Prevalence and management of delirium in intensive care units in the Netherlands: An observational multicentre study.

OBJECTIVES: This study aimed to determine the prevalence, risk factors of delirium and current practice of delirium management in intensive care units of various levels of care. RESEARCH METHODOLOGY/DESIGN: Prospective multicentre cohort study. SETTING: In all adult patients admitted to one of the participating intensive care units on World Delirium Awareness Day 2018, delirium point and period prevalence rates were measured between ICU admission and seven days after the index day. RESULTS: In total, 28 (33%) Dutch intensive care units participated in this study. Point-prevalence was 23% (range 41), and period-prevalence was 42% (range 70). University intensive care units had a significantly higher delirium point-prevalence compared with non-university units (26% vs.15%, p = 0.02). No significant difference were found in period prevalence (50% vs. 39%, p = 0.09). Precipitating risk factors, infection and mechanical ventilation differed significantly between delirium and non-delirium patients. No differences were observed for predisposing risk factors. A delirium protocol was present in 89% of the ICUs. Mean delirium assessment compliance measured was 84% (±19) in 14 units and estimated 59% (±29) in the other 14. CONCLUSION: Delirium prevalence in Dutch intensive care units is substantial and occurs with a large variation, with the highest prevalence in university units. Precipitating risk factors were more frequent in patients with delirium. In the majority of units a delirium management protocol is in place.

Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial.

BACKGROUND: In critically ill patients, antibiotic therapy is of great importance but long duration of treatment is associated with the development of antimicrobial resistance. Procalcitonin is a marker used to guide antibacterial therapy and reduce its duration, but data about safety of this reduction are scarce. We assessed the efficacy and safety of procalcitonin-guided antibiotic treatment in patients in intensive care units (ICUs) in a health-care system with a comparatively low use of antibiotics. METHODS: We did a prospective, multicentre, randomised, controlled, open-label intervention trial in 15 hospitals in the Netherlands. Critically ill patients aged at least 18 years, admitted to the ICU, and who received their first dose of antibiotics no longer than 24 h before inclusion in the study for an assumed or proven infection were eligible to participate. Patients who received antibiotics for presumed infection were randomly assigned (1:1), using a computer-generated list, and stratified (according to treatment centre, whether infection was acquired before or during ICU stay, and dependent on severity of infection [ie, sepsis, severe sepsis, or septic shock]) to receive either procalcitonin-guided or standard-of-care antibiotic discontinuation. Both patients and investigators were aware of group assignment. In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0·5 µg/L or lower. In the standard-of-care group, patients were treated according to local antibiotic protocols. Primary endpoints were antibiotic daily defined doses and duration of antibiotic treatment. All analyses were done by intention to treat. Mortality analyses were completed for all patients (intention to treat) and for patients in whom antibiotics were stopped while being on the ICU (per-protocol analysis). Safety endpoints were reinstitution of antibiotics and recurrent inflammation measured by C-reactive protein concentrations and they were measured in the population adhering to the stopping rules (per-protocol analysis). The study is registered with ClinicalTrials.gov, number NCT01139489, and was completed in August, 2014. FINDINGS: Between Sept 18, 2009, and July 1, 2013, 1575 of the 4507 patients assessed for eligibility were randomly assigned to the procalcitonin-guided group (761) or to standard-of-care (785). In 538 patients (71%) in the procalcitonin-guided group antibiotics were discontinued in the ICU. Median consumption of antibiotics was 7·5 daily defined doses (IQR 4·0-12·7) in the procalcitonin-guided group versus 9·3 daily defined doses (5·0-16·6) in the standard-of-care group (between-group absolute difference 2·69, 95% CI 1·26-4·12, p<0·0001). Median duration of treatment was 5 days (3-9) in the procalcitonin-guided group and 7 days (4-11) in the standard-of-care group (between-group absolute difference 1·22, 0·65-1·78, p<0·0001). Mortality at 28 days was 149 (20%) of 761 patients in the procalcitonin-guided group and 196 (25%) of 785 patients in the standard-of-care group (between-group absolute difference 5·4%, 95% CI 1·2-9·5, p=0·0122) according to the intention-to-treat analysis, and 107 (20%) of 538 patients in the procalcitonin-guided group versus 121 (27%) of 457 patients in the standard-of-care group (between-group absolute difference 6·6%, 1·3-11·9, p=0·0154) in the per-protocol analysis. 1-year mortality in the per-protocol analysis was 191 (36%) of 538 patients in the procalcitonin-guided and 196 (43%) of 457 patients in the standard-of-care groups (between-group absolute difference 7·4, 1·3-13·8, p=0·0188). INTERPRETATION: Procalcitonin guidance stimulates reduction of duration of treatment and daily defined doses in critically ill patients with a presumed bacterial infection. This reduction was associated with a significant decrease in mortality. Procalcitonin concentrations might help physicians in deciding whether or not the presumed infection is truly bacterial, leading to more adequate diagnosis and treatment, the cornerstones of antibiotic stewardship. FUNDING: Thermo Fisher Scientific.

