Dynamic prediction of mortality in COVID-19 patients in the intensive care unit: A retrospective multi-center cohort study.

Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU. Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure. Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of -0.04 [-0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of -0.19 [-0.27; -0.10] and slope of 0.89 [0.84; 0.94] for the random forest model. Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research.

The impact of COVID-19 on nursing workload and planning of nursing staff on the Intensive Care: A prospective descriptive multicenter study.

INTRODUCTION: The impact of the care for COVID-19 patients on nursing workload and planning nursing staff on the Intensive Care Unit has been huge. Nurses were confronted with a high workload and an increase in the number of patients per nurse they had to take care of. OBJECTIVE: The primary aim of this study is to describe differences in the planning of nursing staff on the Intensive Care in the COVID period versus a recent non-COVID period. The secondary aim was to describe differences in nursing workload in COVID-19 patients, pneumonia patients and other patients on the Intensive Care. We finally wanted to assess the cause of possible differences in Nursing Activities Scores between the different groups. METHODS: We analyzed data on nursing staff and nursing workload as measured by the Nursing Activities Score of 3,994 patients and 36,827 different shifts in 6 different hospitals in the Netherlands. We compared data from the COVID-19 period, March 1st 2020 till July 1st 2020, with data in a non-COVID period, March 1st 2019 till July 1st 2019. We analyzed the Nursing Activities Score per patient, the number of patients per nurse and the Nursing Activities Score per nurse in the different cohorts and time periods. Differences were tested by a Chi-square, non-parametric Wilcoxon or Student's t-test dependent on the distribution of the data. RESULTS: Our results showed both a significant higher number of patients per nurse (1.1 versus 1.0, p<0.001) and a significant higher Nursing Activities Score per Intensive Care nurse (76.5 versus 50.0, p<0.001) in the COVID-19 period compared to the non-COVID period. The Nursing Activities Score was significantly higher in COVID-19 patients compared to both the pneumonia patients (55.2 versus 50.0, p<0.001) and the non-COVID patients (55.2 versus 42.6, p<0.001), mainly due to more intense hygienic procedures, mobilization and positioning, support and care for relatives and respiratory care. CONCLUSION: With this study we showed the impact of COVID-19 patients on the planning of nursing care on the Intensive Care. The COVID-19 patients caused a high nursing workload, both in number of patients per nurse and in Nursing Activities Score per nurse.

The development of a glucose prediction model in critically ill patients.

PURPOSE: The aim of the current study is to develop a prediction model for glucose levels applicable for all patients admitted to the ICU with an expected ICU stay of at least 24 h. This model will be incorporated in a closed-loop glucose system to continuously and automatically control glucose values. METHODS: Data from a previous single-center randomized controlled study was used. All patients received a FreeStyle Navigator II subcutaneous CGM system from Abbott during their ICU stay. The total dataset was randomly divided into a training set and a validation set. A glucose prediction model was developed based on historical glucose data. Accuracy of the prediction model was determined using the Mean Squared Difference (MSD), the Mean Absolute Difference (MAD) and a Clarke Error Grid (CEG). RESULTS: The dataset included 94 ICU patients with a total of 134,673 glucose measurements points that were used for modelling. MSD was 0.410 ± 0.495 for the model, the MAD was 5.19 ± 2.63 and in the CEG 99.8% of the data points were in the clinically acceptable regions. CONCLUSION: In this study a glucose prediction model for ICU patients is developed. This study shows that it is possible to accurately predict a patient's glucose 30 min ahead based on historical glucose data. This is the first step in the development of a closed-loop glucose system.

The objective nursing workload and perceived nursing workload in Intensive Care Units: Analysis of association.

