elimination. Detrimental effects have been shown for high molecular weight HES. Medium molecular weight (MMW)-HES with a high degree of substitution (HES 200/0.62) and MMW-HES with high C2/C6 hydroxyethylation ratio (HES 200/0.5/13) are slowly degradable and have been shown to impair blood coagulation after repeated administration. Rapidly degradable HES 200/0.5/6 and gelatin-based plasma expanders appear not to impair hemostasis. However, based on the reviewed literature, all artificial colloids could potentially induce increased bleeding tendency after infusion of very large volumes and especially when given to patients with even mild forms of von Willebrand disease. In those circumstances, crystalloid solutions or alternatives such as plasma or albumin, although associated with other serious complications, could be considered.

Evaluation of SOFA-based models for predicting mortality in the ICU: A systematic review

IntroductionTo systematically review studies evaluating the performance of Sequential Organ Failure Assessment (SOFA)-based models for predicting mortality in patients in the intensive care unit (ICU).MethodsMedline, EMBASE and other databases were searched for English-language articles with the major objective of evaluating the prognostic performance of SOFA-based models in predicting mortality in surgical and/or medical ICU admissions. The quality of each study was assessed based on a quality framework for prognostic models.ResultsEighteen articles met all inclusion criteria. The studies differed widely in the SOFA derivatives used and in their methods of evaluation. Ten studies reported about developing a probabilistic prognostic model, only five of which used an independent validation data set. The other studies used the SOFA-based score directly to discriminate between survivors and non-survivors without fitting a probabilistic model. In five of the six studies, admission-based models (Acute Physiology and Chronic Health Evaluation (APACHE) II/III) were reported to have a slightly better discrimination ability than SOFA-based models at admission (the receiver operating characteristic curve (AUC) of SOFA-based models ranged between 0.61 and 0.88), and in one study a SOFA model had higher AUC than the Simplified Acute Physiology Score (SAPS) II model. Four of these studies used the Hosmer-Lemeshow tests for calibration, none of which reported a lack of fit for the SOFA models. Models based on sequential SOFA scores were described in 11 studies including maximum SOFA scores and maximum sum of individual components of the SOFA score (AUC range: 0.69 to 0.92) and delta SOFA (AUC range: 0.51 to 0.83). Studies comparing SOFA with other organ failure scores did not consistently show superiority of one scoring system to another. Four studies combined SOFA-based derivatives with admission severity of illness scores, and they all reported on improved predictions for the combination. Quality of studies ranged from 11.5 to 19.5 points on a 20-point scale.ConclusionsModels based on SOFA scores at admission had only slightly worse performance than APACHE II/III and were competitive with SAPS II models in predicting mortality in patients in the general medical and/or surgical ICU. Models with sequential SOFA scores seem to have a comparable performance with other organ failure scores. The combination of sequential SOFA derivatives with APACHE II/III and SAPS II models clearly improved prognostic performance of either model alone. Due to the heterogeneity of the studies, it is impossible to draw general conclusions on the optimal mathematical model and optimal derivatives of SOFA scores. Future studies should use a standard evaluation methodology with a standard set of outcome measures covering discrimination, calibration and accuracy.

Evaluation of short-term consequences of hypoglycemia in an intensive care unit.