Gastric feeding intolerance is not caused by mucosal ischemia measured by intragastric air tonometry in the critically ill.

BACKGROUND: Gastric mucosal ischemia may be a risk factor for gastrointestinal intolerance to early feeding in the critically ill. AIMS: To study intragastric PCO2 air tonometry and gastric residual volumes (GRV) before and after the start of gastric feeding. METHODS: This is a two-center study in intensive care units of a university and teaching hospital. Twenty-nine critically ill, consecutive and consenting patients scheduled to start gastric feeding were studied after insertion of a gastric tonometry catheter and prior to and after start of gastric feeding (500 ml over 1 h), when clinically indicated. RESULTS: Blood gasometry and intragastric tonometry were performed prior to and 2 h after gastric feeding. The intragastric to arterial PCO2 gap (normal <8 mm Hg) was elevated in 41% of patients prior to feeding and measured (mean ± standard deviation) 13 ± 20 and 16 ± 23 mm Hg in patients with normal (<100 ml, 42 ± 34 ml, n = 19) and elevated GRV (250 ± 141 ml, n = 10, P = 0.75), respectively. After feeding, the gradient did not increase and measured 27 ± 25 and 23 ± 34 mm Hg, respectively (P = 0.80). CONCLUSION: Gastric mucosal ischemia is not a major risk factor for intolerance to early gastric feeding in the critically ill.

Vasopressin facilitates presynaptic sympathetic nerve activity in humans.

OBJECTIVE: It was the objective of this study to investigate whether a facilitatory role of vasopressin (AVP) on sympathetic nerve activity can be demonstrated in humans at the peripheral level. METHODS: Eight subjects (32 +/- 2.3 years) participated in this study. Forearm blood flow (FABF) was measured using the venous occlusion plethysmography model. Each session was performed in the presence of a continuous infusion (into the brachial artery) of AVP in sub-pressor dosage of 0.008 ng/kg per min, or NaCl 0.9%. Using lower-body negative pressure (LBNP) (-10, -20 and -30 mmHg) the combined pre- and postsynaptic action of AVP on the sympathetic nervous system was investigated. This was followed by a second protocol in which the possible postsynaptic effects of AVP were evaluated with intra-arterial infused norepinephrine (NE). RESULTS: The baseline FABF was 5.2 +/- 0.6 ml/100 ml per min. After infusion of AVP (0.008 ng/kg per min), the FABF remained unchanged at a flow of 5.5 +/- 0.6 ml/100 ml per min (P = 0.26). LBNP caused a pressure-dependent decrease in FABF (25.6 +/- 4.4, 29.0 +/- 6.1 and 38.6 +/- 6.9%, for -10, -20 and -30 mmHg, respectively). AVP significantly enhanced the FABF responses to lower-body negative pressures (38.0 +/- 8.6, 49.3 +/- 5.1 and 58.9 +/- 6.3%, respectively (P = 0.014). NE caused a dose-dependent vasoconstriction by 3.1 +/- 4.6, 17.0 +/- 4.3 and 23.2 +/- 4.9%, at dosages of 10, 20 and 40 pg/min, respectively, unaffected by AVP (P = 0.91). CONCLUSIONS: We conclude that AVP can facilitate vasoconstriction mediated by the peripheral sympathetic nervous system at the presynaptic level in humans.

Vasopressin-induced vasoconstriction is dependent on MAPKerk1/2 phosphorylation.

