Suboptimal plasma concentrations with posaconazole suspension as prophylaxis in critically ill COVID-19 patients at risk of Covid-associated pulmonary aspergillosis.

WHAT IS KNOWN AND OBJECTIVE: The safety and efficacy of different antifungal agents in the prophylaxis of invasive fungal infection in patients with haematological disorders are known. We comment on the poor bioavailability of posaconazole suspension to suggest that it is not useful in critically ill COVID patients. COMMENT: The increased mortality and high incidence of COVID-associated pulmonary aspergillosis (CAPA) might justify administration of off-label posaconazole for preventing CAPA, being the only drug officially registered for prophylaxis of fungal infections. We decided to initiate off-label posaconazole prophylaxis in COVID-19 patients, who were mechanically ventilated and exposed to high-dose steroids for progressive pulmonary disease or ARDS. We found that posaconazole suspension was inadequate. Very low trough levels were observed after administration, and the dose adjustments necessary for the therapeutic drug monitoring (TDM) of the drug in our critically ill ICU patients were not useful. WHAT IS NEW AND CONCLUSION: Posaconazole suspension should not be used to prevent CAPA in COVID-19 patients on high-dose steroid therapy.

Electroencephalogram predicts outcome in patients with postanoxic coma during mild therapeutic hypothermia.

OBJECTIVE: To assess the value of electroencephalogram for prediction of outcome of comatose patients after cardiac arrest treated with mild therapeutic hypothermia. DESIGN: Prospective cohort study. SETTING: Medical ICU. PATIENTS: One hundred forty-two patients with postanoxic encephalopathy after cardiac arrest, who were treated with mild therapeutic hypothermia. MEASUREMENTS AND MAIN RESULTS: Continuous electroencephalogram was recorded during the first 5 days of ICU admission. Visual classification of electroencephalogram patterns was performed in 5-minute epochs at 12 and 24 hours after cardiac arrest by two independent observers, blinded for patients' conditions and outcomes. Patterns were classified as isoelectric, low voltage, epileptiform, burst-suppression, diffusely slowed, or normal. Burst-suppression was subdivided into patterns with and without identical bursts. Primary outcome measure was the neurologic outcome based on each patient's best achieved Cerebral Performance Category score within 6 months after inclusion. 67 patients (47%) had favorable outcome (Cerebral Performance Category, 1-2). In patients with favorable outcome, electroencephalogram patterns improved within 24 hours after cardiac arrest, mostly toward diffusely slowed or normal. At 24 hours after cardiac arrest, the combined group of isoelectric, low voltage, and "burst-suppression with identical bursts" was associated with poor outcome with a sensitivity of 48% (95% CI, 35-61) and a specificity of 100% (95% CI, 94-100). At 12 hours, normal or diffusely slowed electroencephalogram patterns were associated with good outcome with a sensitivity of 56% (95% CI, 41-70) and a specificity of 96% (95% CI, 86-100). CONCLUSIONS: Electroencephalogram allows reliable prediction of both good and poor neurologic outcome of patients with postanoxic encephalopathy treated with mild therapeutic hypothermia within 24 hours after cardiac arrest.

Global end-diastolic volume increases to maintain fluid responsiveness in sepsis-induced systolic dysfunction.

