David Schnell

Determinants of recovery from severe posterior reversible encephalopathy syndrome.

Objective Few outcome data are available about posterior reversible encephalopathy syndrome (PRES). We studied 90-day functional outcomes and their determinants in patients with severe PRES. Design 70 patients with severe PRES admitted to 24 ICUs in 2001–2010 were included in a retrospective cohort study. The main outcome measure was a Glasgow Outcome Scale (GOS) of 5 (good recovery) on day 90. Main Results Consciousness impairment was the most common clinical sign, occurring in 66 (94%) patients. Clinical seizures occurred in 57 (81%) patients. Median mean arterial pressure was 122 (105–143) mmHg on scene. Cerebral imaging abnormalities were bilateral (93%) and predominated in the parietal (93%) and occipital (86%) white matter. Median number of brain areas involved was 4 (3–5). Imaging abnormalities resolved in 43 (88%) patients. Ischaemic and/or haemorrhagic complications occurred in 7 (14%) patients. The most common causes were drug toxicity (44%) and hypertensive encephalopathy (41%). On day 90, 11 (16%) patients had died, 26 (37%) had marked functional impairments (GOS, 2 to 4), and 33 (56%) had a good recovery (GOS, 5). Factors independently associated with GOS<5 were highest glycaemia on day 1 (OR, 1.22; 95%CI, 1.02–1.45, p = 0.03) and time to causative-factor control (OR, 3.3; 95%CI, 1.04–10.46, p = 0.04), whereas GOS = 5 was associated with toxaemia of pregnancy (preeclampsia/eclampsia) (OR, 0.06; 95%CI, 0.01–0.38, p = 0.003). Conclusions By day 90 after admission for severe PRES, 44% of survivors had severe functional impairments. Highest glycaemia on day 1 and time to causative-factor control were strong early predictors of outcomes, suggesting areas for improvement.

Acylguanidines as Bioisosteres of Guanidines : NG-Acylated Imidazolylpropylguanidines, a New Class of Histamine H2 Receptor Agonists

N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.

Delayed intensive care unit admission is associated with increased mortality in patients with cancer with acute respiratory failure

Abstract Acute respiratory failure (ARF) is the leading reason for intensive care unit (ICU) admission in patients with cancer. The aim of this study was to identify early predictors of death in patients with cancer admitted to the ICU for ARF who were not intubated at admission. We conducted analysis of a prospective randomized controlled trial including 219 patients with cancer with ARF in which day-28 mortality was a secondary endpoint. Mortality at day 28 was 31.1%. By multivariate analysis, independent predictors of day-28 mortality were: age (odds ratio [OR] 1.30/10 years, 95% confidence interval [CI] [1.01–1.68], p = 0.04), more than one line of chemotherapy (OR 2.14, 95% CI [1.08–4.21], p = 0.03), time between respiratory symptoms onset and ICU admission > 2 days (OR 2.50, 95% CI [1.25–5.02], p = 0.01), oxygen flow at admission (OR 1.07/L, 95% CI [1.00–1.14], p = 0.04) and extra-respiratory symptoms (OR 2.84, 95%CI [1.30–6.21], p = 0.01). After adjustment for the logistic organ dysfunction (LOD) score at admission, only time between respiratory symptoms onset and ICU admission > 2 days and LOD score were independently associated with day-28 mortality. Determinants of death include both factors non-amenable to change, and delay in ARF management. These results suggest that early intensive care management of patients with cancer with ARF may translate to better survival.

N(G)-Acylated imidazolylpropylguanidines as potent histamine H4 receptor agonists: selectivity by variation of the N(G)-substituent

3-(1H-Imidazol-4-yl)propylguanidine (SK&F 91486, 4) was identified as a potent partial agonist at the human histamine H(3) receptor (hH(3)R) and human histamine H(4) receptor (hH(4)R). With the aim to increase selectivity for the hH(4)R, the guanidine group in 4 was acylated. N(1)-Acetyl-N(2)-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-PI288, 13) was a potent full agonist at the hH(4)R (pEC(50) = 8.31; alpha = 1.00), possessing more than 1000- and 100-fold selectivity relative to the hH(1)R and hH(2)R, respectively, and possessing only low intrinsic activity (alpha = 0.27) at the hH(3)R.