To investigate the involvement of the mitogen-activated protein kinase (MAPK) family of extracellular signal-regulated kinase (ERK) 1 and 2 (MAPKerk1/2) in the vasopressin-mediated vasoconstriction in the rat aorta. Vasopressin-induced vasoconstriction was measured in isolated rat thoracic aortae in the presence or absence of MAPKerk1/2 kinase (MKKmek1/2) inhibitors. Thereafter the MAPKerk1/2 phosphorylation in the rat aorta was quantified using Western blot analysis. Vasopressin (1-300 nm) induced a concentration-dependent vasoconstriction, which could be inhibited concentration dependently by the selective MKKmek1/2 inhibitors, PD 98059 (10 and 100 microm) and U 0126 (10 and 100 microm). Western blot analysis revealed a 2.7 +/- 0.6-fold increase in the MAPKerk1/2 phosphorylation induced by vasopressin (300 nm). This phosphorylation could be dose dependently prevented by both PD 98059 (100 microm) and U 0126 (10 and 100 microm). These results indicate that vasoconstriction induced by vasopressin is partly regulated by the MAPKerk1/2 pathway.

Endothelium-dependent, vasopressin-induced contractions in rabbit renal arteries.

OBJECTIVES: To identify and quantify the stimulatory and inhibitory activity of endothelial factors on Arginine vasopressin (AVP)-induced contractions. METHODS: In a standard organ bath set-up for isometric force recording, rabbit isolated renal artery rings were exposed to cumulative concentrations of AVP. Experiments were performed in the presence or absence of functional endothelium, or in the presence of N-Nitro-L-Arginine 10 microM (L-NNA) (NO-synthase inhibitor). RESULTS: Arginine vasopressin induced a maximal contractile response of 6.5 +/- 0.1 mN in vessels with and 6.3 +/- 0.3 mN in vessels without endothelium. The preincubation with l-NNA resulted in an enhanced response to AVP of 12.6 +/- 0.8 mN (P < 0.05). The augmentation of the AVP induced contractile response by NOS inhibition, which was not seen in preparations after the removal of the endothelium, suggests an endothelium dependent factor that is co-released with NO. The unknown nature of this endothelium dependent contractile factor was not influenced by indomethacin 100 microM (cyclooxygenase inhibitor), meclofenamic acid 20 microM (cyclooxygenase and lipoxygenase inhibitor), or bosentan 100 microM (endothelin antagonist). Charybdotoxin 0.1 microM (inhibitor of Ca2+ -activated K+ channels) specifically increased the contractile force in preparations with and without endothelium, or in the presence of l-NNA to 11.2 +/- 0.4 mN, 14.0 +/- 0.8 mN, and 19.0 +/- 0.8 mN, respectively (P < 0.05 compared with the experiments without charybdotoxin). SR 49059 (vasopressin 1 receptor (V1) antagonist) antagonized the effects of AVP, whereas SR 121463 B (V2 antagonist) was ineffective. In contrast to the results obtained with AVP, desmopressin (V2 agonist) showed no effect. CONCLUSION: The completely V1 dependent AVP-induced contraction is partly inhibited by the stimulated release of NO. This was only demonstrable in endothelium intact vessels in the presence of l-NNA and not after removal of the endothelium. This strongly suggests the involvement of an unknown endothelium V1 receptor dependent contractile factor that is not influenced by inhibition of the prostaglandin, lipoxygenase, or endothelin pathway, or by blockade of the V2 receptor.

Vasopressin-induced presynaptic facilitation of sympathetic neurotransmission in the pithed rat.

