Plasma HMGB1 levels and physical performance in ICU survivors.

PURPOSE: Physical impairment after critical illness is recognized as a part of the post-intensive care syndrome (PICS). About one third of intensive care unit (ICU) survivors suffer from long-term physical disability, yet the underlying pathophysiological mechanisms remain poorly understood. The pro-inflammatory alarmin, high mobility group box 1 (HMGB1), promotes muscle dysfunction in experimental models, and HMGB1 stays elevated in some patients after ICU discharge. Accordingly, we investigated the relationship between HMGB1 plasma levels and physical performance in ICU survivors. METHODS: Prospective cohort study of 100 ICU survivors from the general ICU at the Karolinska University Hospital, Sweden. Patients returned for follow up at 3 (58 patients) and 6 months (51 patients) after ICU discharge. Blood samples were collected, and a 6-minute walk test (6-MWT), a handgrip-strength test (HST), and a timed-stands test (TST) were performed. RESULTS: Compared to reference values of the different physical tests, 16% of patients underperformed at all tests at 3 months and 12% at 6 months. All test results, except hand-grip strength left, improved significantly over the follow-up period (P < .05). There was no significant association between plasma HMGB1 levels at 3 and 6 months and scores on the three tests (6-MWT, TST, and HST) (P = .50-0.69). CONCLUSION: In this follow-up study of ICU survivors, we found no significant association between plasma HMGB1 levels and physical performance. Additional follow-up studies of HMGB1 plasma levels and muscle function in ICU survivors are still warranted. EDITORIAL COMMENT: HMGB-1, a marker of cell damage and activation, is known to increase in ICU patients. In study participants at 3- to 6-month post-ICU stay, HMGB-1 levels were still elevated, although no association to the primary outcome, physical performance, was found. Mechanisms for failure to recover physical performance post-ICU remain unclear, and investigations into cause of post-intensive care syndrome need to continue. TRIAL REGISTRATIONS: ClinicalTrials.gov identifier NCT02914756.

Standardized Unloading of Respiratory Muscles during Neurally Adjusted Ventilatory Assist: A Randomized Crossover Pilot Study.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Currently, there is no standardized method to set the support level in neurally adjusted ventilatory assist (NAVA). The primary aim was to explore the feasibility of titrating NAVA to specific diaphragm unloading targets, based on the neuroventilatory efficiency (NVE) index. The secondary outcome was to investigate the effect of reduced diaphragm unloading on distribution of lung ventilation. METHODS: This is a randomized crossover study between pressure support and NAVA at different diaphragm unloading at a single neurointensive care unit. Ten adult patients who had started weaning from mechanical ventilation completed the study. Two unloading targets were used: 40 and 60%. The NVE index was used to guide the titration of the assist in NAVA. Electrical impedance tomography data, blood-gas samples, and ventilatory parameters were collected. RESULTS: The median unloading was 43% (interquartile range 32, 60) for 40% unloading target and 60% (interquartile range 47, 69) for 60% unloading target. NAVA with 40% unloading led to more dorsal ventilation (center of ventilation at 55% [51, 56]) compared with pressure support (52% [49, 56]; P = 0.019). No differences were found in oxygenation, CO2, and respiratory parameters. The electrical activity of the diaphragm was higher during NAVA with 40% unloading than in pressure support. CONCLUSIONS: In this pilot study, NAVA could be titrated to different diaphragm unloading levels based on the NVE index. Less unloading was associated with greater diaphragm activity and improved ventilation of the dependent lung regions.

Neurally adjusted ventilatory assist feasibility during anaesthesia: A randomised crossover study of two anaesthetics in a large animal model.