BACKGROUND: A range of classification systems are in use for the measurement of nursing workload in Intensive Care Units. However, it is unknown to what extent the measured (objective) nursing workload, usually in terms of the amount of nursing activities, is related to the workload actually experienced (perceived) by nurses. OBJECTIVES: The aim of this study was to assess the association between the objective nursing workload and the perceived nursing workload and to identify other factors associated with the perceived nursing workload. METHODS: We measured the objective nursing workload with the Nursing Activities Score and the perceived nursing workload with the NASA-Task Load Index during 228 shifts in eight different Intensive Care Units. We used linear mixed-effect regression models to analyze the association between the objective and perceived nursing workload. Furthermore, we investigated the association of patient characteristics (severity of illness, comorbidities, age, body mass index, and planned or unplanned admission), education level of the nurse, and contextual factors (numbers of patients per nurse, the type of shift (day, evening, night) and day of admission or discharge) with perceived nursing workload. We adjusted for confounders. RESULTS: We did not find a significant association between the observed workload per nurse and perceived nursing workload (p=0.06). The APACHE-IV Acute Physiology Score of a patient was significantly associated with the perceived nursing workload, also after adjustment for confounders (p=0.02). None of the other patient characteristics was significantly associated with perceived nursing workload. Being a certified nurse or a student nurse was the only nursing or contextual factor significantly associated with the perceived nursing workload, also after adjustment for confounders (p=0.03). CONCLUSION: Workload is perceived differently by nurses compared to the objectively measured workload by the Nursing Activities Score. Both the severity of illness of the patient and being a student nurse are factors that increase the perceived nursing workload. To keep the workload of nurses in balance, planning nursing capacity should be based on the Nursing Activities Score, on the severity of patient illness and the graduation level of the nurse.

Trends in practice of blood glucose control in critically ill patients in the Netherlands.

BACKGROUND: Publication of the Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial in 2009 and several observational studies caused a change in the recommendations for blood glucose control in intensive care patients. We evaluated local trends in blood glucose control in intensive care units in the Netherlands before and after the publication of the NICE-SUGAR trial and the revised Surviving Sepsis Campaign (SSC) guidelines in 2012. METHODS: Survey focusing on the timing of changes in thresholds in local guidelines for blood glucose control and interrupted time-series analysis of patients admitted to seven intensive care units in the Netherlands from September 2008 through July 2014. Statistical process control was used to visualise and analyse trends in metrics for blood glucose control in association with the moment changes became effective. RESULTS: Overall, the mean blood glucose level increased and the median percentage of blood glucose levels within the normoglycaemic range and in the hypoglycaemic range decreased, while the relative proportion of hyperglycaemic measurements increased. Changes in metrics were notable after publication of the NICE-SUGAR trial and the SSC guidelines but more frequent after changes in local guidelines; some changes seemed to appear independent of changes in local guidelines. CONCLUSION: Local guidelines for blood glucose practice have changed in intensive care units in the Netherlands since the publication of the NICE-SUGAR trial and the revised SSC guidelines. Trends in the metrics for blood glucose control suggest new, higher target ranges for blood glucose control.

Pain measurement in mechanically ventilated critically ill patients: Behavioral Pain Scale versus Critical-Care Pain Observation Tool.

PURPOSE: The Behavioral Pain Scale (BPS) and Critical-Care Pain Observation Tool (CPOT) are behavioral pain assessment tools for uncommunicative and sedated intensive care unit (ICU) patients. This study compares the discriminant validation and reliability of the CPOT and the BPS, simultaneously, in mechanically ventilated patients on a mixed-adult ICU. MATERIALS AND METHODS: This is a prospective observational cohort study in 68 mechanically ventilated medical ICU patients who were unable to report pain. RESULTS: The BPS and CPOT scores showed a significant increase of 2 points between rest and the painful procedure (turning). The median BPS scores between rest and the nonpainful procedure (oral care) showed a significant increase of 1 point, whereas the median CPOT score remained unchanged. The interrater reliability of the BPS and CPOT scores showed a fair to good agreement (0.74 and 0.75, respectively). CONCLUSIONS: This study showed that the BPS and the CPOT are reliable and valid for use in a daily clinical setting. Although both scores increased with a presumed painful stimulus, the discriminant validation of the BPS use was less supported because it increased during a nonpainful stimulus. The CPOT appears preferable in this particular group of patients, especially with regard to its discriminant validation.

Impact of computerized information systems on workload in operating room and intensive care unit.

The number of operating rooms and intensive care departments equipped with a clinical information system (CIS) is rapidly expanding. Amongst the putative advantages of such an installation, reduction in workload for the clinician is one of the most appealing. The scarce studies looking at workload variations associated with the implementation of a CIS, only focus on direct workload discarding indirect changes in workload. Descriptions of the various methods to quantify workload are provided. The hypothesis that a third generation CIS can reduce documentation time for ICU nurses and increase time they spend on patient care, is supported by recent literature. Though it seems obvious to extrapolate these advantages of a CIS to the anesthesiology department or physicians in the intensive care, studies examining this assumption are scarce.

A subgroup discovery approach for scrutinizing blood glucose management guidelines by the identification of hyperglycemia determinants in ICU patients.