OBJECTIVE: Several studies have shown that arginine vasopressin (AVP) potentiates the sympathetic nervous transmission in isolated vessels. The present study investigates such a potentiation in the pithed rat model. METHODS: Male Wistar rats weighing 270-310 g were used. Spinal-cord stimulation was applied, with frequencies of 0.25-4 Hz, in the presence or absence of a subpressor dose of intravenous (i.v.) AVP (1 pmol/kg per min). In addition, the effect of AVP on postsynaptic alpha-adrenoceptor-mediated responses was studied using exogenously administered noradrenaline (NA). For this purpose dose-response curves (DRCs) for NA (i.v.) were constructed. RESULTS: In the pithed rat model endogenously generated angiotensin II facilitates neurally mediated increments in vascular resistance. Without the administration of the angiotensin II type 1 (AT1) antagonist, irbesartan, the facilitating effect of AVP was not visible. However, after the administration of the AT1 antagonist, irbesartan, the facilitating effect of AVP became apparent. The stimulation-induced rise in diastolic blood pressure (DBP) was enhanced in the presence of AVP from 63.7 +/- 4.5 to 78.6 +/- 4.2 mmHg, at a stimulation frequency of 4 Hz. The vasopressin receptor V1 antagonist, SR-49059, completely inhibited this AVP-induced facilitation, whereas the V2 antagonist, SR-121463B, or the V2 agonist, desmopressin, did not. The DRC of exogenously administered NA was not influenced by AVP. CONCLUSION: The stimulating effect of AVP on sympathetic neurotransmission is completely dependent on the stimulation of presynaptically located V1 receptors. The facilitating effect of angiotensin II on the sympathetic nervous system (SNS) in the pithed rat model masks the facilitating effect of AVP in this preparation.

Influence of the nature of pre-contraction on the responses to commonly employed vasodilator agents in rat-isolated aortic rings.

The relaxing properties of vasodilator drugs in vitro may depend on the characteristics of the contractile state of the vessel investigated. Rat-isolated thoracic aortas were exposed to different types of pre-contraction. The following vasoconstrictor agents were used: phenylephrine (PhE), a selective alpha1-adrenoceptor agonist; St 587, a partial alpha1-adrenoceptor stimulant; U46619 (U-46). a thromboxane A2 agonist: and potassium ions causing receptor-independent depolarization of the membrane. After pre-contraction, various differential vasodilator drugs were investigated: methacholine (MCh, endothelium dependent), sodium nitroprusside (SNP, NO donor), forskolin (FSK, adenylyl cyclase stimulant) and nifedipine, a Ca2+-antagonist (selective L-type calcium antagonist). The vasodilator activity of these compounds was quantified by their vasodilator potency value (pD2) and efficacy (Emax) obtained from their concentration-response curves. PhE (0.1, 0.3, 3 microM) caused isometric responses of 4.8 +/- 0.3, 6.5 +/- 0.3 and 7.8 +/- 0.5 mN, respectively. An increase of the PhE concentration from 0.1 to 3 microM did not influence the response to FSK while it reduced the pD2 of SNP (8.6 +/- 0.1 to 7.35 +/- 0.1). Under these conditions, only the Emax of MCh was reduced (96.3 +/- 4.3% to 43.3 +/- 6.9%). U46 (0.18, 0.3, 1 microM) increased the contractile force by 7.4 +/- 0.4, 8.8 +/- 0.3 and 10.4 +/- 0.3 mN, respectively. Increasing the concentration of U-46 from 0.18 to 1 microM affected only the efficacy of SNP (84 +/- 4.4% to 17 +/- 8.8%) and MCh (64.5 +/- 12.3% to 0.0 +/- 9.2%) and reduced the potency of FSK (7.91 +/- 0.26 to 7.15 +/- 0.10). The concentration of K+-ions from 25 to 30 and 40 mM increased the contractile force by 4.0 +/- 0.4, 7.0 +/- 0.5 and 10.8 +/- 0.4 mN, respectively. The increase in [K+] caused a potency decrease of FSK (7.1 +/- 0.0 to 5.8 +/- 0.0) whereas both efficacy and potency were reduced for SNP (95.6 +/- 1.8% to 65.8 +/- 1.9% and 8.7 +/- 0.1 to 7.2 +/- 0.1) and MCh (55.4 +/- 3.5% to 24.5 +/- 0.8% and 7.4 +/- 0.3 to 6.1 +/- 0.4). Inhibiting of the endothelial NO production by L-NAME 100 microM resulted after pre-contraction with PhE and potassium in comparable differences in properties for SNP. Pre-contraction with St 587 1, 3, 10 and 30 microM shows comparable results after nifedepine relaxation. The present experiments clearly demonstrate that the characteristics of the applied pre-contraction strongly, but differentially influence both the potency and efficacy of various vasodilator drugs in vitro. Accordingly, in vitro characterization of vasodilator drugs should be performed under a carefully standardized protocol of pre-contraction.