BACKGROUND: Sepsis-induced cardiac dysfunction may limit fluid responsiveness and the mechanism thereof remains unclear. Since cardiac function may affect the relative value of cardiac filling pressures, such as the recommended central venous pressure (CVP), versus filling volumes in guiding fluid loading, we studied these parameters as determinants of fluid responsiveness, according to cardiac function. METHODS: A delta CVP-guided, 90 min colloid fluid loading protocol was performed in 16 mechanically ventilated patients with sepsis-induced hypotension and three 30 min consecutive fluid loading steps of about 450 mL per patient were evaluated. Global end-diastolic volume index (GEDVI), cardiac index (CI) and global ejection fraction (GEF) were assessed from transpulmonary dilution. Baseline and changes in CVP and GEDVI were compared among responding (CI increase ≥10% and ≥15%) and non-responding fluid loading steps, in patient with low (<20%, n = 9) and near-normal (≥20%) GEF (n = 7) at baseline. RESULTS: A low GEF was in line with other indices of impaired cardiac (left ventricular) function, prior to and after fluid loading. Of 48 fluid loading steps, 9 (of 27) were responding when GEF <20% and 6 (of 21) when GEF ≥20. Prior to fluid loading, CVP did not differ between responding and non-responding steps and levels attained were 23 higher in the latter, regardless of GEF (P = 0.004). Prior to fluid loading, GEDVI (and CI) was higher in responding (1007 ± 306 mL/m(2)) than non-responding steps (870 ± 236 mL/m(2)) when GEF was low (P = 0.002), but did not differ when GEF was near-normal. Increases in GEDVI were associated with increases in CI and fluid responsiveness, regardless of GEF (P < 0.001). CONCLUSIONS: As estimated from transpulmonary dilution, about half of patients with sepsis-induced hypotension have systolic cardiac dysfunction. During dysfunction, cardiac dilation with a relatively high baseline GEDVI maintains fluid responsiveness by further dilatation (increase in GEDVI rather than of CVP) as in patients without dysfunction. Absence of fluid responsiveness during systolic cardiac dysfunction may be caused by diastolic dysfunction and/or right ventricular dysfunction.

Volume-limited versus pressure-limited hemodynamic management in septic and nonseptic shock.

OBJECTIVES: To evaluate the effect of hemodynamic management guided by upper limits of cardiac filling volumes or pressures on durations of mechanical ventilation and lengths of stay in critically ill patients with shock. DESIGN: Prospective, randomized, clinical trial. SETTING: Mixed intensive care unit of a large teaching hospital and mixed intensive care unit of a tertiary care, academic medical center. PATIENTS: A total 120 septic (n = 72) and nonseptic (n = 48) shock patients, randomized (after stratification) to transpulmonary thermodilution (n = 60) or pulmonary artery catheter (n = 60) between February 2007 and July 2009. INTERVENTIONS: Hemodynamic management was guided by algorithms including upper limits for fluid resuscitation of extravascular lung water (<10 mL/kg) and global end-diastolic volume index (<850 mL/m) in the transpulmonary thermodilution group and pulmonary artery occlusion pressure (<18-20 mm Hg) in the pulmonary artery catheter group for 72 hrs after enrollment. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were ventilator-free days and lengths of stay in the intensive care unit and the hospital. Secondary outcomes included organ failures and mortality. Cardiac comorbidity was more frequent in nonseptic than in septic shock. Ventilator-free days, lengths of stay, organ failures, and 28-day mortality (overall 33.3%) were similar between monitoring groups. Transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with more days on mechanical ventilation and longer intensive care unit and hospital lengths of stay in nonseptic (p = .001) but not in septic shock. In both conditions, fewer patients met the upper limit of volume than of pressure criteria at baseline and transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with a more positive fluid balance at 24 hrs. CONCLUSIONS: Hemodynamic management guided by transpulmonary thermodilution vs. pulmonary artery catheter in shock did not affect ventilator-free days, lengths of stay, organ failures, and mortality of critically ill patients. Use of the a transpulmonary thermodilution algorithm resulted in more days on mechanical ventilation and intensive care unit length of stay compared with the pulmonary artery catheter algorithm in nonseptic shock but not in septic shock. This may relate to cardiac comorbidity and a more positive fluid balance with use of transpulmonary thermodilution in nonseptic shock.

Cardiac filling volumes versus pressures for predicting fluid responsiveness after cardiovascular surgery: the role of systolic cardiac function.

