Hyperammonemia during treatment with valproate in critically ill patients.

INTRODUCTION: Hyperammonemia (HA) is a potential side-effect of valproate (VPA) treatment, which has been described during long-term administration. The aim of this study was to evaluate the incidence, the impact and the risk factors of HA in critically ill patients. METHODS: We reviewed the data of all adult patients treated in our mixed 35-bed Department of Intensive Care over a 12-year period (2004-2015) who: a) were treated with VPA for more than 72 h and b) had at least one measurement of ammonium and VPA levels during the ICU stay; patients with Child-Pugh C liver cirrhosis were excluded. HA was defined as ammonium levels above 60 µg/dl. RESULTS: Of a total of 2640 patients treated with VPA, 319 patients met the inclusion criteria (median age 64 years; male gender 55%); 78% of them were admitted for neurological reasons and ICU mortality was 30%. Median ammonium levels were 88 [63-118] µg/dl. HA was found in 245 (77%) patients. For those patients with HA, median time from start of VPA therapy to HA was 3 [2-5] days. In a multivariable analysis, high VPA serum levels, mechanical ventilation and sepsis were independently associated with HA during VPA therapy. In 98/243 (40%) of HA patients, VPA was interrupted; VPA interruption was more frequent in patients with ammonium levels > 100 µg/dl than others (p = 0.001). HA was not an independent predictor of ICU mortality or poor neurological outcome. CONCLUSIONS: In this study, HA was a common finding during treatment with VPA in acutely ill patients. VPA levels, sepsis and mechanical ventilation were risk factors for HA. Hyperammonemia did not influence patients' outcome.

Quality of targeted temperature management and outcome of out-of-hospital cardiac arrest patients: A post hoc analysis of the TTH48 study.

BACKGROUND: No data are available on the quality of targeted temperature management (TTM) provided to out-of-hospital cardiac arrest (OHCA) patients and its association with outcome. METHODS: Post hoc analysis of the TTH48 study (NCT01689077), which compared the effects of prolonged TTM at 33 °C for 48 h to standard 24-h TTM on neurologic outcome. Admission temperature, speed of cooling, rewarming rates, precision (i.e. temperature variability), overcooling and overshooting as post-cooling fever (i.e. >38.0 °C) were collected. A specific score, ranging from 1 to 9, was computed to define the "quality of TTM". RESULTS: On a total of 352 patients, most had a moderate quality of TTM (n = 217; 62% - score 4-6), while 80 (23%) patients had a low quality of TTM (score 1-3) and only 52 (16%) a high quality of TTM (score 7-9). The proportion of patients with unfavorable neurological outcome (UO; Cerebral Performance Category of 3-5 at 6 months) was similar between the different quality of TTM groups (p = 0.90). Although a shorter time from arrest to target temperature and a lower proportion of time outside the target ranges in the TTM 48-h than in the TTM 24-h group, quality of TTM was similar between groups. Also, the proportion of patients with UO was similar between the different quality of TTM groups when TTM 48-h and TTM 24-h were compared. CONCLUSIONS: In this study, high quality of TTM was provided to a small proportion of patients. However, quality of TTM was not associated with patients' outcome.

Incoherence between Systemic Hemodynamic and Microcirculatory Response to Fluid Challenge in Critically Ill Patients.

BACKGROUND: The aim of the study was to assess the coherence between systemic hemodynamic and microcirculatory response to a fluid challenge (FC) in critically ill patients. METHODS: We prospectively collected data in patients requiring a FC whilst cardiac index (CI) and microcirculation were monitored. The sublingual microcirculation was assessed using the incident dark field (IDF) CytoCam device (Braedius Medical, Huizen, The Netherlands). The proportion of small perfused vessels (PPV) was calculated. Fluid responders were defined by at least a 10% increase in CI during FC. Responders according to changes in microcirculation were defined by at least 10% increase in PPV at the end of FC. Cohen's kappa coefficient was measured to assess the agreement to categorize patients as "responders" to FC according to CI and PPV. RESULTS: A total of 41 FC were performed in 38 patients, after a median time of 1 (0-1) days after ICU admission. Most of the fluid challenges (39/41, 95%) were performed using crystalloids and the median total amount of fluid was 500 (500-500) mL. The main reasons for fluid challenge were oliguria (n = 22) and hypotension (n = 10). After FC, CI significantly increased in 24 (58%) cases; a total of 19 (46%) FCs resulted in an increase in PPV. Both CI and PPV increased in 13 responders and neither in 11; the coefficient of agreement was only 0.21. We found no correlation between absolute changes in CI and PPV after fluid challenge. CONCLUSIONS: The results of this heterogenous population of critically ill patients suggest incoherence in fluid responsiveness between systemic and microvascular hemodynamics; larger cohort prospective studies with adequate a priori sample size calculations are needed to confirm these findings.

Effect of different methods of cooling for targeted temperature management on outcome after cardiac arrest: a systematic review and meta-analysis.

