Prediction of Long-Term Physical, Mental, and Cognitive Problems Following Critical Illness: Development and External Validation of the PROSPECT Prediction Model.

OBJECTIVES: ICU survivors often suffer from long-lasting physical, mental, and cognitive health problems after hospital discharge. As several interventions that treat or prevent these problems already start during ICU stay, patients at high risk should be identified early. This study aimed to develop a model for early prediction of post-ICU health problems within 48 hours after ICU admission. DESIGN: Prospective cohort study in seven Dutch ICUs. SETTING/PATIENTS: ICU patients older than 16 years and admitted for greater than or equal to 12 hours between July 2016 and March 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes were physical problems (fatigue or ≥ 3 new physical symptoms), mental problems (anxiety, depression, or post-traumatic stress disorder), and cognitive impairment. Patient record data and questionnaire data were collected at ICU admission, and after 3 and 12 months, of 2,476 patients. Several models predicting physical, mental, or cognitive problems and a composite score at 3 and 12 months were developed using variables collected within 48 hours after ICU admission. Based on performance and clinical feasibility, a model, PROSPECT, predicting post-ICU health problems at 3 months was chosen, including the predictors of chronic obstructive pulmonary disease, admission type, expected length of ICU stay greater than or equal to 2 days, and preadmission anxiety and fatigue. Internal validation using bootstrapping on data of the largest hospital ( n = 1,244) yielded a C -statistic of 0.73 (95% CI, 0.70-0.76). External validation was performed on data ( n = 864) from the other six hospitals with a C -statistic of 0.77 (95% CI, 0.73-0.80). CONCLUSIONS: The developed and externally validated PROSPECT model can be used within 48 hours after ICU admission for identifying patients with an increased risk of post-ICU problems 3 months after ICU admission. Timely preventive interventions starting during ICU admission and follow-up care can prevent or mitigate post-ICU problems in these high-risk patients.

MiCare study, an evaluation of structured, multidisciplinary and personalised post-ICU care on physical and psychological functioning, and quality of life of former ICU patients: a study protocol of a stepped-wedge cluster randomised controlled trial.

INTRODUCTION: Over 70% of the intensive care unit (ICU) survivors suffer from long-lasting physical, mental and cognitive problems after hospital discharge. Post-ICU care is recommended by international guidelines, but evidence for cost-effectiveness lacks. The aim of this study is to evaluate the clinical effectiveness and cost-effectiveness of structured, multidisciplinary and personalised post-ICU care versus usual care on physical and psychological functioning and health-related quality of life (HRQoL) of ICU survivors, 1- and 2-year post-ICU discharge. METHODS AND ANALYSIS: The MONITOR-IC post-ICU care study (MiCare study) is a multicentre stepped-wedge randomised controlled trial conducted in five hospitals. Adult patients at high risk for critical illness-associated morbidity post-ICU will be selected and receive post-ICU care, including an invitation to the post-ICU clinic 3 months after ICU discharge. A personalised long-term recovery plan tailored to patients' reported outcome measures will be made. 770 (intervention) and 1480 (control) patients will be included. Outcomes are 1- and 2-year HRQoL (EuroQol Instrument (EQ-5D-5L)), physical (fatigue and new physical problems), mental (anxiety, depression and post-traumatic stress disorder), and cognitive symptoms and cost-effectiveness. Medical data will be retrieved from patient records and cost data from health insurance companies. ETHICS AND DISSEMINATION: Due to the lack of evidence, Dutch healthcare insurers do not reimburse post-ICU care. Therefore, evaluation of cost-effectiveness and integration in guidelines supports the evidence. Participation of several societies for physicians, nurses, paramedics, and patients and relatives in the project team increases the support for implementation of the intervention in clinical practice. Patients and relatives will be informed by the patient associations, hospitals and professional associations. Informing healthcare insurers about this project's results is important for the consideration for inclusion of post-ICU care in Dutch standard health insurance. The study is approved by the Radboud University Medical Centre research ethics committee (2021-13125). TRIAL REGISTRATION NUMBER: NCT05066984.

Using long-term predicted Quality of Life in ICU clinical practice to prepare patients for life post-ICU: A feasibility study.