INTRODUCTION: Static cardiac filling volumes have been suggested to better predict fluid responsiveness than filling pressures, but this may not apply to hearts with systolic dysfunction and dilatation. We evaluated the relative value of cardiac filling volume and pressures for predicting and monitoring fluid responsiveness, according to systolic cardiac function, estimated by global ejection fraction (GEF, normal 25 to 35%) from transpulmonary thermodilution. METHODS: We studied hypovolemic, mechanically ventilated patients after coronary (n = 18) or major vascular (n = 14) surgery in the intensive care unit. We evaluated 96 colloid fluid loading events (200 to 600 mL given in three consecutive 30-minute intervals, guided by increases in filling pressures), divided into groups of responding events (fluid responsiveness) and non-responding events, in patients with low GEF (<20%) or near-normal GEF (≥ 20%). Patients were monitored by transpulmonary dilution and central venous (n = 9)/pulmonary artery (n = 23) catheters to obtain cardiac index (CI), global end-diastolic volume index (GEDVI), central venous (CVP) and pulmonary artery occlusion pressure (PAOP). RESULTS: Fluid responsiveness occurred in 8 (≥ 15% increase in CI) and 17 (≥ 10% increase in CI) of 36 fluid loading events when GEF was <20%, and 7 (≥ 15% increase in CI) and 17 (≥ 10% increase in CI) of 60 fluid loading events when GEF was ≥ 20%. Whereas a low baseline GEDVI predicted fluid responsiveness particularly when GEF was ≥ 20% (P = 0.002 or lower), a low PAOP was of predictive value particularly when GEF was <20% (P = 0.004 or lower). The baseline CVP was lower in responding events regardless of GEF. Changes in CVP and PAOP paralleled changes in CI particularly when GEF was <20%, whereas changes in GEDVI paralleled CI regardless of GEF. CONCLUSIONS: Regardless of GEF, CVP may be useful for predicting fluid responsiveness in patients after coronary and major vascular surgery provided that positive end-expiratory pressure is low. When GEF is low (<20%), PAOP is more useful than GEDVI for predicting fluid responsiveness, but when GEF is near-normal (≥20%) GEDVI is more useful than PAOP. This favors predicting and monitoring fluid responsiveness by pulmonary artery catheter-derived filling pressures in surgical patients with systolic left ventricular dysfunction and by transpulmonary thermodilution-derived GEDVI when systolic left ventricular function is relatively normal.

Hepatosplanchnic ischemia/reperfusion is a major determinant of lung vascular injury after aortic surgery.

OBJECTIVES: To study risk factors, including the level of cross-clamping and ischemia/reperfusion, for lung vascular injury after aortic surgery. DESIGN: Single-center prospective observational study. PATIENTS AND METHODS: Twenty-seven consecutive and mechanically ventilated patients were included within 3 h after elective aortic surgery, i.e., surgery on the thoracoabdominal aorta supported by left atrial to femoral bypass (n = 3), surgery on the suprarenal aorta (n = 5), surgery on the infrarenal aorta (n = 15), and reconstructions of the celiac and mesenteric arteries (n = 4). The (67)Gallium (Ga)-transferrin pulmonary leak index (PLI) served as a measure of lung vascular injury. RESULTS: The PLI was elevated (> or =14.1 x 10(-3)/min) in 74% of all patients and more so in patients undergoing suprarenal aortic surgery or reconstruction of celiac and mesenteric arteries than in the patients undergoing the other types of surgery (P = 0.006). Clamping of the celiac and/or mesenteric arteries during surgery (n = 6) resulted in an almost 4 times higher PLI compared with not clamping these arteries (P = 0.001). In general linear models, the elevated PLI was particularly associated with suprarenal and celiac/mesenteric artery surgery, independently of aortic camping time and transfusion of blood products, even though the PLI directly correlated with aortic clamping time and number of red blood cell concentrates transfused (P = 0.031 or less). CONCLUSIONS: This study suggests that hepatosplanchnic rather than lower body/leg ischemia/reperfusion is a major risk factor for pulmonary vascular injury, associated with aortic surgery and independent of clamping time and transfusion of blood products.