BACKGROUND: Spontaneous breathing during mechanical ventilation improves gas exchange by redistribution of ventilation to dependent lung regions. Neurally adjusted ventilatory assist (NAVA) supports spontaneous breathing in proportion to the electrical activity of the diaphragm (EAdi). NAVA has never been used in the operating room and no studies have systematically addressed the influence of different anaesthetic drugs on EAdi. OBJECTIVES: The aim of this study was to test the feasibility of NAVA under sedation and anaesthesia with two commonly used anaesthetics, sevoflurane and propofol, with and without remifentanil, and to study their effects on EAdi and breathing mechanics. DESIGN: A crossover study with factorial design of NAVA during sedation and anaesthesia in pigs. SETTING: University basic science laboratory in Uppsala, Sweden, from March 2009 to February 2011. ANIMALS: Nine juvenile pigs were used for the experiment. INTERVENTIONS: The lungs were ventilated using NAVA while the animals were sedated and anaesthetised with continuous low-dose ketamine combined with sevoflurane and propofol, with and without remifentanil. MAIN OUTCOME MEASURES: During the last 5  min of each study period (total eight steps) EAdi, breathing pattern, blood gas analysis, neuromechanical efficiency (NME) and neuroventilatory efficiency (NVE) during NAVA were determined. RESULTS: EAdi was preserved and normoventilation was reached with both sevoflurane and propofol during sedation as well as anaesthesia. Tidal volume (Vt) was significantly lower with sevoflurane anaesthesia than with propofol. NME was significantly higher with sevoflurane than with propofol during anaesthesia with and without remifentanil. NVE was significantly higher with sevoflurane than with propofol during sedation and anaesthesia. CONCLUSION: NAVA is feasible during ketamine-propofol and ketamine-sevoflurane anaesthesia in pigs. Sevoflurane promotes lower Vt, and affects NME and NVE less than propofol. Our data warrant studies of NAVA in humans undergoing anaesthesia.

Inhaled isoflurane sedation during therapeutic hypothermia after cardiac arrest: a case series.

OBJECTIVE: Therapeutic hypothermia in the ICU requires mechanical ventilation and sedation. Hypothermia reduces the metabolism of commonly used IV sedatives. The use of long-acting sedative agents may confound neurologic assessment. Volatile anesthetics have been reported to provide protection against ischemia-reperfusion injury and have been safely used in the ICU to provide sedation in trials with shorter wake-up times. There are no clinical studies in this setting. We describe a case series and discuss potential benefits. DESIGN: Retrospective study. SETTINGS: Ten-bed ICU, university hospital. PATIENTS: Twelve patients resuscitated from cardiac arrest with Glasgow Coma Scale score less than or equal to 4. INTERVENTION: Isoflurane sedation with the AnaConDa during 24 hours therapeutic hypothermia, until rewarming. MEASUREMENTS AND MAIN RESULTS: Data were extracted from the computerized ICU chart/monitors, hospital and prehospital charts, and the national death index. Patients were 49-76 years old. Median return of spontaneous circulation was 14 minutes. Glasgow Coma Scale scores were assessed within 24 hours from reaching normal body temperature and compared with outcomes at 6 months: six patients had poor Glasgow Coma Scale scores (< 8) that remained low and all died before 6-month follow-up, whereas another six patients had high scores (> 8) and survived to 6 months with good Cerebral Performance Category. In the ICU, four of the survivors were directly extubated after rewarming while two were once more sedated due to pneumonia requiring invasive ventilator therapy. All patients required norepinephrine to maintain adequate mean arterial pressure. Isoflurane sedation was changed to midazolam in two nonsurviving patients because of hemodynamic instability, which persisted despite the change. CONCLUSIONS: Sedation with volatile anesthetics during therapeutic hypothermia may be a feasible short-acting option with potential postconditioning effects protecting vital organs from ischemia-reperfusion injury. Its measurability and insignificant drug accumulation could facilitate early neurologic assessment. Prospective clinical trials are warranted.

Developing an early screening instrument for predicting psychological morbidity after critical illness.

