Background: Health economic evaluations are increasingly used to make the decision to adopt new medical interventions. Before such decisions, various stakeholders have invested in clinical research. But health economic factors are seldom considered in research funding decisions. Cost-effectiveness analysis could be informative before the launch of clinical research projects, particularly when a targeted intervention is resource-intensive, total cost for the trial is very high, and expected gain of health benefits is uncertain. This study analyzed cost-effectiveness using a decision analytic model before initiating a large clinical research project on goal-directed hemodynamic treatment of elderly patients with hip fracture.

Methods: A probabilistic decision analytic cost-effectiveness model was developed; the model contains a decision tree for the postoperative short-term outcome and a Markov structure for long-term outcome. Clinical effect estimates, costs, health-related quality-of-life measures, and long-term survival constituted model input that was extracted from clinical trials, national databases, and surveys. Model output consisted of estimated medical care costs related to quality-adjusted life-years.

Results: In the base care analysis, goal-directed hemodynamic treatment reduced average medical care costs by €1,882 and gained 0.344 qualilty-adjusted life-years. In 96.5% of the simulations, goal-directed hemodynamic treatment is less costly and provides more quality-adjusted life-years. The results are sensitive to clinical effect size variations, although goal-directed hemodynamic treatment seems to be cost-effective even with moderate clinical effect.

Conclusion: This study demonstrates that cost-effectiveness analysis is feasible, meaningful, and recommendable before launch of costly clinical research projects.

Editors PerspectiveWhat We Already Know about This Topic For most bacterial pneumonia, the lung interstitium is considered to be the site of infection, and adequate antibiotic concentrations are important for drug effect Despite systemic antibiotic therapy, therapeutic failure is common, perhaps due to poor lung penetration, and resulting low interstitial space fluid antibiotic concentrations Increasing systemic antibiotic doses in order to increase interstitial space fluid antibiotic concentrations could lead to toxicities such as nephrotoxicity What This Article Tells Us That Is New In a mechanically ventilated healthy large animal model, nebulized tobramycin produced higher peak lung interstitial space fluid concentrations, as well as higher initial epithelial lining fluid concentrations, with lower plasma concentrations than were observed after intravenous administration due to more extensive lung penetration Background: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Methods: Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. Results: The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P amp;lt; 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P amp;lt; 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P amp;lt; 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P amp;lt; 0.001). Conclusions: Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.

BACKGROUND: In sheep, isoflurane causes extravascular accumulation of infused crystalloid fluid. The current study evaluates whether isoflurane has a greater tendency than propofol to cause extravascular retention in surgical patients.

METHODS: Thirty patients undergoing thyroid surgery lasting for 143 +/- 32 min (mean +/- SD) received an intravenous infusion of 25 ml/kg acetated Ringer's solution over 30 min. Anesthesia was randomized to consist of isoflurane or propofol supplemented by fentanyl. The distribution and elimination of the infused fluid was estimated using volume kinetics based on the fractional dilution of blood hemoglobin over 150 min. Extravascular retention of infused fluid was taken as the difference between the model-predicted elimination and the urinary excretion. The sodium and fluid balances were measured.

RESULTS: The fractional plasma dilution increased gradually to approximately 30% during the infusion and thereafter remained at 15-20%. Urinary excretion averaged 11% of the infused volume. Mean arterial pressure was 10 mmHg lower in the isoflurane group (P < 0.001). The excess fluid volumes in the central and peripheral functional body fluid spaces were virtually identical in the groups. The sum of water losses by evaporation and extravascular fluid retention amounted to 2.0 +/- 2.5 ml/min for isoflurane and 2.2 +/- 2.1 ml/min for propofol. The sodium balance refuted that major fluid shifts occurred between the extracellular and intracellular spaces.

CONCLUSIONS: The amount of evaporation and extravascular retention of fluid was small during thyroid surgery, irrespective of whether anesthesia was maintained by isoflurane or propofol.

Volume kinetics is a method for analyzing and simulating the distribution and elimination of infusion fluids. Approximately 50 studies describe the disposition of 0.9% saline, acetated and lactated Ringer´s solution, based on repeated measurements of the hemoglobin concentration and (sometimes) the urinary excretion.