Background:Introduction of strict glycemic control has increased the risk for hypoglycemia in the intensive care unit. Little is known about the consequences of hypoglycemia in this setting. We examined short-term consequences (seizures, coma, and death) of hypoglycemia in the intensive care unit. Patients and Methods:All occurrences of hypoglycemia (glucose of <45 mg/dL) in our intensive care unit between September 1, 2002, and September 1, 2004, were identified. Patients with hypoglycemia (n = 156) were matched for time to hypoglycemia with control patients drawn from the at-risk population (nested case control method). Seizures observed within 8 hrs after hypoglycemia were scored. Discharge summaries for cases and controls were reviewed for occurrence of possible hypoglycemia-associated coma and death. A hazard ratio for in-hospital death was calculated with Cox regression analysis. Results:The hazard ratio for in-hospital death was 1.03 (95% confidence interval, 0.68–1.56; p = .88) in patients with a first occurrence of hypoglycemia relative to the controls without hypoglycemia, corrected for duration of intensive care unit admittance before hypoglycemia, age, sex, and Acute Physiology and Chronic Health Evaluation II score at admission. No cases of hypoglycemia-associated death were reported. Hypoglycemic coma was reported in two patients. Seizures after hypoglycemia were observed in one patient. Conclusions:In this study, no association between incidental hypoglycemia and mortality was found. However, this data set is too small to definitely exclude the possibility that hypoglycemia is associated with intensive care unit mortality. In three patients with possible hypoglycemia-associated coma or seizures, a causal role for hypoglycemia seemed likely but could not fully be established.

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.

Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors

Venous thromboembolism is a frequent complication in patients admitted to intensive care units (ICU), despite prophylactic treatment with subcutaneous low-molecular-weight (LMW) heparin. We postulated that poor efficacy of subcutaneous heparin might be due to administration of vasopressors, which could cause impaired peripheral circulation and inadequate systemic bioavailability of the anticoagulant. We compared concentrations of factor Xa activity in three groups of 15 patients: individuals in ICU who had and had not received vasopressors, and general surgery patients. Those who received vasopressors had lower plasma concentrations of factor-Xa activity than patients in ICU not on vasopressors and postoperative controls. Patients in ICU who take vasopressors could need higher doses of LMW heparin, or a different mode of administration of the drug, to attain adequate thrombosis prophylaxis.

Sepsis and disseminated intravascular coagulation

Sepsis almost invariably leads to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation, may deplete platelets and coagulation factors, which may in turn cause bleeding. Recent insights into important pathogenetic mechanisms that may lead to DIC have resulted in novel preventive and therapeutic approaches to patients with sepsis and a derangement of coagulation. Thrombin generation proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin III and the protein C system. Also, impaired fibrin degradation, due to high circulating levels of PAI-1, contributes to enhanced intravascular fibrin deposition. Supportive strategies aimed at the inhibition of coagulation activation may be justified on theoretical grounds and have been found to be beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, by means of the administration of antithrombin concentrate or recombinant human activated protein C.

Rationale for restoration of physiological anticoagulant pathways in patients with sepsis and disseminated intravascular coagulation.

ObjectiveIn the pathogenesis of disseminated intravascular coagulation, dysfunctional natural anticoagulant pathways appear to play a pivotal role. In this article, we will address the mechanisms that contribute to this defect in the regulation of coagulation activation. Furthermore, we will explore the experimental and clinical evidence that restoration of these anticoagulant pathways results in clinical improvement. Data SourcesWe have searched and reviewed published articles on experimental studies of disseminated intravascular coagulation models in animals and clinical studies in patients with disseminated intravascular coagulation. Data Synthesis All three major anticoagulant pathways, that is, the antithrombin pathway, the protein C system, and tissue factor pathway inhibitor, are defective in sepsis and disseminated intravascular coagulation. Several mechanisms contribute to this defect. Restoration of these pathways, in principle, by administration of coagulation inhibitor concentrates or recombinant anticoagulant factors, appears to ameliorate the coagulation disorder and, more important, result in improvement of clinically relevant outcomes, such as a reduction of organ failure and mortality. ConclusionsRestoration of disrupted physiologic anticoagulant pathways in disseminated intravascular coagulation is not only a logical point of impact in patients with sepsis and an activated coagulation system, but also is associated with an improved outcome in experimental and (initial) clinical studies.

Cognitive, Functional, and Quality‐of‐Life Outcomes of Patients Aged 80 and Older Who Survived at Least 1 Year After Planned or Unplanned Surgery or Medical Intensive Care Treatment

OBJECTIVES: To investigate long‐term cognitive, functional, and quality‐of‐life outcomes in very elderly survivors at least 1 year after planned or unplanned surgery or medical intensive care treatment.