Development and internal validation of the multivariable CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) clinical risk prediction model.

BACKGROUND: Intensive care unit (ICU) outcome prediction models, such as Acute Physiology And Chronic Health Evaluation (APACHE), were designed in general critical care populations and their use in obstetric populations is contentious. The aim of the CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) study was to develop and internally validate a multivariable prognostic model calibrated specifically for pregnant or recently delivered women admitted for critical care. METHODS: A retrospective observational cohort was created for this study from 13 tertiary facilities across five high-income and six low- or middle-income countries. Women admitted to an ICU for more than 24 h during pregnancy or less than 6 weeks post-partum from 2000 to 2012 were included in the cohort. A composite primary outcome was defined as maternal death or need for organ support for more than 7 days or acute life-saving intervention. Model development involved selection of candidate predictor variables based on prior evidence of effect, availability across study sites, and use of LASSO (Least Absolute Shrinkage and Selection Operator) model building after multiple imputation using chained equations to address missing data for variable selection. The final model was estimated using multivariable logistic regression. Internal validation was completed using bootstrapping to correct for optimism in model performance measures of discrimination and calibration. RESULTS: Overall, 127 out of 769 (16.5%) women experienced an adverse outcome. Predictors included in the final CIPHER model were maternal age, surgery in the preceding 24 h, systolic blood pressure, Glasgow Coma Scale score, serum sodium, serum potassium, activated partial thromboplastin time, arterial blood gas (ABG) pH, serum creatinine, and serum bilirubin. After internal validation, the model maintained excellent discrimination (area under the curve of the receiver operating characteristic (AUROC) 0.82, 95% confidence interval (CI) 0.81 to 0.84) and good calibration (slope of 0.92, 95% CI 0.91 to 0.92 and intercept of -0.11, 95% CI -0.13 to -0.08). CONCLUSIONS: The CIPHER model has the potential to be a pragmatic risk prediction tool. CIPHER can identify critically ill pregnant women at highest risk for adverse outcomes, inform counseling of patients about risk, and facilitate bench-marking of outcomes between centers by adjusting for baseline risk.

The influence of rewarming after therapeutic hypothermia on outcome after cardiac arrest.

INTRODUCTION: Treatment with hypothermia has been shown to improve outcome after cardiac arrest (CA). Current consensus is to rewarm at 0.25-0.5 °C/h and avoid fever. The aim of this study was to investigate whether active rewarming, the rate of rewarming or development of fever after treatment with hypothermia after CA was correlated with poor outcome. METHODS: This retrospective cohort study included adult patients treated with hypothermia after CA and admitted to the intensive care unit between January 2006 and January 2009. The average rewarming rate from end of hypothermia treatment (passive rewarming) or start active rewarming until 36 °C was dichotomized in a high (≥ 0.5 °C/h) or normal rate (<0.5 °C/h). Fever was defined as >38 °C within 72 h after admission. Poor outcome was defined as death, vegetative state, or severe disability after 6 months. RESULTS: From 128 included patients, 56% had a poor outcome. Actively rewarmed patients (38%) had a higher risk for poor outcome, OR 2.14 (1.01-4.57), p<0.05. However, this effect disappeared after adjustment for the confounders age and initial rhythm, OR 1.51 (0.64-3.58). A poor outcome was found in 15/21 patients (71%) with a high rewarming rate, compared to 54/103 patients (52%) with a normal rewarming rate, OR 2.61 (0.88-7.73), p = 0.08. Fever was not associated with outcome, OR 0.64 (0.31-1.30), p = 0.22. CONCLUSIONS: This study showed that patients who needed active rewarming after therapeutic hypothermia after CA did not have a higher risk for a poor outcome. In addition, neither speed of rewarming, nor development of fever had an effect on outcome.

Spontaneous hypothermia on intensive care unit admission is a predictor of unfavorable neurological outcome in patients after resuscitation: an observational cohort study.