OBJECTIVE: Despite the wide use of blood glucose management guidelines in intensive care (IC), hyperglycemia is still common. The aim of this study was the discovery of possible hyperglycemia determinants by applying the Patient Rule Induction Method (PRIM) to routinely collected data within the first 24 hours of admission, and to relate them to the literature. METHODS: PRIM was applied in two set-ups to data of 2001 IC patients including 50,021 records of blood glucose levels and other variables. The independent predictors of blood glucose measurements were variables whose value is known before the time of the corresponding measurement. Subgroups were validated using a random split design, and time-sensitivity of performance was analyzed. RESULTS: PRIM was able to identify relatively large subgroups having markedly high mean glucose values. PRIM also discovered possible determinants of which less is known about their relationship to hyperglycemia. Some possible determinants reported in the literature were not found by PRIM. CONCLUSIONS: We demonstrated for the first time the utility of using subgroup discovery to uncover possible determinants for non-responsiveness to treatment. This implies the possible use of this technology to scrutinize the effects of various guidelines in clinical medicine on patient outcomes without requiring the development of a global predictive model. We hypothesize that by focusing on the identified subgroups, clinical guidelines may be improved. Further research is required to test this hypothesis.

[Differential diagnosis in patients with suspected anoxic-ischaemic coma]. / Differentiaaldiagnose bij patiënten bij wie een anoxisch-ischemisch coma wordt vermoed.

Three case studies illustrate that suspected anoxic-ischaemic coma often requires careful differential diagnosis to detect treatable conditions. A 47-year-old man underwent cardiopulmonary resuscitation for ventricular fibrillation caused by myocardial ischaemia. He exhibited rhythmic eyelid movements while in a coma. Epilepsy was suspected, and the patient regained consciousness after being treated with antiepileptic drugs. A 34-year-old man underwent cardiopulmonary resuscitation for multiple episodes of ventricular fibrillation. Treatment was directed toward myocardial ischaemia and included anticoagulants. The patient had bilateral, fixed dilated pupils. A CT of the brain showed traumatic contrecoup haemorrhage in the left temporal lobe with signs of transtentorial herniation. The patient died. A 74-year-old woman was found unconscious at home. An ECG performed by the paramedics showed ST segment elevation in the precordial leads. Anoxic-ischaemic coma following cardiac arrest was suspected. However, a coronary angiogram was normal and a CT of the brain revealed subarachnoid haemorrhage caused by a ruptured intracranial aneurysm. She recovered after cranial surgery.

External validation of prognostic models for critically ill patients required substantial sample sizes.

OBJECTIVE: To investigate the behavior of predictive performance measures that are commonly used in external validation of prognostic models for outcome at intensive care units (ICUs). STUDY DESIGN AND SETTING: Four prognostic models (Simplified Acute Physiology Score II, the Acute Physiology and Chronic Health Evaluation II, and the Mortality Probability Models II) were evaluated in the Dutch National Intensive Care Evaluation registry database. For each model discrimination (AUC), accuracy (Brier score), and two calibration measures were assessed on data from 41,239 ICU admissions. This validation procedure was repeated with smaller subsamples randomly drawn from the database, and the results were compared with those obtained on the entire data set. RESULTS: Differences in performance between the models were small. The AUC and Brier score showed large variation with small samples. Standard errors of AUC values were accurate but the power to detect differences in performance was low. Calibration tests were extremely sensitive to sample size. Direct comparison of performance, without statistical analysis, was unreliable with either measure. CONCLUSION: Substantial sample sizes are required for performance assessment and model comparison in external validation. Calibration statistics and significance tests should not be used in these settings. Instead, a simple customization method to repair lack-of-fit problems is recommended.

Low-dose fondaparinux in suspected heparin-induced thrombocytopenia in the critically ill.

BACKGROUND: In critically ill patients, heparin-induced thrombocytopenia (HIT) is estimated to account for approximately 1 to 10% of all causes of thrombocytopenia. HIT exerts a strong procoagulant state. In case of suspected HIT, it is an important clinical decision to stop heparin and start treatment with alternative nonheparin anticoagulation, awaiting the results of laboratory testing for the final diagnosis of HIT (bridging therapy). Fondaparinux acts by factor Xa inhibition and expresses no cross-reactivity with HIT antibodies. Excretion of fondaparinux is mainly renal. We describe our early experience with fixed low-dose fondaparinux bridging therapy and monitoring of anticoagulant activity for safety reasons. METHODS: This retrospective cohort study was conducted in a closed format general intensive care unit in a teaching hospital. Consecutive critically ill patients suspected of HIT were treated with fondaparinux after discontinuation of unfractionated heparin or nadroparin. Anti-Xa levels were determined afterwards. RESULTS: Seven patients were treated with fondaparinux 2.5 mg/day for 1.8 to 6.5 days. Anti-Xa levels varied from 0.1 to 0.6 U/ml. A negative correlation was found between creatinine clearance and mean and maximum anti-Xa levels. No thromboembolic complications occurred. Bleeding complications were only minor during fondaparinux treatment. Transfusion requirements did not differ significantly between treatment episodes with fondaparinux or with heparin anticoagulants. CONCLUSION: In this small sample of critically ill patients suspected of HIT, bridging therapy with fixed low-dose fondaparinux resulted in prophylactic and therapeutic anti-Xa levels. Monitoring of anticoagulant activity is advised in patients with renal insufficiency.