The slow distribution to the peripheral compartment results in a 50-75% larger plasma dilution during an infusion of crystalloid fluid than would be expected if distribution had been immediate. A drop in the arterial pressure during induction of anesthesia reduces the rate of distribution even further.

The renal clearance of the infused fluid during surgery is only 10-20% compared to conscious volunteers. Some of this temporary decrease can be attributed to the anesthesia and probably also to preoperative psychological stress and/or dehydration. 

Crystalloid fluid might be allocated to “non-functional” fluid spaces where it is unavailable for excretion. This amounts to approximately 20-25% during minor (thyroid) surgery.

BACKGROUND: Previously, the authors found "liberal" fluid administration (approximately 3 l Ringer's lactate [RL]) to improve early rehabilitation after laparoscopic cholecystectomy, suggesting functional hypovolemia to be present in patients receiving "restrictive" fluid administration (approximately 1 l RL). Because volume kinetic analysis after a volume load may distinguish between hypovolemic versus normovolemic states, the authors applied volume kinetic analysis after laparoscopic cholecystectomy to explain the difference in outcome between 3 and 1 l RL.

METHODS: In a prospective, nonrandomized trial, the authors studied 20 patients undergoing laparoscopic cholecystectomy. Ten patients received 15 ml/kg RL (group 1) and 10 patients received 40 ml/kg RL (group 2) intraoperatively. All other aspects of perioperative management were standardized. A 12.5-ml/kg RL volume load was infused preoperatively and 4 h postoperatively. The distribution and elimination of the fluid load was estimated using volume kinetic analysis.

RESULTS: Patient baseline demographics and intraoperative data did not differ between groups, except for intraoperative RL, having a median of 1,118 ml (range, 900-1,400 ml) in group 1 compared with a median of 2,960 ml (range, 2,000-3,960 ml) in group 2 (P<0.01). There were no significant preoperative versus postoperative differences in the size of the body fluid space expanded by infused fluid (V), whereas the clearance constant kr was higher postoperatively versus preoperatively (P=0.03). The preoperative versus postoperative changes in volume kinetics including V were not different between the two groups.

CONCLUSIONS: Elimination of an intravenous fluid load was increased after laparoscopic cholecystectomy per se but not influenced by the amount of intraoperative fluid administration.

Background: There is an unsettled discussion about whether the distribution of local anesthetic is free or inhibited when performing brachial plexus blocks. This is the first study to use magnetic resonance imaging (MRI) to help answer this question. Methods: Thirteen patients received axillary block by a catheter-nerve stimulator technique. After locating the median nerve, a total dose of 50 ml local anesthetic was injected via the catheter in four divided doses of 1, 4, 15, and 30 ml. Results of sensory and motor testing were compared with the spread of local anesthetic as seen by MRI scans taken after each dose. The distribution of local anesthetic was described with reference to a 20-mm diameter circle around the artery. Results: Thirty minutes after the last dose, only two patients demonstrated analgesia or anesthesia in the areas of the radial, median, and ulnar nerve. At that time, eight of the patients had incomplete spread of local anesthetic around the artery, as seen by MRI. Their blocks were significantly poorer than those of the five patients with complete filling of the circle, although incomplete blocks were also present in the latter group. Conclusion: This study demonstrated that MRI is useful in examining local anesthetic distribution in axillary blocks because it can show the correlation between MRI distribution pattern and clinical effect. The cross-sectional spread of fluid around the brachial-axillary artery was often incomplete-inhibited, and the clinical effect often inadequate.

BACKGROUND: The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele.

METHODS: The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele.

RESULTS: The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice.

CONCLUSIONS: This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids.

Lung ultrasound is increasingly used in emergency departments, medical wards, and critical care units-adult, pediatric, and neonatal. In vitro and in vivo studies show that the number and type of artifacts visualized change with lung density. This has led to the idea of a quantitative lung ultrasound approach, opening up new prospects for use not only as a diagnostic but also as a monitoring tool. Consequently, the multiple scoring systems proposed in the last few years have different technical approaches and specific clinical indications, adaptable for more or less time-dependent patients. However, multiple scoring systems may generate confusion among physicians aiming at introducing lung ultrasound in their clinical practice. This review describes the various lung ultrasound scoring systems and aims to clarify their use in different settings, focusing on technical aspects, validation with reference techniques, and clinical applications.