BACKGROUND: Although targeted temperature management (TTM) is recommended in comatose survivors after cardiac arrest (CA), the optimal method to deliver TTM remains unknown. We performed a meta-analysis to evaluate the effects of different TTM methods on survival and neurological outcome after adult CA. METHODS: We searched on the MEDLINE/PubMed database until 22 February 2019 for comparative studies that evaluated at least two different TTM methods in CA patients. Data were extracted independently by two authors. We used the Newcastle-Ottawa Scale and a modified Cochrane ROB tools for assessing the risk of bias of each study. The primary outcome was the occurrence of unfavorable neurological outcome (UO); secondary outcomes included overall mortality. RESULTS: Our search identified 6886 studies; 22 studies (n = 8027 patients) were included in the final analysis. When compared to surface cooling, core methods showed a lower probability of UO (OR 0.85 [95% CIs 0.75-0.96]; p = 0.008) but not mortality (OR 0.88 [95% CIs 0.62-1.25]; p = 0.21). No significant heterogeneity was observed among studies. However, these effects were observed in the analyses of non-RCTs. A significant lower probability of both UO and mortality were observed when invasive TTM methods were compared to non-invasive TTM methods and when temperature feedback devices (TFD) were compared to non-TFD methods. These results were significant particularly in non-RCTs. CONCLUSIONS: Although existing literature is mostly based on retrospective or prospective studies, specific TTM methods (i.e., core, invasive, and with TFD) were associated with a lower probability of poor neurological outcome when compared to other methods in adult CA survivors (CRD42019111021).

Intravascular versus surface cooling for targeted temperature management after out-of-hospital cardiac arrest: an analysis of the TTH48 trial.

BACKGROUND: The aim of this study was to explore the performance and outcomes for intravascular (IC) versus surface cooling devices (SFC) for targeted temperature management (TTM) after out-of-hospital cardiac arrest. METHODS: A retrospective analysis of data from the Time-differentiated Therapeutic Hypothermia (TTH48) trial (NCT01689077), which compared whether TTM at 33 °C for 48 h results in better neurologic outcomes compared with standard 24-h duration. Devices were assessed for the speed of cooling and rewarming rates. Precision was assessed by measuring temperature variability (TV), i.e., the standard deviation (SD) of all temperature measurements in the cooling phase. Main outcomes were overall mortality and poor neurological outcome, including death, severe disability, or vegetative status. RESULTS: A total of 352 patients had available data and were included in the analysis; of those, 218 (62%) were managed with IC. A total of 114/218 (53%) patients with IC and 61/134 (43%) with SFC were cooled for 48 h (p = 0.22). Time to target temperature (≤ 34 °C) was significantly shorter for patients treated with endovascular devices (2.2 [1.1-4.0] vs. 4.2 [2.7-6.0] h, p < 0.001), but temperature was also lower on admission (35.0 [34.2-35.6] vs. 35.3 [34.5-35.8]°C; p = 0.02) and cooling rate was similar (0.4 [0.2-0.8] vs. 0.4 [0.2-0.6]°C/h; p = 0.14) when compared to SFC. Temperature variability was significantly lower in the endovascular device group when compared with SFC methods (0.6 [0.4-0.9] vs. 0.7 [0.5-1.0]°C; p = 0.007), as was rewarming rate (0.31 [0.22-0.44] vs. 0.37 [0.29-0.49]°C/hour; p = 0.02). There was no statistically significant difference in mortality (endovascular 65/218, 29% vs. others 43/134, 32%; p = 0.72) or poor neurological outcome (endovascular 69/218, 32% vs. others 51/134, 38%; p = 0.24) between type of devices. CONCLUSIONS: Endovascular cooling devices were more precise than SFC methods in patients cooled at 33 °C after out-of-hospital cardiac arrest. Main outcomes were similar with regard to the cooling methods.

Platelet indices and outcome after cardiac arrest.

BACKGROUND: Platelet variables, including platelet distribution width (PDW) and mean platelet volume (MPV), have been associated with outcome in critically ill patients. We evaluated these variables in patients after cardiac arrest (CA). METHODS: All adult CA patients admitted to the intensive care unit (ICU) over an 8-year period (2006-2014) and treated with targeted temperature management were included. We retrieved all data concerning CA characteristics as well as platelet count, PDW and MPV on the first 2 days of admission. Unfavorable 3-month neurological outcome was defined as a cerebral performance category score of 3-5. RESULTS: We included 384 patients (age 62 [52-75] years; 270/384 male): 231 patients (60%) died within 30-days and 246 patients (64%) had an unfavorable 3-month neurological outcome. On admission, platelet count, PDW and MPV were 87 [126-261] *103cells/mm3, 17 [16.3-17.3]% and 8.3 [7.6-9.2] µm3, respectively. Platelet count decreased significantly over the first 2 days, whereas PDW and MPV did not change significantly. There were no significant differences between the values on admission or time-courses of platelet count, PDW or MPV between survivors and non-survivors or between patients with unfavorable and favorable neurological outcome. CONCLUSIONS: In our cohort of post-CA patients, PDW and MPV were not associated with outcome.