Significant modification of traditional rapid sequence induction improves safety and effectiveness of pre-hospital trauma anaesthesia.
Faut-il utiliser la kétamine ou l'étomidate ? Le travail présenté milite pour l'emploi de la kétamine, mais ceci reste controversé (voir également ici)). C'est aussi le choix présenté dans la procédure du sauvetage au combat, du fait de la polyvalence d'emploi de la kétamine tant dans ses indications que de ses voies d'administration. On rappelle quand même que si l'ISR facilite grandement les conditions de l'intubation oro-trachéale en médecine préhospitalière métropolitaine, nos conditions spécifiques d'exercice ne correspondent pas à cette dernière. Avant de réaliser une telle induction, encore faut-il être valider l'indication de l'intubation au milieu de nulle part. Par ailleurs la réalisation de ce geste sous anesthésie locale doit également être envisagée. Ceci est conforme aux recommandations sur le sujet.
Rapid Sequence Induction of anaesthesia (RSI) is the recommended method to facilitate emergency tracheal intubation in trauma patients. In emergency situations, a simple and standardised RSI protocol may improve the safety and effectiveness of the procedure. A crucial component of developing a standardised protocol is the selection of induction agents. The aim of this study is to compare the safety and effectiveness of a traditional RSI protocol using etomidate and suxamethonium with a modified RSI protocol using fentanyl, ketamine and rocuronium.
We performed a comparative cohort study of major trauma patients undergoing pre-hospital RSI by a physician-led Helicopter Emergency Medical Service. Group 1 underwent RSI using etomidate and suxamethonium and Group 2 underwent RSI using fentanyl, ketamine and rocuronium. Apart from the induction agents, the RSI protocol was identical in both groups. Outcomes measured included laryngoscopy view, intubation success, haemodynamic response to laryngoscopy and tracheal intubation, and mortality.
Compared to Group 1 (n = 116), Group 2 RSI (n = 145) produced significantly better laryngoscopy views (p = 0.013) and resulted in significantly higher first-pass intubation success (95% versus 100%; p = 0.007). A hypertensive response to laryngoscopy and tracheal intubation was less frequent following Group 2 RSI (79% versus 37%; p < 0.0001). A hypotensive response was uncommon in both groups (1% versus 6%; p = 0.05). Only one patient in each group developed true hypotension (SBP < 90 mmHg) on induction.
In a comparative, cohort study, pre-hospital RSI using fentanyl, ketamine and rocuronium produced superior intubating conditions and a more favourable haemodynamic response to laryngoscopy and tracheal intubation. An RSI protocol using fixed ratios of these agents delivers effective pre-hospital trauma anaesthesia.
Coagulation function of stored whole blood is preserved for 14 days in austere conditions: A ROTEM feasibility study during a Norwegian antipiracy mission and comparison to equal ratio reconstituted blood.
Formulation of a medical preparedness plan for treating severely bleeding casualties during naval deployment is a significant challenge because of territory covered during most missions. The aim of this study was to evaluate the concept of "walking blood bank" as a supportable plan for supplying safe blood and blood products.
In 2013, the Royal Norwegian Navy conducted antipiracy operations from a frigate, beginning in the Gulf of Aden and ending in the Indian Ocean. Crews were on 24-hour emergency alert in preparation for an enemy assault on the frigate. Under an approved command protocol, a "walking blood bank," using crew blood donations, was established for use on board and on missions conducted in rigid-hulled inflatable boats, during which freeze-dried plasma and leukoreduced, group O low anti-A/anti-B titer, cold-stored whole blood were stored in Golden Hour Boxes. Data demonstrating the ability to collect, store, and provide whole blood were collected to establish feasibility of implementing a whole blood-focused remote damage-control resuscitation program aboard a naval vessel. In addition, ROTEM data were collected to demonstrate feasibility of performing this analysis on a large naval vessel and to also measure hemostatic efficacy of cold-stored leukoreduced whole blood (CWB) stored during a period of 14 days. ROTEM data on CWB was compared with reconstituted whole blood.