BACKGROUND: Hemorrhage is commonly treated with intravenous infusion of crystalloids. However, the dynamics of fluid shifts between body fluid spaces are not completely known, causing contradictory recommendations regarding timing and volume of fluid infusions. The authors have developed a turnover model that characterizes these fluid shifts.

METHODS: Conscious, chronically instrumented sheep (n = 12) were randomly assigned to three protocol groups: infusion of 25 ml/kg of 0.9% saline over 20 min (infusion only), hemorrhage of 300 ml (7.8 +/- 1.1 ml/kg) over 5 min (hemorrhage only), and hemorrhage of 300 ml over 5 min followed by infusion as noted above (hemorrhage plus infusion). A two-compartment volume turnover kinetic model containing seven model parameters was fitted to data obtained by repeated sampling of hemoglobin concentration and urinary excretion.

RESULTS: The volume turnover model successfully predicted fluid shifts. Mean baseline volumes of the central and tissue compartments were 1799 +/- 1276 ml and 7653 +/- 5478 ml, respectively. Immediate fluid infusion failed to prevent hemorrhage-induced depression of cardiac output and diuresis. The model suggested that volume recruitment to the central compartment after hemorrhage was primarily achieved by mechanisms other than volume equilibration between the two model compartments.

CONCLUSION: Volume turnover kinetics is a promising tool for explaining fluid shifts between body compartments after perturbations such as hemorrhage and intravenous fluid infusions. The pronounced inhibition of renal output after hemorrhage prevailed regardless of fluid infusion and caused fluid retention, which expanded the tissue compartment.

BACKGROUND: In previous work, extravascular expansion was observed to be enhanced by isoflurane anesthesia in sheep when a crystalloid bolus was administered. The aim of the current study was to further elaborate these investigations to humans and to explore the use of population kinetics in the analysis of fluid shifts.

METHODS: Eleven healthy volunteers participated in two experiments each, either awake or isoflurane anesthetized, during which they received 25 ml/kg saline, 0.9%, intravenously over 20 min. Plasma dilution data were derived from repeated sampling of hemoglobin concentration, and population pharmacokinetic analysis was conducted using the WinNonMix 2.0.1 software (Pharsight Corporation, Mountain View, CA). Plasma hormones were measured, and hemodynamic values were monitored.

RESULTS: Fluid infusion during isoflurane anesthesia was followed by a higher cardiac output, lower arterial pressure, and lower urinary excretion as compared with the awake protocol (P < 0.05). Albumin dilution was greater than hemoglobin concentration-derived plasma dilution, which indicates a transcapillary leak of albumin. A two-compartment model with an isoflurane-depressed, intercompartmental distribution parameter predicted that more than 50% of the infused volume was retained in the peripheral compartment at 180 min in both protocols. Isoflurane markedly increased the plasma levels of renin and aldosterone, whereas vasopressin was mostly unchanged.

CONCLUSION: Fluid retention after rapid infusion of 0.9% saline was prominent in both awake and isoflurane-anesthetized subjects. Altered kinetics of infused 0.9% saline during isoflurane anesthesia was expressed as reduced clearance and a slower distribution, resulting in a small but significant increase in fluid accumulation in the body fluid compartments. These changes may be due to the associated decreasing of mean arterial pressure and increased release of renin and aldosterone.