INTRODUCTION: Guidelines recommend follow-up for patients after an intensive care unit (ICU) stay. Methods for identifying patients with psychological problems after intensive care would be of value, to optimize treatment and to improve adequate resource allocation in ICU follow-up of ICU survivors. The aim of the study was to develop a predictive screening instrument, for use at ICU discharge, to identify patients at risk for post-traumatic stress, anxiety or depression. METHODS: Twenty-one potential risk factors for psychological problems - patient characteristics and ICU-related variables - were prospectively collected at ICU discharge. Two months after ICU discharge 252 ICU survivors received the questionnaires Post-Traumatic Stress Symptom scale -10 (PTSS-10) and Hospital Anxiety and Depression Scale (HADS) to estimate the degree of post-traumatic stress, anxiety and depression. RESULTS: Of the 150 responders, 46 patients (31%) had adverse psychological outcome, defined as PTSS-10 >35 and/or HADS subscales ≥8. After analysis, six predictors were included in the screening instrument: major pre-existing disease, being a parent to children younger than 18 years of age, previous psychological problems, in-ICU agitation, being unemployed or on sick-leave at ICU admission and appearing depressed in the ICU. The total risk score was related to the probability for adverse psychological outcome in the individual patient. The predictive accuracy of the screening instrument, as assessed with area under the receiver operating characteristic curve, was 0.77. When categorizing patients in three risk probability groups - low (0 to 29%), moderate (30 to 59%) high risk (60 to 100%), the actual prevalence of adverse psychological outcome in respective groups was 12%, 50% and 63%. CONCLUSION: The screening instrument developed in this study may aid ICU clinicians in identifying patients at risk for adverse psychological outcome two months after critical illness. Prior to wider clinical use, external validation is needed.

Palmar skin conductance variability and the relation to stimulation, pain and the motor activity assessment scale in intensive care unit patients.

INTRODUCTION: Many intensive care unit (ICU) patients describe pain and other adverse feelings that may impact long-term psychological morbidity. Sympathetically mediated palmar skin conductance variability is related to emotionally induced perspiration and correlates with pain levels in the perioperative setting but has not been studied in ICU patients. METHODS: Twenty non-intubated and 20 intubated general ICU patients were included in this observational study. Patients were monitored with the MED-STORM Pain Monitoring System®. The number of skin conductance fluctuations per second (NSCF) was measured in parallel with bedside observation during one hour of intensive care, including rest, procedures and patient-staff interactions. Arousal-agitation level was monitored with the motor activity assessment scale (MAAS). Pain was monitored with the numeric rating scale (0 to 10) in patients able to communicate or by observation in patients unable to communicate. RESULTS: In non-intubated patients, NSCF increased with increasing stimulation/pain but also with higher MAAS (P=0.002). An interaction effect was found, with increased NSCF response to stimulation/pain with increasing MAAS (P<0.001). CONCLUSIONS: In critically ill patients, NSCF may be more useful evaluating emotional distress rather than pain alone. It needs to be assessed whether NSCF monitoring is clinically useful and whether controlling emotional distress with the aid of such monitoring may impact on patient care and outcomes.

Wake-up times following sedation with sevoflurane versus propofol after cardiac surgery.

OBJECTIVES: Intravenous sedation in the intensive care unit (ICU) may contribute to altered consciousness and prolonged mechanical ventilation. We tested the hypothesis that replacing intravenous propofol with inhaled sevoflurane for sedation after cardiac surgery would lead to shorter wake-up times, quicker patient cooperation, and less delusional memories. DESIGN: Following coronary artery bypass surgery with cardiopulmonary bypass, 100 patients were randomized to sedation with sevoflurane via the anesthetic conserving device or propofol. Study drugs were administered for a minimum of 2 hours until criteria for extubation were met. Primary endpoints were time from drug stop to extubation and to adequate verbal response. Secondary endpoints were adverse recovery events, memories reported in the ICU Memory Tool test, and ICU/hospital stay. RESULTS: Median time from drug stop to extubation (interquartile range/total range) was shorter after sevoflurane compared to propofol sedation; 10 (10/100) minutes versus 25 (21/240) minutes (p <0.001). Time from extubation to adequate verbal response was shorter (p =0.036). No differences were found in secondary endpoints. CONCLUSIONS: Sevoflurane sedation after cardiac surgery leads to shorter wake-up times and quicker cooperation compared to propofol. No differences were seen in ICU-stay, adverse memories or recovery events in our short-term sedation.

Screening and treatment of problems after intensive care: a descriptive study of multidisciplinary follow-up.

OBJECTIVES: To describe a multidisciplinary intensive care follow-up and the methods used for identifying and managing physical and psychological problems in ICU survivors. METHODS: Patients treated>four days in an intensive care unit (ICU) were invited three, six and 12 months after intensive care for screening of physical problems with function tests and psychological problems with the Impact of Event Scale (IES) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: 40 of 61 patients had clinically impaired physical function, with no ongoing physical rehabilitation at three months. Twenty-two patients received specific training instructions and 18 patients were referred for physiotherapy. 34 of 61 patients had symptoms of moderate to severe posttraumatic stress and/or symptoms of clinically significant anxiety or depression. Twelve patients accepted referral for psychiatric evaluation and treatment. CONCLUSION: Multidisciplinary follow-up after intensive care can be of value in identifying untreated physical and psychological problems in ICU survivors. Liaison with specialists enables referral for identified problems. Patients screened and treated in the first six months appear to have little need for further follow-up after intensive care.