Drills simulating massive transfusion activation were conducted, in which 2 U of warm fresh whole blood with platelet sparing leukoreduction were produced in 40 minutes, followed by collection of two additional units at 15-minute increments. The ROTEM machine performed well during ship-rolling, as shown by the overlapping calculated and measured mechanical piston movements measured by the ROTEM device. Error messages were recorded in 4 (1.5%) of 267 tests. CWB yielded reproducible ROTEM results demonstrating preserved fibrinogen function and platelet function for at least 3.5 weeks and 2 weeks, respectively. The frequency of ROTEM tests were as follows: EXTEM (n = 88), INTEM (n = 85), FIBTEM (n = 82), and APTEM (n = 12). CWB results were grouped. Compared with Days 0 to 2, EXTEM maximum clot firmness was significantly reduced, beginning on Days 10 to 14; however, results through that date remained within reference ranges and were comparable with the EXTEM maximum clot firmness for the reconstituted whole blood samples containing Day 5 room temperature-stored platelets.
A "walking blood bank" can provide a balanced transfusion product to support damage-control resuscitation/remote damage-control resuscitation aboard a frigate in the absence of conventional blood bank products. ROTEM analysis is feasible to monitor damage-control resuscitation and blood product quality. ROTEM analysis was possible in challenging operational conditions.
Inducing metabolic suppression in severe hemorrhagic shock: Pilot study results from the Biochronicity Project.
Suspended animation-like states have been achieved in small animal models, but not in larger species. Inducing metabolic suppression and temporary oxygen independence could enhance survivability of massive injury. Based on prior analyses of key pathways, we hypothesized that phosphoinositol-3-kinase inhibition would produce metabolic suppression without worsening organ injury or systemic physiology.
Twenty swine were studied using LY294002 (LY), a nonselective phosphoinositol-3-kinase inhibitor. Animals were assigned to trauma only (TO, n = 3); dimethyl sulfoxide only (DMSO, n = 4), LY drug only (LYO, n = 3), and drug + trauma (LY + T, n = 10) groups. Both trauma groups underwent laparotomy, 35% hemorrhage, severe ischemia/reperfusion injury, and protocolized resuscitation. Laboratory, physiologic, cytokine, and metabolic cart data were obtained. Histology of key end organs was also compared.
Baseline values were similar among the groups. Compared with the TO group, the LYO group had reversible decreases in heart rate, mean arterial pressure, cardiac output, oxygen consumption, and carbon dioxide production. Compared with TO, LY + T showed sustained decreases in heart rate (113 vs. 76, p = 0.03), mean arterial pressure (40 vs. 31 mm Hg, p = 0.02), and cardiac output (3.8 vs. 1.9 L/min, p = 0.05) at 6 hours. Metabolic parameters showed profound suppression in the LY + T group. Oxygen consumption in LY + T was lower than both TO (119 vs. 229 mL/min, p = 0.012) and LYO (119 vs. 225 mL/min, p = 0.014) at 6 hours. Similarly, carbon dioxide production was decreased at 6 hours in LY + T when compared with TO (114 vs. 191 mL/min, p = 0.043) and LYO (114 vs. 195 mL/min, p = 0.034) groups. There was no worsening of acidosis (lactate 6.4 vs. 8.3 mmol/L, p = 0.4) or other endpoints. Interleukin 6 (IL-6) showed a significant increase in LY + T when compared with TO at 6 hours (60.5 vs. 2.47, p = 0.043). Tumor necrosis factor α and IL-1β were decreased, and IL-10 increased in TO and LY + T at 6 hours. Markers of liver and kidney injury were no different between TO and LY + T groups at 6 hours.
Phosphoinositol-3-kinase inhibition produced metabolic suppression in healthy and injured swine without increasing end-organ injury or systemic physiologic markers and demonstrated prolonged efficacy in injured animals. Further study may lead to targeted therapies to prolong tolerance to hemorrhage and extend the "golden hour" for injured patients.
Low-volume resuscitation using polyethylene glycol-20k in a preclinical porcine model of hemorrhagic shock
Une nouvelle approche de la prise en compte des lésions induites par l'ischémie tissulaire qui est basée sur l'expérience de l'emploi des solutés utilisés pour conserver les organes en instance de transplantation. Grosso-modo: Remplir les espaces interstitiels par des solutés ne dépendant pas de mécanismes énergétiques. Une explication ici.