BACKGROUND: Hemospan® (Sangart Inc., San Diego, CA), a polyethylene glycol-modified hemoglobin with unique oxygen transport properties, has successfully completed a phase I trial in healthy volunteers. Because adverse events are expected to increase with age, the authors conducted a phase II safety study of Hemospan in elderly patients undergoing elective hip arthroplasty during spinal anesthesia. METHODS: Ninety male and female patients, American Society of Anesthesiologists physical status I-III, aged 50-89 yr, in six Swedish academic hospitals were randomly assigned to receive either 250 or 500 ml Hemospan or Ringer's acetate (30 patients/group) before induction of spinal anesthesia. Safety assessment included vital signs and Holter monitoring from infusion to 24 h, evaluation of laboratory values, and fluid balance. The hypothesis to be tested was that the incidence of adverse events would be no more frequent in patients who received Hemospan compared with standard of care (Ringer's acetate). RESULTS: Three serious adverse events were noted, none of which was deemed related to study treatment. Liver enzymes, amylase, and lipase increased transiently in patients in all three groups. There were no significant differences in electrocardiogram or Holter parameters, but there was a suggestion of more bradycardic events in the treated groups. Hypotension was less frequent in the treated patients compared with controls. CONCLUSIONS: In comparison with Ringer's acetate, Hemospan mildly elevates hepatic enzymes and lipase and is associated with less hypotension and more bradycardic events. The absence of a high frequency of serious adverse events suggests that further clinical trials should be undertaken. © 2006 American Society of Anesthesiologists, Inc.

Editors Perspective What We Already Know about This Topic Hospital mortality in acute respiratory distress syndrome is approximately 40%, but mortality and trajectory in mild acute respiratory distress syndrome (classified only since 2012) are unknown, and many cases are not detected What This Article Tells Us That Is New Approximately 80% of cases of mild acute respiratory distress syndrome persist or worsen in the first week; in all cases, the mortality is substantial (30%) and is higher (37%) in those in whom the acute respiratory distress syndrome progresses Background: Patients with initial mild acute respiratory distress syndrome are often underrecognized and mistakenly considered to have low disease severity and favorable outcomes. They represent a relatively poorly characterized population that was only classified as having acute respiratory distress syndrome in the most recent definition. Our primary objective was to describe the natural course and the factors associated with worsening and mortality in this population. Methods: This study analyzed patients from the international prospective Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) who had initial mild acute respiratory distress syndrome in the first day of inclusion. This study defined three groups based on the evolution of severity in the first week: worsening if moderate or severe acute respiratory distress syndrome criteria were met, persisting if mild acute respiratory distress syndrome criteria were the most severe category, and improving if patients did not fulfill acute respiratory distress syndrome criteria any more from day 2. Results: Among 580 patients with initial mild acute respiratory distress syndrome, 18% (103 of 580) continuously improved, 36% (210 of 580) had persisting mild acute respiratory distress syndrome, and 46% (267 of 580) worsened in the first week after acute respiratory distress syndrome onset. Global in-hospital mortality was 30% (172 of 576; specifically 10% [10 of 101], 30% [63 of 210], and 37% [99 of 265] for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively), and the median (interquartile range) duration of mechanical ventilation was 7 (4, 14) days (specifically 3 [2, 5], 7 [4, 14], and 11 [6, 18] days for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively). Admissions for trauma or pneumonia, higher nonpulmonary sequential organ failure assessment score, lower partial pressure of alveolar oxygen/fraction of inspired oxygen, and higher peak inspiratory pressure were independently associated with worsening. Conclusions: Most patients with initial mild acute respiratory distress syndrome continue to fulfill acute respiratory distress syndrome criteria in the first week, and nearly half worsen in severity. Their mortality is high, particularly in patients with worsening acute respiratory distress syndrome, emphasizing the need for close attention to this patient population. © 2018, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.