PURPOSE: To examine the feasibility of using the PREdicting PAtients' long-term outcome for Recovery (PREPARE) prediction model for Quality of Life (QoL) 1 year after ICU admission in ICU practice to prepare expected ICU survivors and their relatives for life post-ICU. MATERIALS AND METHODS: Between June 2020 and February 2021, the predicted change in QoL after 1 year was discussed in 25 family conferences in the ICU. 13 physicians, 10 nurses and 19 patients and/or family members were interviewed to evaluate intervention feasibility in ICU practice. Interviews were analysed qualitatively using thematic coding. RESULTS: Patients' median age was 68.0 years, five patients (20.0%) were female and seven patients (28.0%) died during ICU stay. Generally, study participants thought the intervention, which clarified the concept of QoL through visualization and served as a reminder to discuss QoL and expectations for life post-ICU, had merit. However, some participants, especially physicians, thought the prediction model needed more data on more severely ill ICU patients to curb uncertainty. CONCLUSIONS: Using predicted QoL scores in ICU practice to prepare patients and family members for life after ICU discharge is feasible. After optimising the model and implementation strategy, its effectiveness can be evaluated in a larger trial.

Development of a practically usable prediction model for quality of life of ICU survivors: A sub-analysis of the MONITOR-IC prospective cohort study.

PURPOSE: As the goal of ICU treatment is survival in good health, we aimed to develop a prediction model for ICU survivors' change in quality of life (QoL) one year after ICU admission. MATERIALS & METHODS: This is a sub-study of the prospective cohort MONITOR-IC study. Adults admitted ≥12 h to the ICU of a university hospital between July 2016-January 2019 were included. Moribund patients were excluded. Change in QoL one year after ICU admission was quantified using the EuroQol five-dimensional (EQ-5D-5L) questionnaire, and Short-Form 36 (SF-36). Multivariable linear regression analysis and best subsets regression analysis (SRA) were used. Models were internally validated by bootstrapping. RESULTS: The PREdicting PAtients' long-term outcome for Recovery (PREPARE) model was developed (n = 1308 ICU survivors). The EQ-5D-models had better predictive performance than the SF-36-models. Explained variance (adjusted R2) of the best model (33 predictors) was 58.0%. SRA reduced the number of predictors to 5 (adjusted R2 = 55.3%, SE = 0.3), including QoL, diagnosis of a Cardiovascular Incident and frailty before admission, sex, and ICU-admission following planned surgery. CONCLUSIONS: Though more long-term data are needed to ascertain model accuracy, in future, the PREPARE model may be used to better inform and prepare patients and their families for ICU recovery.

[Autointoxication with 'suicide powder']. / Auto-intoxicatie met 'zelfmoordpoeder'.

We present two patients who were treated for an intentional overdose of sodium nitrite. When ingested sodium nitrite leads to severe methaemoglobinaemia, resulting in severe hypoxia (as methaemoglobin does not transport oxygen), vasodilation and hypotension. Symptoms include cyanosis, headache, nausea, convulsions, coma and death. When measured by pulse oximetry, patients with a sodium nitrite intoxication and severe methaemoglobinaemia generally have an oxygen saturation of around 85%. This value is unreliable as the oxygen content of the blood is often extremely low - this can be confirmed by arterial blood gas analysis. Treatment of sodium nitrite intoxication consists of intravenous administration of methylthioninium chloride 1-2 mg/kg. Methylthioninium chloride converts the methaemoglobin back to haemoglobin. Due to the pharmacokinetics of methylthioninium chloride and sodium nitrite, a rebound effect is not to be expected. The only contra-indication for methylthioninium chloride is glucose-6-phosphate dehydrogenase deficiency, which is extremely rare in the Netherlands.

Seventy-two hours of mild hypothermia after cardiac arrest is associated with a lowered inflammatory response during rewarming in a prospective observational study.