Polyethylene glycol-20k (PEG-20k) is highly effective for low-volume resuscitation (LVR) by increasing tolerance to the low-volume state. In our rodent shock model, PEG-20k increased survival and expanded the "golden hour" 16-fold compared to saline. The molecular mechanism is largely attributed to normalizations in cell and tissue fluid shifts after low-flow ischemia resulting in efficient microvascular exchange. The objective of this study was to evaluate PEG-20k as an LVR solution for hemorrhagic shock in a preclinical model.
Anesthetized male Yorkshire pigs (30-40 kg) were hemorrhaged to a mean arterial pressure (MAP) of 35 to 40 mm Hg. Once lactate reached 7 mmol/L, either saline (n = 5) or 10% PEG-20k (n = 5) was rapidly infused at 10% calculated blood volume. The primary outcome was LVR time, defined by the time from LVR administration to the time when lactate again reached 7 mmol/L. Other outcomes measured included MAP, heart rate, cardiac output, mixed venous oxygen saturation, splanchnic blood flow, and hemoglobin.
Relative to saline, PEG-20k given after controlled hemorrhage increased LVR time by 16-fold, a conservative estimate given that the lactate never rose after LVR in the PEG-20k group. Survival was 80% for PEG-20k LVR compared to 0% for the saline controls (p < 0.05).
Polyethylene glycol-20k also significantly decreased heart rate after hemorrhage and increased cardiac output, MAP, splanchnic flow, and mixed venous oxygen saturation. Falling hemoglobin concentrations suggested sizable hemodilution from fluid shifts into the intravascular compartment.
In a preclinical model of controlled hemorrhagic shock, PEG-20k-based LVR solution increased tolerance to the shock state 16-fold compared to saline. Polyethylene glycol-20k is a superior crystalloid for LVR that may increase safe transport times in the prehospital setting and find use in hospital emergency departments and operating rooms for patients awaiting volume replacement or normalization of cell, tissue, and compartment fluid volumes.
Pre-Hospital Resuscitation of Traumatic Hemorrhagic Shock with Hypertonic Solutions Worsen Hypo-Coagulation and Hyper-Fibrinolysis
Le choix d'un liquide de remplissage vasculaire n'est pas simple. Au delà des contraintes d'efficacité en termes de remplissage vasculaire, de bonne tolérance notamment rénale il y a également les effets de ce dernier sur la coagulation. On sait qu'une partie importante des blessés actuellement pris en charge présentent une coagulopathie traumatique (1). Le NaCl 7.5% est le soluté recommandé par la procédure du sauvetage au combat (2) car il représente le meilleur compromis intérêt médical/logistique. Le travail ici présenté met en évidence les effets délétères des solutés hypertoniques sur la coagulation. Ce document mérite cependant d'être pondéré car il s'appuie sur une petite cohorte de patients de traumatologie civile, que le profil du remplissage vasculaire préhospitalier n'est pas clairement rapporté hormis le premier liquide, qu'il ne précise pas le niveau de calcémie plasmatique car ce dernier peut être affecté selon la nature des solutés utilisés (4), que le groupe HS a des marqueurs d'hypoperfusion tissulaire identique au groupe NS, que la comparaison se fait avec un groupe de sujets sains et non entre les groupes. Par ailleurs on sait également qu'il est mis en avant l'intérêt des solutions HS en matière de prise en charge des HTIC des plaies cranio-cérébrales (4) et la réduction de l'activation des polynucléaires neutrophiles (5). Donc il ne s'agit pas de remettre en question le choix actuel, mais de le repositionner dans le débat notamment avec l'emploi du Plama lyophylisé comme soluté de remplissage premier des blessés les plus graves (6). Une chose apparait certaine: Ne plus utiliser une association HS/Dextran type RescueFlow (7).
