The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

Importance Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. Objective To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Design, Setting, and Participants Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. Interventions Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). Main Outcomes and Measures Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. Results No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, −4.2% [95% CI, −9.6% to 1.1%]; P  = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, −3.7% [95% CI, −10.2% to 2.7%]; P  = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, −5.4% [95% CI, −10.4% to −0.5%]; P  = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P  = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P P Conclusions and Relevance Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. Trial Registration clinicaltrials.gov Identifier:NCT01545232

/pdf/transfusion-of-plasma-platelets-and-red-blood-cells-in-a-1-1-6vj8qjp35k.pdf

Transfusion of plasma, platelets, and red blood cells in a 1: 1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: The PROPPR randomized clinical trial

Severe trauma continues to represent a global public health issue and mortality and morbidity in trauma patients remains substantial. A number of initiatives have aimed to provide guidance on the management of trauma patients. This document focuses on the management of major bleeding and coagulopathy following trauma and encourages adaptation of the guiding principles to each local situation and implementation within each institution. The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2004 and included representatives of six relevant European professional societies. The group used a structured, evidence-based consensus approach to address scientific queries that served as the basis for each recommendation and supporting rationale. Expert opinion and current clinical practice were also considered, particularly in areas in which randomised clinical trials have not or cannot be performed. Existing recommendations were reconsidered and revised based on new scientific evidence and observed shifts in clinical practice; new recommendations were formulated to reflect current clinical concerns and areas in which new research data have been generated. This guideline represents the fourth edition of a document first published in 2007 and updated in 2010 and 2013. The guideline now recommends that patients be transferred directly to an appropriate trauma treatment centre and encourages use of a restricted volume replacement strategy during initial resuscitation. Best-practice use of blood products during further resuscitation continues to evolve and should be guided by a goal-directed strategy. The identification and management of patients pre-treated with anticoagulant agents continues to pose a real challenge, despite accumulating experience and awareness. The present guideline should be viewed as an educational aid to improve and standardise the care of the bleeding trauma patients across Europe and beyond. This document may also serve as a basis for local implementation. Furthermore, local quality and safety management systems need to be established to specifically assess key measures of bleeding control and outcome. A multidisciplinary approach and adherence to evidence-based guidance are key to improving patient outcomes. The implementation of locally adapted treatment algorithms should strive to achieve measureable improvements in patient outcome.

/pdf/the-european-guideline-on-management-of-major-bleeding-and-50g3zxrre8.pdf

The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition

Introduction. Bias and precision statistics have succeeded regression analysis when measurement techniques are compared. However, when applied to cardiac output measurements, inconsistencies occur in reporting the results of this form of analysis. Methods. A MEDLINE search was performed, dating from 1986. Studies comparing techniques of cardiac output measurement using bias and precision statistics were surveyed. An error-gram was constructed from the percentage errors in the test and reference methods and was used to determine acceptable limits of agreement between methods. Results. Twenty-five articles were found. Presentation of statistical data varied greatly. Four different statistical parameters were used to describe the agreement between measurements. The overall limits of agreement in studies evaluating bioimpedance (n = 23) was ±37% (15–82%) and in those evaluating Doppler ultrasound (n = 11) ±65% (25–225%). Objective criteria used to assess outcome were given in only 44% of the articles. These were (i) limits of agreement approaching ±15–20%, (ii) limits of agreement of less than 1 L/min, and (iii) more than 75% of bias measurements within ±20% of the mean. Graphically, we showed that limits of agreement of up to ±30% were acceptable. Conclusions. When using bias and precision statistics, cardiac output, bias, limits of agreement, and percentage error should be presented. Using current reference methods, acceptance of a new technique should rely on limits of agreement of up to ±30%.

A meta-analysis of studies using bias and precision statistics to compare cardiac output measurement techniques.

Objective To relate in-hospital mortality to early transfusion of plasma and/or platelets and to time-varying plasma:red blood cell (RBC) and platelet:RBC ratios. Design Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models. Setting Ten US level I trauma centers. Patients Adult trauma patients surviving for 30 minutes after admission who received a transfusion of at least 1 unit of RBCs within 6 hours of admission (n = 1245, the original study group) and at least 3 total units (of RBCs, plasma, or platelets) within 24 hours (n = 905, the analysis group). Main Outcome Measure In-hospital mortality. Results Plasma:RBC and platelet:RBC ratios were not constant during the first 24 hours (P  Conclusions Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.

https://jamanetwork.com/journals/jamasurgery/articlepdf/1379768/soa120062_127_136.pdf

The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: Comparative effectiveness of a time-varying treatment with competing risks

When validating new methods of cardiac output, measurement comparisons are made using Bland-Altman and percentage errors are generated that rely on a precision error for thermodilution of ± 20% [1]; data collected 30 years ago [2]. We have re-evaluated this precision against an aortic flow probe.