INTRODUCTION: Whole-body ischemia and reperfusion trigger a systemic inflammatory response. In this study, we analyzed the effect of temperature on the inflammatory response in patients treated with prolonged mild hypothermia after cardiac arrest. METHODS: Ten comatose patients with return of spontaneous circulation after pulseless electrical activity/asystole or prolonged ventricular fibrillation were treated with mild therapeutic hypothermia for 72 hours after admission to a tertiary care university hospital. At admission and at 12, 24, 36, 48, 72, 96 and 114 hours, the patients' temperature was measured and blood samples were taken from the arterial catheter. Proinflammatory interleukin 6 (IL-6) and anti-inflammatory (IL-10) cytokines and chemokines (IL-8 and monocyte chemotactic protein 1), intercellular adhesion molecule 1 and complement activation products (C1r-C1s-C1inhibitor, C4bc, C3bPBb, C3bc and terminal complement complex) were measured. Changes over time were analyzed with the repeated measures test for nonparametric data. Dunn's multiple comparisons test was used for comparison of individual time points. RESULTS: The median temperature at the start of the study was 34.3°C (33.4°C to 35.2°C) and was maintained between 32°C and 34°C for 72 hours. All patients were passively rewarmed after 72 hours, from (median (IQR)) 33.7°C (33.1°C to 33.9°C) at 72 hours to 38.0°C (37.5°C to 38.1°C) at 114 hours (P <0.001). In general, the cytokines and chemokines remained stable during hypothermia and decreased during rewarming, whereas complement activation was suppressed during the whole hypothermia period and increased modestly during rewarming. CONCLUSIONS: Prolonged hypothermia may blunt the inflammatory response after rewarming in patients after cardiac arrest. Complement activation was low during the whole hypothermia period, indicating that complement activation is also highly temperature-sensitive in vivo. Because inflammation is a strong mediator of secondary brain injury, a blunted proinflammatory response after rewarming may be beneficial.

Effects of viscosity on cerebral blood flow after cardiac arrest.

OBJECTIVES: To determine blood viscosity in adult comatose patients treated with mild therapeutic hypothermia after cardiac arrest and to assess the relation between blood viscosity, cerebral blood flow, and cerebral oxygen extraction. DESIGN: Observational study. SETTING: Tertiary care university hospital. PATIENTS: Ten comatose patients with return of spontaneous circulation after out-of-hospital cardiac arrest. INTERVENTION: Treatment with mild therapeutic hypothermia for 24 hours followed by passive rewarming to normothermia. MEASUREMENTS AND MAIN RESULTS: Median viscosity at shear rate 50/s was 5.27 mPa · s (4.29-5.91 mPa · s) at admission; it remained relatively stable during the first 12 hours and decreased significantly to 3.00 mPa · s (2.72-3.58 mPa · s) at 72 hours (p < 0.001). Median mean flow velocity in the middle cerebral artery was low (27.0 cm/s [23.8-30.5 cm/s]) at admission and significantly increased to 63.0 cm/s (51.0-80.0 cm/s) at 72 hours. Median jugular bulb saturation at the start of the study was 61.5% (55.5-75.3%) and significantly increased to 73.0% (69.0-81.0%) at 72 hours. Median hematocrit was 0.41 L/L (0.36-0.44 L/L) at admission and subsequently decreased significantly to 0.32 L/L (0.27-0.35 L/L) at 72 hours. Median C-reactive protein concentration was low at admission (2.5 mg/L [2.5-6.5 mg/L]) and increased to 101 mg/L (65-113.3 mg/L) in the following hours. Median fibrinogen concentration was increased at admission 2,795 mg/L (2,503-3,565 mg/L) and subsequently further increased to 6,195 mg/L (5,843-7,368 mg/L) at 72 hours. There was a significant negative association between blood viscosity and the mean flow velocity in the middle cerebral artery (p = 0.0008). CONCLUSIONS: Changes in blood viscosity in vivo are associated with changes in flow velocity in the middle cerebral artery. High viscosity early after cardiac arrest may reduce cerebral blood flow and may contribute to secondary brain injury. Further studies are needed to determine the optimal viscosity during the different stages of the postcardiac arrest syndrome.

On-line blood viscosity monitoring in vivo with a central venous catheter, using electrical impedance technique.