Combining Hebbian and reinforcement learning in a minibrain model.

A toy model of a neural network in which both Hebbian learning and reinforcement learning occur is studied. The problem of 'path interference', which makes that the neural net quickly forgets previously learned input-output relations is tackled by adding a Hebbian term (proportional to the learning rate nu) to the reinforcement term (proportional to delta) in the learning rule. It is shown that the number of learning steps is reduced considerably if 1/4

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

CASE PRESENTATION: Despite 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. TREATMENT: The patient received antituberculous drugs (ethambutol, isoniazid, pyrazinamide, rifampicin), amphotericin B, flucytosine, and valaciclovir, along with prolonged intensive care treatment and mechanical ventilation. CONCLUSIONS: The 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.

[Intensive care medicine in the Netherlands, 1997-2001. I. Patient population and treatment outcome]. / Intensivecaregeneeskunde in Nederland, 1997-2001. I. Patiëntenpopulatie en resultaten van behandeling.

OBJECTIVE: To describe the patients admitted to intensive care units (ICUs) in the Netherlands between 1997-2001 and the treatment outcome. DESIGN: Descriptive. METHOD: For the years 1997-2001, prospective admission and discharge data as well as all data necessary for calculating prospective severity of illness scores (e.g. APACHE II and SAPS II) were collected for all patients that were admitted to 18 ICUs participating in the Dutch National Intensive Care Evaluation (NICE). Outcome measures were ICU mortality and hospital mortality, length of hospital and ICU admission, and standardised mortality ratio (SMR). RESULTS: Data from 55,016 admissions were registered. The median APACHE II score was 15 (P25-P75: 10-20) and the median SAPS II score was 29 (19-43). The median ICU length of admission for individual ICUs varied between 0.86 and 2.76 days. The occupied ICU capacity of individual ICUs varied between 220 and 1260 days per 100 patients admitted for non-cardiosurgical patients and between 110 and 330 days per 100 patients admitted for cardiosurgical patients. The ICU mortality and hospital mortality were 9.0% and 12.9% respectively. The mean SMR according to APACHE II was 0.95 (95% CI: 0.93-0.98). The SMR of the individual participating hospitals varied between 0.55 (95% CI: 0.37-0.80) and 1.20 (1.13-1.28). CONCLUSION: Hospital mortality for ICU-admitted patients in the NICE registration was 12.9%. For patients who could be evaluated with the APACHE II model, actual hospital mortality was lower than predicted by this model. Significant differences in length of admission, hospital mortality and SMR were found between individual hospitals.

[Intensive care medicine in the Netherlands, 1997-2001. II. Changes over time and differences between hospitals]. / Intensivecaregeneeskunde in Nederland, 1997-2001. II. Verandering in de tijd en verschillen tussen ziekenhuizen.

OBJECTIVE: To describe efficacy (mortality) and efficiency (length of admission) of intensive care (IC) treatment after admission due to a prior cardiothoracic operation or pneumonia, based on data from the Dutch National Intensive Care Evaluation (NICE) foundation. DESIGN: Descriptive. METHOD: Data for the period 1 January 1997-31 December 2001 were extracted from the NICE databank for patients admitted after cardiothoracic surgery and for patients admitted with pneumonia. The variables changes in time, risk factors for mortality, and differences between hospitals were analysed. RESULTS: There were 25,463 admissions to 5 hospitals following cardiothoracic surgery and 1408 admissions to 18 hospitals due to pneumonia. An increase in valve surgery was noted in the cardiothoracic surgery group: from about 10% to about 25%. In the group undergoing valve operations, there was an increase in the average age of the patients and in the number of patients with comorbidity. No significant differences in mortality between hospitals were detected. However, the length of ICU treatment differed. Hospital mortality in the pneumonia group was 33.9%. Differences between hospitals with respect to mortality (both crude mortality and severity-of-illness adjusted mortality) and length of ICU admission were found. CONCLUSION: With the NICE registration it is possible to detect differences and trends. This is a valuable tool for indicating where and how quality and efficiency in intensive care medicine can be improved.