Frontal EEG for intensive care unit sedation: treating numbers or patients?

In this issue of Critical Care, Dr Haenggi and co-workers present a study evaluating bispectral index (BIS), state entropy (SE) and response entropy in 44 patients sedated in the intensive care unit (ICU). As in recent studies attempting to correlate frontal electroencephalogram (EEG) measurements with clinical evaluations of sedative efficacy, there is considerable overlap in numerical EEG values and different clinical levels of sedation. This precludes the use of these monitors for monitoring or titrating sedation in the critically ill. Despite many attempts, no study has yet presented data showing improved outcome with the use of EEG monitors in ICU sedation. Meanwhile, clinical sedation protocols have emerged, improving important endpoints in critically ill patients needing sedation. A major underlying problem in applying EEG monitors in the ICU is that they have been developed for measuring anesthetic depth and the related risk of recall, rather than the acknowledged endpoints of sedation, namely reduction of anxiety and discomfort. Until an 'objective' monitor is developed to measure the degree of such symptoms, physicians should continue treating patients and not numbers.

Short- and long-term follow-up of intensive care unit patients after sedation with isoflurane and midazolam--a pilot study.

OBJECTIVE: To compare memories from the intensive care unit (ICU) and short- and long-term psychological morbidity in patients after sedation with intravenous midazolam or inhaled isoflurane. DESIGN: Prospective long-term follow-up after randomized controlled trial. SETTING: General ICU at Karolinska University Hospital, Solna, Stockholm. PATIENTS: Forty patients in need of sedation during ventilator treatment. INTERVENTIONS: Patients were randomized to receive isoflurane or midazolam for goal-directed sedation until extubation or for a maximum of 96 hrs. MEASUREMENTS AND MAIN RESULTS: For short-term follow-up, doctors', nurses', and physiotherapists' notes from the 4 days following exposure to the study drugs were reviewed for words indicating adequate or pathologic cognitive and psychological recovery. For long-term follow-up, all 6-month survivors received questionnaires including the ICU Memory Tool (ICU-MT), Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), and Well-Being Index. Additionally, several screening questions for previous posttraumatic stress symptoms were included. In the short term follow-up, no significant differences were found between groups. In the long-term follow-up, a trend toward fewer hallucinations/delusions after isoflurane sedation than after midazolam (two of ten isoflurane patients vs. five of seven midazolam patients) was found (p = .06). None of the five solely isoflurane-sedated patients reported hallucinations/delusions from the ICU. There was no difference in groups in long-term psychological morbidity as measured with HADS and IES. Memories of negative feelings in the ICU (ICU-MT) were associated with high HADS and IES scores (Fisher's exact test, p = .02 and p = .01, respectively). CONCLUSIONS: Sedation of ICU patients with isoflurane may result in fewer delusional memories or hallucinations from the ICU compared with more commonly used intravenous sedation. Memories of negative feelings from the ICU were associated with symptoms of depression or anxiety or symptoms indicating posttraumatic stress disorder. Further study of memory and cognitive/psychological recovery after prolonged isoflurane sedation beyond 96 hrs is warranted.

Three cases of PICU sedation with isoflurane delivered by the 'AnaConDa'.

Prolonged sedation in the pediatric intensive care unit may be difficult because of tolerance, drug dependence and withdrawal, drug interactions and unwanted drug effects. We present three patients sedated with isoflurane via the Anesthetic Conserving Device, AnaConDa. AnaConDa is a modified heat and moisture exchanger that allows evaporation and delivery of inhalational anesthetics without an anesthesia machine, vaporizer or adapted ventilator. Two patients with abdominal complications and prolonged sedation for mechanical ventilation were converted to isoflurane sedation for several days. The third patient with refractory status epilepticus received isoflurane to treat epileptiform electroencephalogram activity. Patients weighing 40 and 30 kg were treated with AnaConDa placed at the Y-piece, while the patient weighing 20 kg was treated with AnaConDa in the inspiratory limb of the respiratory circuit. Adequate sedation was achieved with endtidal isoflurane concentration of 0.3-0.4%, while antiepileptic effect was achieved at a higher dose, 0.9%. Intravenous sedatives could be reduced or discontinued during isoflurane sedation. Inhaled sedation of isoflurane with AnaConDa was effective in these patients. It may provide an alternative in difficult cases needing prolonged sedation and should be evaluated further.