Blood viscosity is an important determinant of microvascular hemodynamics and also reflects systemic inflammation. Viscosity of blood strongly depends on the shear rate and can be characterized by a two parameter power-law model. Other major determinants of blood viscosity are hematocrit, level of inflammatory proteins and temperature. In-vitro studies have shown that these major parameters are related to the electrical impedance of blood. A special central venous catheter was developed to measure electrical impedance of blood in-vivo in the right atrium. Considering that blood viscosity plays an important role in cerebral blood flow, we investigated the feasibility to monitor blood viscosity by electrical bioimpedance in 10 patients during the first 3 days after successful resuscitation from a cardiac arrest. The blood viscosity-shear rate relationship was obtained from arterial blood samples analyzed using a standard viscosity meter. Non-linear regression analysis resulted in the following equation to estimate in-vivo blood viscosity (Viscosity(imp)) from plasma resistance (R(p)), intracellular resistance (R(i)) and blood temperature (T) as obtained from right atrium impedance measurements: Viscosity(imp)=(-15.574+15.576R(p)T)SR ((-.138RpT-.290Ri)). This model explains 89.2% (R(2)=.892) of the blood viscosity-shear rate relationship. The explained variance was similar for the non-linear regression model estimating blood viscosity from its major determinants hematocrit and the level of fibrinogen and C-reactive protein (R(2)=.884). Bland-Altman analysis showed a bias between the in-vitro viscosity measurement and the in-vivo impedance model of .04 mPa s at a shear rate of 5.5s(-1) with limits of agreement between -1.69 mPa s and 1.78 mPa s. In conclusion, this study demonstrates the proof of principle to monitor blood viscosity continuously in the human right atrium by a dedicated central venous catheter equipped with an impedance measuring device. No safety problems occurred and there was good agreement with in-vitro measurements of blood viscosity.

Effects of prolonged mild hypothermia on cerebral blood flow after cardiac arrest.

OBJECTIVE: The aim of the present study was to assess the cerebral blood flow and cerebral oxygen extraction in adult patients after pulseless electrical activity/asystole or resistant ventricular fibrillation who were treated with mild therapeutic hypothermia for 72 hrs. DESIGN: Observational study. SETTING: Tertiary care university hospital. PATIENTS: Ten comatose patients with return of spontaneous circulation after pulseless electrical activity/asystole or prolonged ventricular fibrillation. INTERVENTION: Treatment with mild therapeutic hypothermia for 72 hrs. MEASUREMENTS AND MAIN RESULTS: Mean flow velocity in the middle cerebral artery was measured by transcranial Doppler at 12, 24, 36, 48, 60, 72, 84, 96, and 108 hrs after admission. Jugular bulb oxygenation was measured at the same intervals. Mean flow velocity in the middle cerebral artery was low (26.5 (18.7-48.0) cm/sec) at admission and significantly increased to 63.9 (45.6-65.6) cm/sec at 72 hrs (p=.002). Upon rewarming, the mean flow velocity in the middle cerebral artery remained relatively constant with a mean flow velocity in the middle cerebral artery of 71.5 (56.0-78.5) at 108 hrs (p=.381). Jugular bulb oxygenation at the start of the study was 57.0 (51.0-61.3)% and gradually increased to 81.0 (78.5-88.0)% at 72 hrs (p=.003). Upon rewarming, the jugular bulb oxygenation remained constant with a jugular bulb oxygenation of 84.0 (77.3-86.3)% at 108 hrs (p=.919). There were no differences in mean flow velocity in the middle cerebral artery, pulsatility index, and jugular bulb oxygenation between survivors and nonsurvivors. CONCLUSIONS: Temperature by itself is probably not a major determinant in regulation of cerebral blood flow after cardiac arrest. The relatively low mean flow velocity in the middle cerebral artery in combination with normal jugular bulb oxygenation values suggests a reduction in cerebral metabolic activity that may contribute to the neuroprotective effect of (prolonged) mild therapeutic hypothermia in the delayed hypoperfusion phase.

Rewarming after hypothermia after cardiac arrest shifts the inflammatory balance.