Impact of the DRY Motif and the Missing “Ionic Lock” on Constitutive Activity and G-Protein Coupling of the Human Histamine H4 Receptor

It is assumed that many G protein-coupled receptors (GPCRs) are restrained in an inactive state by the “ionic lock,” an interaction between an arginine in transmembrane domain (TM) 3 (R3.50) and a negatively charged residue in TM6 (D/E6.30). In the human histamine H4 receptor (hH4R), alanine is present in position 6.30. To elucidate whether this mutation causes the high constitutive activity of hH4R, we aimed to reconstitute the ionic lock by constructing the A6.30E mutant. The role of R3.50 was investigated by generating hH4R-R3.50A. Both mutants were expressed alone or together with Gαi2 and Gβ1γ2 in Sf9 cells and characterized in GTPase, 35S-labeled guanosine 5′-[γ-thio]triphosphate binding, and high-affinity agonist binding assays. Unexpectedly, compared with hH4R, hH4R-A6.30E showed only nonsignificant reduction of constitutive activity and G protein-coupling efficiency. The KD of [3H]histamine was unaltered. By contrast, hH4R-R3.50A did not stimulate G proteins. Thioperamide affinity at hH4R-R3.50A was increased by 300 to 400%, whereas histamine affinity was reduced by approximately 50%. A model of the active hH4R state in complex with the Gαi2 C terminus was compared with the crystal structures of turkey β1 and human β2 adrenoceptors. We conclude that 1) constitutive activity of hH4R is facilitated by the salt bridge D5.69-R6.31 rather than by the missing ionic lock, 2) Y3.60 may form alternative locks in active and inactive GPCR states, 3) R3.50 is crucial for hH4R–G protein coupling, and 4) hH4R-R3.50A represents an inactive state with increased inverse agonist and reduced agonist affinity. Thus, the ionic lock, although stabilizing the inactive rhodopsin state, is not generally important for all class A GPCRs.

Renal perfusion assessment by renal Doppler during fluid challenge in sepsis.

Objectives:To assess renal resistive index variations in response to fluid challenge. Design:Prospective cohort study. Setting:Three ICUs in French teaching hospitals. Patients:Consecutive patients receiving mechanical ventilation and requiring a fluid challenge. Intervention:Resistive index measurement before and after fluid challenge. Measurements and Main Results:Renal Doppler was used to measure resistive index and esophageal Doppler to monitor aortic blood flow. Of the 35 included patients, 17 (49%) met our definition for fluid challenge responsiveness, that is, had at least a 10% increase in aortic blood flow. After fluid challenge, mean arterial pressure increased from 73 mm Hg (interquartile range 68–79) to 80 mm Hg (75–86; p < 0.0001) and stroke volume from 50 mL (30–77) to 55 mL (39–84; p < 0.0001). Stroke volume changes after fluid challenge were +28.6% (+18.8% to +38.8%) in fluid challenge responders and +3.1% (–1.6% to 7.4%) in fluid challenge nonresponders. Renal resistive index was unchanged after fluid challenge in both nonresponders (0.72 [0.67–0.75] before and 0.71 [0.67–0.75] after fluid challenge; p = 0.62) and responders (0.70 [0.65–0.75] before and 0.72 [0.68–0.74] after fluid challenge; p = 0.11). Stroke volume showed no correlations with resistive index changes after fluid challenge in the overall population (r2 = 0.04, p = 0.25), in fluid challenge responders (r2 = –0.02, p = 0.61), or in fluid challenge nonresponders (r2 = 0.08, p = 0.27). Stroke volume did not correlate with resistive index changes after fluid challenge in the subgroups without acute kidney injury (AKIN definition), with transient acute kidney injury, or with persistent acute kidney injury. Conclusion:Systemic hemodynamic changes induced by fluid challenge do not translate into resistive index variations in patients without acute kidney injury, with transient acute kidney injury, or with persistent acute kidney injury.

Outcomes of mechanically ventilated hematology patients with invasive pulmonary aspergillosis

BackgroundInvasive pulmonary aspergillosis (IPA) is a life-threatening infection documented in up to 15% of hematology patients who require intensive care for acute respiratory failure. We report outcomes in hematology patients given mechanical ventilation (MV) with IPA.MethodsRetrospective study of all hematology patients given MV with IPA between January 1998 and March 2011 at a single center. Predictors of 6-month survival or mortality were identified using multivariable analysis.ResultsWe studied 67 patients including 49 (73%) with neutropenia, 23 (34%) with long-term steroid therapy, and 14 (21%) with allogeneic bone marrow transplantation. Incidence of IPA in the ICU decreased between 1998 and 2011, and mortality in patients receiving mechanical ventilation did not change. IPA was confirmed in 6 patients by autopsy and was probable in 61 patients based on host factors, clinical and radiographic features, and either Aspergillus isolation (50 patients) or Aspergillus antigen detection alone (11 patients). Concomitant bacterial infections were documented in 24 (36%) patients. ICU and 6-month mortality rates were 67 and 82%, respectively. Mortality was stable throughout the study period. Concomitant bacterial infection was independently associated with higher mortality [HR, 2.1 (1.2–3.8)]. Mortality was lower in patients given voriconazole [OR, 0.5 (0.3–0.9)].ConclusionHospital mortality remains high in hematology patients requiring MV with IPA, particularly when concommittant infection occurred. The use of voriconazole improved survival.