INTRODUCTION: A large number of patients resuscitated for primary cardiac arrest arrive in the intensive care unit (ICU) with a body temperature < 35.0 degrees C. The aim of this observational cohort study was to determine the association between ICU admission temperature and neurological outcome in this patient group. METHODS: Demographics and parameters influencing neurological outcome were retrieved from the charts of all patients resuscitated for primary cardiac arrest and treated with induced mild hypothermia in our ICU from January 2006 until January 2008. Patients were divided into two groups according to their body temperature on ICU admission: a hypothermia group (< 35.0 degrees C) and a non-hypothermia group (>or=35.0 degrees C). Neurological outcome after six months was assessed by means of the Glasgow Outcome Score (GOS), with GOS 1 to 3 defined as unfavorable and GOS 4 to 5 as favorable. A logistic regression model was used to analyze the influence of the different parameters on neurological outcome. RESULTS: The data of 105 consecutive patients resuscitated for primary cardiac arrest and treated with induced mild hypothermia were analyzed. Median ICU admission temperature was 35.1 degrees C (interquartile range (IQR) 34.3 to 35.7). After six months, 61% of the patients had an unfavorable outcome (59% died and 2% were severely disabled), whereas 39% had a favorable outcome (moderate disability or good recovery). Among patients with spontaneous hypothermia on ICU admission, the percentage with unfavorable outcome was higher (69% versus 50%, P = 0.05). Logistic regression showed that age, acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores and spontaneous hypothermia on ICU admission all had an increased odds ratio (OR) for an unfavorable outcome after six months. Spontaneous hypothermia had the strongest association with unfavorable outcome (OR 2.6, 95% CI (confidence interval) 1.1 to 5.9), which became even stronger after adjustment for age, presenting heart rhythm, APACHE II and SOFA scores (OR 3.8, CI 1.3 to 11.0). CONCLUSIONS: In this observational cohort study, spontaneous hypothermia on ICU admission was the strongest predictor of an unfavorable neurological outcome in patients resuscitated for primary cardiac arrest.

Individual and joint expert judgments as reference standards in artifact detection.

OBJECTIVE: To investigate the agreement among clinical experts in their judgments of monitoring data with respect to artifacts, and to examine the effect of reference standards that consist of individual and joint expert judgments on the performance of artifact filters. DESIGN: Individual judgments of four physicians, a majority vote judgment, and a consensus judgment were obtained for 30 time series of three monitoring variables: mean arterial blood pressure (ABPm), central venous pressure (CVP), and heart rate (HR). The individual and joint judgments were used to tune three existing automated filtering methods and to evaluate the performance of the resulting filters. MEASUREMENTS: The interrater agreement was calculated in terms of positive specific agreement (PSA). The performance of the artifact filters was quantified in terms of sensitivity and positive predictive value (PPV). RESULTS: PSA values between 0.33 and 0.85 were observed among clinical experts in their selection of artifacts, with relatively high values for CVP data. Artifact filters developed using judgments of individual experts were found to moderately generalize to new time series and other experts; sensitivity values ranged from 0.40 to 0.60 for ABPm and HR filters (PPV: 0.57-0.84), and from 0.63 to 0.80 for CVP filters (PPV: 0.71-0.86). A higher performance value for the filters was found for the three variable types when joint judgments were used for tuning the filtering methods. CONCLUSION: Given the disagreement among experts in their individual judgment of monitoring data with respect to artifacts, the use of joint reference standards obtained from multiple experts is recommended for development of automatic artifact filters.

Extracorporeal treatment of intoxications.

PURPOSE OF REVIEW: The purpose of this article is to provide the critical care clinician with a comprehensive review of the indications for extracorporeal elimination of toxic substances, to summarize the different techniques and the intoxications for which these techniques are suitable. RECENT FINDINGS: In the last year, several excellent reviews about toxicological topics have been published. These reviews focused on intoxications in children, the approach of the patient with an unknown overdose, management of intoxications with salicylates, beta-blockers and calcium antagonists and liver support systems. Important developments include the use of high-flux, high-efficiency membranes and albumin dialysis using the molecular adsorbent recirculating system (MARS). This system offers possibilities for the removal of protein-bound substances such as diltiazem, phenytoin and theophylline. SUMMARY: Although large randomized controlled trials are scarce in the field of toxicology, the treatment of intoxications is becoming more and more evidence based. This review summarizes the current knowledge and recommendations concerning the extracorporeal treatment of intoxications and discusses new developments in the field, such as the use of high-flux, high-efficiency membranes and albumin dialysis.

Pharmacokinetics and pharmacodynamics of danaparoid during continuous venovenous hemofiltration: a pilot study.