OBJECTIVES: The aim of this study was to simultaneously analyze the key components of the cerebral and systemic inflammatory response over time in cardiac arrest patients during mild therapeutic hypothermia and rewarming. DESIGN AND SETTING: Clinical observational study in a tertiary care university hospital. PATIENTS: Ten comatose patients after out-of-hospital cardiac arrest. INTERVENTIONS: All patients were cooled to 32-34°C for 24 hrs. After 24 hrs patients were passively rewarmed to normothermia. MEASUREMENTS AND MAIN RESULTS: On admission and at 3, 6, 12, 24, and 48 hrs blood samples were taken from the arterial and jugular bulb catheter. Proinflammatory and anti-inflammatory cytokines and chemokines (interleukin-1ra, interleukin-1ß, interleukin-6, interleukin-8, interleukin-10, interleukin-18, monocyte chemotactic protein-1, high-mobility group box-1 and tumor necrosis factor-α), complement activation products (C4d, Bb, C3a, and terminal complement complex), and the adhesion molecule soluble intercellular adhesion molecule were measured. Mean temperatures at the start of the study and at 12 and 24 hrs were 33.7 ± 0.9°C, 32.7 ± 0.92°C, and 34.5 ± 1.5°C, respectively. Passive rewarming resulted in a temperature of 37.8 ± 0.5°C at 48 hrs. The proinflammatory cytokine interleukin-6 increased from 12 to 24 hrs and returned to baseline levels after 48 hrs. In contrast, the chemokines interleukin-8 and monocyte chemotactic protein-1 stayed relatively high from the start and during the hypothermia period, decreasing to baseline levels after 48 hrs. The anti-inflammatory cytokines interleukin-10 and interleukin-1ra did not significantly change during mild therapeutic hypothermia and rewarming, although low values of interleukin-10 were observed after rewarming. A significant increase after rewarming was demonstrated on high-mobility group box-1 concentrations in the jugular bulb, whereas soluble intercellular adhesion molecule increased significantly during hypothermia and remained at this level after rewarming. Complement activation was increased on admission and decreased after induction of hypothermia, followed by a secondary increase during rewarming. No significant differences between any of the biomarkers were found between samples from the arterial and jugular bulb catheter. CONCLUSIONS: Complement activation occurs during rewarming from mild therapeutic hypothermia after cardiac arrest. Interleukin-6 increased already from 12 to 24 hrs, concomitantly with a significant increase in the temperature seen during this period of mild therapeutic hypothermia. The optimal rate of rewarming is unknown. Additional clinical studies are needed to determine the optimal rewarming rate and strategy.

Predictors of poor neurologic outcome in patients after cardiac arrest treated with hypothermia: a retrospective study.

INTRODUCTION: Outcome studies in patients with anoxic-ischemic encephalopathy focus on the early and reliable prediction of an outcome no better than a vegetative state or severe disability. We determined the effect of mild therapeutic hypothermia on the validity of the currently used clinical practice parameters. METHODS: We conducted a retrospective cohort study of adult comatose patients after cardiac arrest treated with hypothermia. All data were collected from medical charts and laboratory files and analyzed from the day of admission to the intensive care unit until day 7, discharge from the intensive care unit or death using the Utstein definitions for the registration of the data. RESULTS: We analyzed the data of 103 patients. The combination of an M1 or M2 on the Glasgow Coma Scale or absent pupillary reactions or absent corneal reflexes on day 3 was present in 80.6% of patients with an unfavourable and 11.1% of patients with a favourable outcome. The combination of M1 or M2 and absent pupillary reactions to light and absent corneal reflexes on day 3 was present in 14.9% of patients with an unfavourable and none of the patients with a favourable outcome. None of the patients with a favourable outcome had a bilaterally absent somatosensory evoked potential of the median nerve. The value of electroencephalogram patterns in predicting outcome was low, except for reactivity to noxious stimuli. CONCLUSIONS: No single clinical or electrophysiological parameter has sufficient accuracy to determine prognosis and decision making in patients after cardiac arrest, treated with hypothermia.

Influence of mild therapeutic hypothermia after cardiac arrest on hospital mortality.