Transpulmonary dilution-derived extravascular lung water as a measure of lung edema.

PURPOSE OF REVIEW: This review highlights current insights concerning the (measurement of) extravascular lung water as an index of pulmonary edema, by transpulmonary dilution techniques. The focus is on the applicability of the technique at the bedside in monitoring critically ill patients. RECENT FINDINGS: Several (animal) studies have been performed to validate the technique by postmortem gravimetry in different conditions. Moreover, recent clinical data emphasize the utility of the thermodilution-derived extravascular lung water, its contribution to the clinical manifestations of acute lung injury/acute respiratory distress syndrome, its response to treatment aimed at edema prevention or resolution, and as a prognostic parameter. SUMMARY: The thermodilution-derived extravascular lung water is a useful adjunct to assess lung vascular injury, cardiogenic edema and overhydration and to guide treatment in critically ill patients. The effects on morbidity and mortality of this approach need to be studied further.

Biomarkers of acute renal injury and renal failure.

Acute renal failure (ARF) is a frequent problem in the intensive care unit and is associated with a high mortality. Early recognition could help clinical management, but current indices lack sufficient predictive value for ARF. Therefore, there might be a need for biomarkers in detecting renal tubular injury and/or dysfunction at an early stage before a decline in glomerular filtration rate is noted by an increased serum creatinine. A MEDLINE/PubMed search was performed, including all articles about biomarkers for ARF. All publication types, human and animal studies, or subsets were searched in English language. An extraction of relevant articles was made for the purpose of this narrative review. These biomarkers include tubular enzymes (alpha- and pi-glutathione S-transferase, N-acetyl-glucosaminidase, alkaline phosphatase, gamma-glutamyl transpeptidase, Ala-(Leu-Gly)-aminopeptidase, and fructose-1,6-biphosphatase), low-molecular weight urinary proteins (alpha1- and beta2-microglobulin, retinol-binding protein, adenosine deaminase-binding protein, and cystatin C), Na+/H+ exchanger, neutrophil gelatinase-associated lipocalin, cysteine-rich protein 61, kidney injury molecule 1, urinary interleukins/adhesion molecules, and markers of glomerular filtration such as proatrial natriuretic peptide (1-98) and cystatin C. These biomarkers, detected in urine or serum shortly after tubular injury, have been suggested to contribute to prediction of ARF and need for renal replacement therapy. However, excretion of these biomarkers may also increase after reversible and mild dysfunction and may not necessarily be associated with persistent or irreversible damage. Large prospective studies in human are needed to demonstrate an improved outcome of biomarker-driven management of the patient at risk for ARF.

Mixed venous O2 saturation and fluid responsiveness after cardiac or major vascular surgery.

BACKGROUND: It is unclear if and how SvO2 can serve as an indicator of fluid responsiveness in patients after cardiac or major vascular surgery. METHODS: This was a substudy of a randomized single-blinded clinical trial reported earlier on critically ill patients with clinical hypovolemia after cardiac or major vascular surgery. Colloid fluid loading was done for 90 min, guided by changes in pulmonary artery occlusion pressure (PAOP) or central venous pressure (CVP). Fluid responsiveness was defined as ≥15% increase in cardiac index (CI). Hemodynamics, including transpulmonary dilution-derived global end-diastolic volume index (GEDVI) and global ejection fraction (GEF), were measured and blood samples taken. RESULTS: Whereas baseline SvO2 (>70% in 68% of patients) did not differ, the SvO2 increased in patients responding to fluid loading (≥15% in CI in n = 26) versus those not responding (n = 11; P = 0.03). The increase in GEDVI was also greater in responders (P = 0.005). The area under the receiver operating characteristic curve for fluid responsiveness of changes in SvO2 was 0.73 (P = 0.007), with an optimal cutoff of 2%, and of those in GEDVI 0.82 (P < 0.001), while the areas did not differ. However, the value of SvO2 increases to reflect CI increases with fluid loading was greatest when GEF was ≤20% (in 53% of patients). CONCLUSIONS: An increase in SvO2 ≥2%, irrespective of a relatively high baseline value, can thus be used as a monitor of fluid responsiveness in clinically hypovolemic patients after cardiac or major vascular surgery, particularly in those with systolic cardiac dysfunction. Fluid responsiveness concurs with increased tissue O2 delivery.