BACKGROUND: In patients with suspected heparin-induced thrombocytopenia (HIT) who need renal replacement therapy, a nonheparin anticoagulant has to be chosen to prevent thrombosis in the extracorporeal circuit. Danaparoid, a low-molecular-weight heparinoid consisting of heparan sulphate, dermatan sulphate, and chondroitin sulphate, is recommended for systemic anticoagulation in patients with HIT. However, there are few data on the use of danaparoid in patients with acute renal failure, especially in patients dependent on renal replacement therapy such as continuous venovenous hemofiltration (CVVH). In the present study, we analyzed the pharmacokinetics and pharmacodynamics of danaparoid during CVVH in patients with suspected HIT. METHODS: Based on a mathematical model, a dosing scheme for danaparoid was designed, aiming at anti-Xa levels of 0.5 to 0.7 U/mL, with a maximum of 1.0 U/mL. This dosing scheme was prospectively tested in the first CVVH run of a cohort of five patients with suspected HIT. CVVH with a blood flow rate of 150 mL/minute and a substitution rate of 2,000 mL/hour was performed with a cellulose triacetate membrane. Danaparoid was administered as a continuous infusion of 100 anti-Xa-U/hour after a loading dose of 3,500 anti-Xa-U. Serial measurements of anti-Xa activity and prothrombin fragment F1+2 were performed at baseline, at t = 5, 15, and 30 minutes, and at t = 1, 2, 4, 8, 16, and 24 hours after the danaparoid loading dose. RESULTS: The median anti-Xa activity reached a maximum of 1.02 (0.66 to 1.31) anti-Xa-U/mL after 15 minutes and gradually declined to 0.40 (0.15 to 0.58) anti-Xa-U/mL over the span of 24 hours. Target anti-Xa levels were reached from 2 to 12 hours after the loading dose. Median prothrombin fragment F1+2 gradually decreased from 432 (200 to 768) to 262 (248 to 317) pmol/L after 24 hours. No bleeding or thromboembolic events occurred throughout the described treatment period. CONCLUSION: Danaparoid administered by a continuous infusion of 100 anti-Xa-U/hour after a loading dose of 3,500 anti-Xa-U elicited target anti-Xa levels from 2 to 12 hours after the loading dose, without bleeding or thromboembolic events during the described CVVH treatment in patients with suspected HIT.

The effects of continuous venovenous hemofiltration on coagulation activation.

INTRODUCTION: The mechanism of coagulation activation during continuous venovenous hemofiltration (CVVH) has not yet been elucidated. Insight into the mechanism(s) of hemostatic activation within the extracorporeal circuit could result in a more rational approach to anticoagulation. The aim of the present study was to investigate whether CVVH using cellulose triacetate filters causes activation of the contact factor pathway or of the tissue factor pathway of coagulation. In contrast to previous studies, CVVH was performed without anticoagulation. METHODS: Ten critically ill patients were studied prior to the start of CVVH and at 5, 15 and 30 minutes and 1, 2, 3 and 6 hours thereafter, for measurement of prothrombin fragment F1+2, soluble tissue factor, activated factor VII, tissue factor pathway inhibitor, kallikrein-C1-inhibitor and activated factor XII-C1-inhibitor complexes, tissue-type plasminogen activator, plasminogen activator inhibitor type I, plasmin-antiplasmin complexes, protein C and antithrombin. RESULTS: During the study period the prothrombin fragment F1+2 levels increased significantly in four patients (defined as group A) and did not change in six patients (defined as group B). Group A also showed a rapid increase in transmembrane pressure, indicating clotting within the filter. At baseline, the activated partial thromboplastin time, the prothrombin time and the kallikrein-C1-inhibitor complex and activated factor XII-C1-inhibitor complex levels were significantly higher in group B, whereas the platelet count was significantly lower in group B. For the other studied markers the differences between group A and group B at baseline were not statistically significant. During CVVH the difference in the time course between group A and group B was not statistically significant for the markers of the tissue factor system (soluble tissue factor, activated factor VII and tissue factor pathway inhibitor), for the markers of the contact system (kallikrein-C1-inhibitor and activated factor XII-C1-inhibitor complexes) and for the markers of the fibrinolytic system (plasmin-antiplasmin complexes, tissue-type plasminogen activator and plasminogen activator inhibitor type I). CONCLUSION: Early thrombin generation was detected in a minority of intensive care patients receiving CVVH without anticoagulation. Systemic concentrations of markers of the tissue factor system and of the contact system did not change during CVVH. To elucidate the mechanism of clot formation during CVVH we suggest that future studies are needed that investigate the activation of coagulation directly at the site of the filter. Early coagulation during CVVH may be related to lower baseline levels of markers of contact activation.