OBJECTIVE: Following two randomized controlled trials that demonstrated reduced mortality and better neurological outcome in cardiac arrest patients, mild therapeutic hypothermia was implemented in many intensive care units. Up to now, no large observational studies have confirmed the beneficial effects of mild therapeutic hypothermia. DESIGN: Internet-based survey combined with a retrospective, observational study. PATIENTS: All patients admitted to an intensive care unit in The Netherlands after cardiac arrest from January 1, 1999 until January 1, 2009. DATA SOURCE: Dutch National Intensive Care Evaluation database. METHODS: The moment of implementation of mild therapeutic hypothermia for each hospital participating in the Dutch National Intensive Care Evaluation database was determined with an Internet survey. To compare mortality before and after implementation of mild therapeutic hypothermia, the odds ratio adjusted for Simplified Acute Physiology Score II score, age, gender, propensity score, and in- or out-of-hospital cardiac arrest was calculated. Patients were excluded if 1) they were admitted to an intensive care unit that did not respond to the survey, 2) they were admitted within 3 months after implementation of mild therapeutic hypothermia, 3) they had a Glasgow Coma Scale score of >8, or 4) they did not satisfy the Simplified Acute Physiology Score II inclusion criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 13,962 patients were admitted to an intensive care unit following cardiac arrest. In total 8,645 patients were excluded, 5,544 because of a Glasgow Coma Scale score of >8. Of the resultant 5,317 patients, 1,547 patients were treated before and 3,770 patients after implementation of mild therapeutic hypothermia. Patients admitted after implementation of mild therapeutic hypothermia had lower minimal and maximal temperatures (p < .0001) during the first 24 hrs on the intensive care unit compared to patients admitted before implementation of mild therapeutic hypothermia. The adjusted odds ratio of the hospital mortality of patients treated after implementation of mild therapeutic hypothermia was 0.80 (95% confidence interval of 0.65-0.98, p = .029). CONCLUSION: The results of this retrospective, observational survey suggest that implementation of mild therapeutic hypothermia in Dutch intensive care units is associated with a 20% relative reduction of hospital mortality in cardiac arrest patients.

Preserved metabolic coupling and cerebrovascular reactivity during mild hypothermia after cardiac arrest.

OBJECTIVE: Although mild hypothermia improves outcome in patients after out-of-hospital cardiac arrest, the cardiodepressive effects of hypothermia may lead to secondary brain damage. This study was performed to assess the cerebral blood flow, cerebral oxygen extraction, and cerebrovascular reactivity to changes in partial pressure of carbon dioxide in the arterial blood in comatose patients after out-of-hospital cardiac arrest treated with mild hypothermia. DESIGN: Observational study. SETTING: Tertiary care university hospital. PATIENTS: Ten comatose patients after out-of-hospital cardiac arrest. INTERVENTIONS: All patients were cooled to 32-34 degrees C for 24 hrs. Cerebrovascular reactivity to changes in carbon dioxide in the arterial blood was measured after increasing or decreasing the minute ventilation by 20%. MEASUREMENTS AND MAIN RESULTS: Mean flow velocity in the middle cerebral artery and pulsatility index were measured by transcranial Doppler at 0, 3, 6, 9, 12, 18, 24, and 48 hrs after admission. Jugular bulb oxygenation was measured at the same intervals. Cerebrovascular reactivity to changes in carbon dioxide in the arterial blood was studied on admission to the intensive care unit and at 6, 12, 18, and 24 hrs by measurement of mean flow velocity in the middle cerebral artery and jugular bulb oxygenation. Mean flow velocity in the middle cerebral artery was low (30.3+/-9.5 cm/sec) on admission and remained relatively stable for the first 24 hrs. After rewarming, it increased to 67.5+/-33.0 cm/sec at 48 hrs after admission from 30.3+/-9.5 at admission (p=.009). Jugular bulb oxygenation at the start of the study was 66.2+/-8.5% and gradually increased to 82.9+/-4.9% at 48 hrs (p<.001). Regression analysis showed a significant correlation between changes in carbon dioxide in the arterial blood, mean flow velocity in the middle cerebral artery (p<.001) and jugular bulb oxygenation (p<.001). The mean percentage change in mean flow velocity in the middle cerebral artery was 3.6+/-2.9% per 1-mm Hg change of carbon dioxide in the arterial blood. CONCLUSIONS: The mean flow velocity in the middle cerebral artery, as a parameter of cerebral blood flow, was low during mild hypothermia, whereas cerebral oxygen extraction remained normal, suggesting decreased cerebral metabolic activity. We demonstrated that CO2 reactivity is preserved during hypothermia in these patients.