Neostigmine resolves critical illness-related colonic ileus in intensive care patients with multiple organ failure--a prospective, double-blind, placebo-controlled trial.

OBJECTIVE: Critical illness-related colonic ileus (CIRCI) is characterized by the non-passage of stools in critically ill patients as a result of the absence of prokinetic movements of the colon, while the upper gastrointestinal tract functions properly and mechanical ileus is absent: We investigated whether neostigmine resulted in defecation in patients with CIRCI. DESIGN: Double-blinded, placebo-controlled prospective study. SETTING: Eighteen-bed intensive care unit. PATIENTS: Thirty ventilated patients with multiple organ failure with CIRCI for > 3 days. INTERVENTION: Continuous intravenous administration of neostigmine 0.4-0.8 mg/h over 24 h, or placebo. MEASUREMENTS AND RESULTS: Time to first defecation and adverse reactions were recorded. Thirty patients were randomized, 24 could be evaluated. The mean prestudy time was 5 days, mean APACHE II score on admission was 23.2, and mean MOF score on the day of the study was 6.4. Of the 13 patients receiving neostigmine, 11 passed stools, whereas none of the placebo-treated patients passed stools (P < 0.001). After 24 h, the non-responders received in a cross-over fashion neostigmine or placebo respectively. Eight out of the 11 neostigmine patients now passed stools (mean 11.4 h), and none of the placebo patients. Overall, in none of the patients did passage of stools occur during placebo infusion, whereas 19 of the 24 neostigmine-treated patients had defecation (79%). No acute serious adverse effects occurred, but three patients had ischemic colonic complications 7-10 days after treatment. CONCLUSION: Continuous infusion of 0.4-0.8 mg/h of neostigmine promotes defecation in ICU patients with a colonic ileus without important adverse reactions.

[Dyspnea after pneumonectomy due to atrial septum defect]. / Dyspnoe na pneumonectomie door een atriumseptumdefect.

A 55-year-old woman presented with complaints of recurrent dyspnoea one year after pneumonectomy carried out as treatment for a tumour of the left lung. During several months her symptoms progressed and eventually mechanical ventilation became necessary. On admission a patent foramen ovale was found with transoesophageal ultrasound but this was judged not to be the cause of her symptoms. The pulmonary angiogram showed a intracardiac shunt with no intrapulmonary shunts. After repeated transoesophageal ultrasound a second defect was found of a sinus venosus type. This large defect was proven to be clinically significant during catherisation of the heart, when occlusion with a balloon was performed. After surgical repair of these defects with an artificial patch, the patient recovered well. Since then she has been without complaints.

Plasma glutamine depletion and patient outcome in acute ICU admissions.

OBJECTIVE: To evaluate whether low plasma glutamine (PG) is related to severity of illness, and actual and predicted hospital mortality. DESIGN: Prospective cohort study. SETTING: 18-bed closed format general intensive care unit (ICU) of a teaching hospital. PATIENTS: Cohort of 80 seriously ill patients non-electively admitted to the ICU. INTERVENTIONS: Blood sampling for the determination of PG at ICU admission. MEASUREMENTS AND RESULTS: Severity of illness and predicted mortality were calculated using the locally validated APACHE II, SAPS II, and MPM II 0 and 24 systems. Illness scores, and actual and predicted hospital mortality were compared between patients with total PG < 0.420 mmol/l ("low PG") and patients with PG > or = 0.420 mmol/l. Mean total PG was 0.523 mmol/l, range 0.220-1.780 mmol/l. Low PG (n = 25) was associated with higher age (P = 0.03), shock as primary diagnosis, and higher actual hospital mortality (60 % vs 29 %, P = 0.01). Normal to high PG was associated with high plasma creatine phosphokinase (P = 0.007) There was a nonsignificant trend towards higher severity of illness scores and predicted mortality rates in the low PG group. The presence of low PG significantly improved mortality prediction when added as a factor to the APACHE II predicted mortality rate (P = 0.02). CONCLUSIONS: Low PG at acute ICU admission is related to higher age, shock as primary diagnosis, and higher hospital mortality. Low PG represents a risk of poor outcome, not fully reflected in the presently used mortality prediction systems.