Greater cardiac response of colloid than saline fluid loading in septic and non-septic critically ill patients with clinical hypovolaemia.

BACKGROUND AND OBJECTIVE: The haemodynamics of crystalloid and colloid fluid loading may depend on underlying disease, i.e. sepsis versus non-sepsis. DESIGN AND SETTING: A single-centre, single-blinded, randomized clinical trial was carried out on 24 critically ill sepsis and 24 non-sepsis patients with clinical hypovolaemia, assigned to loading with normal saline, gelatin 4%, hydroxyethyl starch 6% or albumin 5% in a 90-min (delta) central venous pressure (CVP)-guided fluid loading protocol. Transpulmonary thermodilution was done each 30 min, yielding, among others, global end-diastolic volume and cardiac indices (GEDVI, CI). RESULTS: Sepsis patients had hyperdynamic hypotension in spite of myocardial depression and dilatation, and greater inotropic/vasopressor requirements than non-sepsis patients. Independent of underlying disease, CVP and GEDVI increased more after colloid than saline loading (P < 0.018), so that CI increased by about 2% after saline and 12% after colloid loading (P = 0.029). The increase in preload-recruitable stroke work was also greater with colloids and did not differ among conditions. CONCLUSION: Fluid loading with colloids results in a greater linear increase in cardiac filling, output and stroke work than does saline loading, in both septic and non-septic clinical hypovolaemia, in spite of myocardial depression and presumably increased vasopermeability potentially decreasing the effects of colloid fluid loading in the former.

Relative value of pressures and volumes in assessing fluid responsiveness after valvular and coronary artery surgery.

BACKGROUND AND AIMS: Cardiac function may differ after valvular (VS) and coronary artery (CAS) surgery and this may affect assessment of fluid responsiveness. The aim of the study was to compare VS and CAS in the value of cardiac filling pressures and volumes herein. METHODS: There were eight consecutive patients after VS and eight after CAS, with femoral and pulmonary artery catheters in place. In each patient, five sequential fluid loading steps of 250 ml of colloid each were done. We measured central venous pressure (CVP), pulmonary artery occlusion pressure (PAOP) and, by transpulmonary thermodilution, cardiac index (CI) and global end-diastolic (GEDVI) and intrathoracic blood volume (ITBVI) indices. Fluid responsiveness was defined by a CI increase >5% or >10% per step. RESULTS: Global ejection fraction was lower and PAOP was higher after VS than CAS. In responding steps after VS (n=9-14) PAOP and volumes increased, while CVP and volumes increased in responding steps (n=12-19) after CAS. Baseline PAOP was lower in responding steps after VS only. Hence, baseline PAOP as well as changes in PAOP and volumes were of predictive value after VS and changes in CVP and volumes after CAS, in receiver operating characteristic curves. After VS, PAOP and volume changes equally correlated to CI changes. After CAS, only changes in CVP and volumes correlated to those in CI. CONCLUSIONS: While volumes are equally useful in monitoring fluid responsiveness, the predictive and monitoring value of PAOP is greater after VS than after CAS. In contrast, the CVP is of similar value as volume measurements in monitoring fluid responsiveness after CAS. The different value of pressures rather than of volumes between surgery types is likely caused by systolic left ventricular dysfunction in VS. The study suggests an effect of systolic cardiac function on optimal parameters of fluid responsiveness and superiority of the pulmonary artery catheter over transpulmonary dilution, for haemodynamic monitoring of VS patients.