Background:N-terminal fragment B-type natriuretic peptide (NT-proBNP) prognostic utility is commonly determined post hoc by identifying a single optimal discrimination threshold tailored to the individual study population. The authors aimed to determine how using these study-specific post hoc thresholds impacts meta-analysis results. Methods: The authors conducted a systematic review of studies reporting the ability of preoperative NT-proBNP measurements to predict the composite outcome of all-cause mortality and nonfatal myocardial infarction at 30 days after noncardiac surgery. Individual patient-level data NT-proBNP thresholds were determined using two different methodologies. First, a single combined NT-proBNP threshold was determined for the entire cohort of patients, and a meta-analysis conducted using this single threshold. Second, study-specific thresholds were determined for each individual study, with meta-analysis being conducted using these study-specific thresholds. Results: The authors obtained individual patient data from 14 studies (n = 2,196). Using a single NT-proBNP cohort threshold, the odds ratio (OR) associated with an increased NT-proBNP measurement was 3.43 (95% CI, 2.08 to 5.64). Using individual study-specific thresholds, the OR associated with an increased NT-proBNP measurement was 6.45 (95% CI, 3.98 to 10.46). In smaller studies (less than100 patients) a single cohort threshold was associated with an OR of 5.4 (95% CI, 2.27 to 12.84) as compared with an OR of 14.38 (95% CI, 6.08 to 34.01) for study-specific thresholds. Conclusions:Post hoc identification of study-specific prognostic biomarker thresholds artificially maximizes biomarker predictive power, resulting in an amplification or overestimation during meta-analysis of these results. This effect is accentuated in small studies.

Background: Awareness during general anesthesia can cause late psychological symptoms. Selection bias may have affected the results in previous retrospective studies. The authors used prospective consecutive collection to recruit patients with previous awareness.

Methods: In a cohort of 2,681 consecutive patients scheduled to undergo general anesthesia, 98 considered themselves to have been aware during previous surgery. Six patients died before inclusion, and another 13 were excluded (4 cases of stoke or dementia, 7 declined to participate, and 2 could not be located). Seventy-nine patients were interviewed by telephone, and medical records were checked in uncertain cases. The interview followed a structured protocol, including seven late symptoms (anxiety, chronic fear, nightmares, flashbacks, indifference, loneliness, and lack of confidence in future life). Three persons independently assessed the interviews for classification, to determine whether awareness had occurred.

Results: Four cases were performed using regional anesthesia, and another 29 were not considered as awareness by the assessors. Therefore, the final analyses included 46 patients. Twenty (43%) had experienced pain, and 30 (65%) described acute emotional reactions during the awareness episode. Fifteen (33%) patients had experienced late psychological symptoms afterward. In 6 of those cases, the symptoms lasted for more than 2 months, and 1 patient had a diagnosis of post-traumatic stress disorder. Acute emotional reactions were significantly related to late psychological symptoms (P < 0.05).

Conclusion: The method for recruiting awareness cases in studies on late psychological symptoms may affect the result. The authors found fewer and milder problems, despite a similar degree of initial problems as in previous studies.

Background: Systemic ketamine can trigger apoptosis in the brain of rodents and primates during susceptible developmental periods. Clinically, spinally administered ketamine may improve the duration or quality of analgesia in children. Ketamine-induced spinal cord toxicity has been reported in adult animals but has not been systematically studied in early development. Methods: In anesthetized rat pups, intrathecal ketamine was administered by lumbar percutaneous injection. Changes in mechanical withdrawal threshold evaluated dose-dependent antinociceptive and carrageenan-induced antihyperalgesic effects in rat pups at postnatal day (P) 3 and 21. After intrathecal injection of ketamine at P3, 7, or 21, spinal cords were examined for apoptosis (Fluoro-Jade C and activated caspase-3), histopathologic change, and glial responses (ionized calcium-binding adapter molecule 1 and glial fibrillary acid protein). After maximal doses of ketamine or saline at P3 or P21, sensory thresholds and gait analysis were evaluated at P35. Results: Intrathecal injection of 3 mg/kg ketamine at P3 and 15 mg/kg at P21 reverses carrageenan-induced hyperalgesia. Baseline neuronal apoptosis in the spinal cord was greater at P3 than P7, predominantly in the dorsal horn. Intrathecal injection of 3-10 mg/kg ketamine in P3 pups (but not 15 mg/kg at P21) acutely increased apoptosis and microglial activation in the spinal cord and altered spinal function (reduced mechanical withdrawal threshold and altered static gait parameters) at P35. Conclusions: Because acute pathology and long-term behavioral change occurred in the same dose range as antihyperalgesic effects, the therapeutic ratio of intrathecal ketamine is less than one in the neonatal rat. This measure facilitates comparison of the relative safety of spinally administered analgesic agents.

Background: Preclinical studies demonstrate increased neuro-apoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Methods: Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results: Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions: The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.