/pdf/performance-of-thermodilution-catheters-under-control-and-363uooqnwo.pdf

Performance of thermodilution catheters under control and extreme circulatory conditions in a pig model

Electrical safety and injuries

One of the big advantages of animal over clinical research is that a range of physiologic conditions can be produced that enable testing of the performance of monitoring equipment to an extent that cannot be achieved in human subjects, and this statement could not be more pertinent than when applied to the measurement of cardiac output (CO). 1,2 In this edition, Kutter et al. 3 have performed an exemplary animal study that shows the differences among 4 common CO measurement methods that use either a pulmonary artery (PA) catheter or femoral arterial catheter. A modified Fick method using carbon dioxide (CO2) production, rather than oxygen uptake, was chosen as the reference standard. Their study results are of clinical interest because they compare the performance of several techniques that measure CO from either the pulmonary circulation (i.e., right heart) or the systemic circulation (i.e., left heart) during induced pulmonary hypertension. The pressures in the PA can be affected by acute lung injury and high CO states, and it is clearly important to know how reliable different monitoring techniques are under such circulatory conditions.

The Pulmonary Circulation: A Significant Factor in the Performance of Different Thermodilution Techniques

BACKGROUND:
Cardiac output (CO) measurement with lithium dilution (COLD) has not been fully validated in sheep using precise ultrasonic flow probe technology (COUFP). Sheep generate important cardiovascular research models and the use of COLD has become more popular in experimental settings.

METHODS:
Ultrasonic transit-time perivascular flow probes were surgically implanted on the pulmonary artery of 13 sheep. Paired COLD readings were taken at six time points, before and after implantation of a left ventricular assist device (LVAD) and compared with COUFP recorded just after lithium injection.

RESULTS:
The mean COLD was 5.7 litre min(-1) (range 3.8-9.6 litre min(-1)) and mean COUFP 5.9 litre min(-1) (range 4.0-9.2 litre min(-1)). The bias (standard deviation) was 0.3 (1.0) litre min(-1) [5.1 (16.9)%] and limits of agreement (LOA) were -1.7 to 2.3 litre min(-1) (-28.8 to 39.0%) with a percentage error (PE) of 34.4%. Data to assess trending [rate (95% confidence intervals)] included a 78 (62-93)% concordance rate in the four-quadrant plot (n=27). In the half moon polar plot (n=19), the mean polar angle was +5°, the radial LOA were -49 to +35° and 68 (47-89)% of data points fell within 22.5° of the mean polar angle. Both tests indicated moderate to poor trending ability.

CONCLUSION:
COLD is not precise when evaluated against COUFP in sheep based on the statistical criteria set, but the results are comparable with previously published animal studies.

KEYWORDS:

Reliability of lithium dilution cardiac output in anaesthetized sheep

Background Reliable cardiac output monitoring is particularly useful in the cirrhotic patient undergoing liver transplant surgery, because cirrhosis of the liver is associated with a vasodilated and high output state, known as cirrhotic cardiomyopathy, that challenges the reliability of pulse contour cardiac output technology. The contractility of the ventricle in cirrhosis is impaired, which is tolerated even though the ejection fraction and cardiac output are elevated because of the low peripheral resistance. However, during surgery the cirrhotic patient can decompensate because of the physiological changes and stress of surgery. Recently, we showed that the FloTrac/Vigileo™ failed to perform in cirrhotic patients undergoing transplant surgery. In response, the company upgraded their software. Therefore, we have assessed the accuracy and reliability of this new third-generation (version 3.02) FloTrac/Vigileo algorithm software in the same setting. Methods The cardiac index was measured simultaneously by single-bolus thermodilution (CI(TD)), using a pulmonary artery catheter, and pulse contour analysis, using the FloTrac/Vigileo (CI(V)). Readings were made at 10 time points during and after liver transplant surgery in 21 patients. Comparisons with data from our 2009 study, which used second-generation (version 01.10) software, were also made. Results Our new data show that version 3.02 software significantly reduced the adverse effect on pulse contour cardiac output reading bias in low peripheral resistance states, and thus improves the overall precision and trending ability of the system. Regression analysis between CI(TD) and CI(V) showed that the correlation was moderate (r =0.67, 95% confidence interval, 0.40 to 0.86). The Bland and Altman analysis showed that bias was 0.4 L.min(-1) · m(-2), and the percentage error was 52% (95% confidence interval, 49% to 55%). Trending ability of the new software also was improved but was still well below the current benchmarks. Conclusion The new software (version 3.02) provided substantial improvements over the previous versions with better overall precision and trending ability. Further algorithm refinements will increase this technology's reliability to be extensively used in the highly complex setting of cirrhotic patients undergoing liver transplantation.

Evaluation of a new software version of the FloTrac/Vigileo (version 3.02) and a comparison with previous data in cirrhotic patients undergoing liver transplant surgery.

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