Ambient isoflurane pollution and isoflurane consumption during intensive care unit sedation with the Anesthetic Conserving Device.

OBJECTIVE: To examine ambient isoflurane pollution, scavenging efficacy, and isoflurane consumption using the Anesthetic Conserving Device (ACD) for prolonged isoflurane sedation in the intensive care unit. DESIGN: Prospective observational study. SETTING: Multidisciplinary university intensive care unit. PATIENTS: Fifteen adult ventilator-dependent intensive care unit patients sedated with isoflurane for 12-96 hrs. INTERVENTIONS: Isoflurane was infused to the ACD for sedation of study subjects. Changing of the ACD, isoflurane syringe, and opening of the respiratory circuit were performed in a standardized fashion according to investigator instructions. Active scavenging of waste gas from the ventilator was performed in ten patients; in five patients no active scavenging was performed. MEASUREMENTS AND MAIN RESULTS: Continuous spectrophotometric measurement of ambient isoflurane pollution in parts per million (ppm) at 0.5 m from the patient's head and passive lapel dosimeter sampling for ten staff nurses over 8-hr shifts. Isoflurane requirement and agent consumption were registered in all patients. Spectrophotometric readings (0.1 +/- 0.2 ppm) were well below internationally recommended long-term exposure limits in all cases. Isoflurane peaks during nursing procedures were brief, infrequent, and of low amplitude. There was no observed difference between isoflurane trace levels with or without an active scavenging system in use. Passive dosimeter values were also low, ranging from undetectable to 0.16 ppm. Mean isoflurane consumption was 2.1 +/- 1.0 mL/hr. This is approximately one fourth of predicted and previously reported consumption of isoflurane with vaporizer-administered sedation in the intensive care unit setting. CONCLUSIONS: In the present setting, isoflurane via the ACD is an environmentally safe method of sedation provided users follow instructions for standardizing procedures with potential spillage of isoflurane. This method of sedation requires considerably less isoflurane than with traditional vaporizer technique.

Prolonged isoflurane sedation of intensive care unit patients with the Anesthetic Conserving Device.

OBJECTIVE: To test the efficacy and patient safety of a new method for administering isoflurane for prolonged sedation in the intensive care unit. DESIGN: Randomized controlled trial. SETTING: Multidisciplinary university intensive care unit, January 2002 to July 2003. PATIENTS: Forty ventilator-dependent intensive care unit patients 18-80 yrs old, expected to need >12 hrs sedation. INTERVENTIONS: Patients were randomized to sedation with inhaled isoflurane via the Anesthetic Conserving Device or intravenous midazolam infusion. Study duration was 96 hrs or until extubation. MEASUREMENTS AND MAIN RESULTS: Primary end points were wake-up times from termination of sedative administration and proportion of time within a predefined desired interval on a sedation scale (Bloomsbury Sedation Score). Practical and patient-related complications with the Anesthetic Conserving Device were noted. Hemodynamic, hepatic, and renal side effects were monitored. Wake-up times were significantly shorter in the isoflurane group than in the control group (time to extubation [mean +/- sd] 10 +/- 5 vs. 252 +/- 271 mins, time to follow verbal command 10 +/- 8 vs. 110 +/- 132 mins). Proportion of time within the desired sedation interval was comparable between groups (isoflurane 54%, midazolam 59% of sedation time). Few minor practical problems with this new method for isoflurane administration were noted. No serious complications related to either sedative drug occurred. We found no hemodynamic, hepatic, or renal adverse effects related to either sedative protocol. CONCLUSIONS: Isoflurane via the Anesthetic Conserving Device is a safe and efficacious method for sedation in the intensive care unit, with short wake-up times after termination of administration. The Anesthetic Conserving Device allows easily titratable administration of isoflurane without costly equipment and can be safely managed by nursing staff.