Expression and functional properties of canine, rat, and murine histamine H4 receptors in Sf9 insect cells

The histamine H4 receptor (H4R) is expressed on cells of the immune system including eosinophils, dendritic cells, and T cells and plays an important role in the pathogenesis of bronchial asthma, atopic dermatitis, and pruritus. Analysis of the H4R in these diseases depends on the use of animal models. However, there are substantial pharmacological differences between various H4R species orthologs. The purpose of this study was to analyze the pharmacological properties of canine, rat, and murine H4R in comparison to human H4R expressed in Sf9 insect cells. Only hH4R and cH4R exhibited a sufficiently high [3H]histamine affinity for radioligand binding studies. Generally, cH4R exhibited lower ligand-affinities than hH4R. Similarly, in high-affinity GTPase studies, ligands were more potent at hH4R than at other H4R species orthologs. Unlike the other H4R species orthologs, hH4R exhibited high agonist-independent (constitutive) activity. Most strikingly, the prototypical H4R antagonist (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine) (JNJ7777120) exhibited partial agonistic activity at cH4R, rH4R, and mH4R, whereas at hH4R, JNJ7777120 was a partial inverse agonist. H4R agonists from the class of NG-acylated imidazolylpropylguanidines and cyanoguanidines exhibited substantial differences in terms of affinity, potency, and efficacy among H4R species orthologs, too. The species-dependent pharmacological profiles are not due to the highly variable amino acid sequence position 341. Finally, H4R species orthologs differ from each other in terms of regulation by NaCl. Collectively, there are profound pharmacological differences between H4R species orthologs. Most importantly, caution must be exerted when interpreting pharmacological effects of “the prototypical H4R antagonist” JNJ7777120 as H4R antagonism.

Renal resistive index better predicts the occurrence of acute kidney injury than cystatin C.

ABSTRACT The objective of this study was to determine the predictive value of the renal resistive index (RI) and cystatin C values in serum (SCys) and urine (UCys) in the development of acute kidney injury (AKI) in critically ill patients with severe sepsis or polytrauma. This was a prospective, double-center, descriptive study. There were 58 patients with severe sepsis (n= 28) or polytrauma (n = 30). Renal resistive index, SCys, and UCys were measured within 12 h following admission (day 1 [D1]) to the intensive care unit. Renal function was assessed using the AKI network classification: On day 3 (D3), 40 patients were at stage 0 or 1, and 18 were at stage 2 or 3. Patients with AKI stage 2 or 3 had significantly higher RI (0.80 vs. 0.66, P < 0.0001), SCys (1.23 vs. 0.68 mg/L, P = 0.0002), and UCys (3.32 vs. 0.09 mg/L, P = 0.0008). They also had higher Simplified Acute Physiology Score II, arterial lactate level, and intensive care unit mortality. In multivariate analysis, an RI of greater than 0.707 on D1 was the only parameter predictive of the development of AKI stage 2 or 3 on D3 (P = 0.0004). In the subgroup of patients with AKI stage 2 or 3 on D1, RI remained the only parameter associated with persistent AKI on D3 (P = 0.016). In multivariate analysis comparing the predictive value of RI, SCys, and UCys, RI was the only parameter predictive of AKI stage 2 or 3 on D3. Renal resistive index seems to be a promising tool to assess the risk of AKI.

NG-Acylated Aminothiazolylpropylguanidines as Potent and Selective Histamine H2 Receptor Agonists

Bioisosteric replacement of the guanidino group in arpromidine‐like histamine H2 receptor (H2R) agonists by an acylguanidine moiety is useful for obtaining potent H2R agonists with improved oral bioavailability and blood–brain barrier penetration. We show that bioisosteric replacement of the imidazole ring in NG‐acylated imidazolylpropylguanidines by a 2‐aminothiazol‐5‐yl group resulted in potent H2R agonists with much greater selectivity for the human H2R over H3 and H4 receptors.