Impaired hemostasis frequently occurs after traumatic shock and resuscitation. The prehospital fluid administered can exacerbate subsequent bleeding and coagulopathy. Hypertonic solutions are recommended as first-line treatment of traumatic shock; however, their effects on coagulation are unclear. This study explores the impact of resuscitation with various hypertonic solutions on early coagulopathy after trauma. We conducted a prospective observational subgroup analysis of large clinical trial on out-of-hospital single-bolus (250 mL) hypertonic fluid resuscitation of hemorrhagic shock trauma patients (systolic blood pressure, e70 mmHg). Patients received 7.5% NaCl (HS), 7.5% NaCl/6% Dextran 70 (HSD), or 0.9% NaCl (normal saline [NS]) in the prehospital setting. Thirty-four patients were included: 9 HS, 8 HSD, 17 NS. Treatment with HS/HSD led to higher admission systolic blood pressure, sodium, chloride, and osmolarity, whereas lactate, base deficit, fluid requirement, and hemoglobin levels were similar in all groups. The HSD-resuscitated patients had higher admission international normalized ratio values and more hypocoagulable patients, 62% (vs. 55% HS, 47% NS; P G 0.05). Prothrombotic tissue factor was elevated in shock treated with NS but depressed in both HS and HSD groups. Fibrinolytic tissue plasminogen activator and antiYfibrinolytic plasminogen activator inhibitor type 1 were increased by shock but not thrombin-activatable fibrinolysis inhibitor. The HSD patients had the worst imbalance between procoagulation/anticoagulation and profibrinolysis/antifibrinolysis, resulting in more hypocoagulability and hyperfibrinolysis. We concluded that resuscitation with hypertonic solutions, particularly HSD, worsens hypocoagulability and hyperfibrinolysis after hemorrhagic shock in trauma through imbalances in both procoagulants and anticoagulants and both profibrinolytic and antifibrinolytic activities
Risk Management Analysis of Air Ambulance Blood Product Administration in Combat Operations
Between June-October 2012, 61 flight-medic-directed transfusions took place aboard U.S. Army Medical Evacuation (medevac) helicopters in Afghanistan. This represents the initial experience for pre-hospital blood product transfusion by U.S. Army flight medics.
We performed a retrospective review of clinical records, operating guidelines, after-action reviews, decision and information briefs, bimonthly medical conferences, and medevac-related medical records.
A successful program was administered at 10 locations across Afghanistan. Adherence to protocol transfusion indications was 97%. There were 61 casualties who were transfused without any known instance of adverse reaction or local blood product wastage. Shock index (heart rate/systolic blood pressure) improved significantly en route, with a median shock index of 1.6 (IQR 1.2-2.0) pre-transfusion and 1.1 (IQR 1.0-1.5) post-transfusion (P < 0.0001). Blood resupply, training, and clinical procedures were standardized across each of the 10 areas of medevacoperations.
Potential risks of medical complications, reverse propaganda, adherence to protocol, and diversion and/or wastage of limited resources were important considerations in the development of the pilot program. Aviation-specific risk mitigation strategies were important to ensure mission success in terms of wastage prevention, standardized operations at multiple locations, and prevention of adverse clinical outcomes. Consideration of aviation risk mitigation strategies may help enable other helicopter emergency medical systems to develop remote pre-hospital transfusion capability. This pilot program provides preliminary evidence that blood product administration by medevac is safe.
Comparison of the effects of ketamine and morphine on performance of representative military tasks
When providing care under combat or hostile conditions, it may be necessary for a casualty to remain engaged in military tasks after being wounded. Prehospital care under other remote, austere conditions may be similar, whereby an individual may be forced to continue purposeful actions despite traumatic injury. Given the adverse side-effect profile of intramuscular (i.m.) morphine, alternative analgesics and routes of administration are of interest. Ketamine may be of value in this capacity.
To delineate performance decrements in basic soldier tasks comparing the effects of the standard battlefield analgesic (10 mg i.m. morphine) with 25 mg i.m. ketamine.
Representative military skills and risk propensity were tested in 48 healthy volunteers without pain stimuli in a double-blind, placebo-controlled, crossover design.
Overall, participants reported more symptoms associated with ketamine vs. morphine and placebo, chiefly dizziness, poor concentration, and feelings of happiness. Performance decrements on ketamine, when present, manifested as slower performance times rather than procedural errors.
Participants were more symptomatic with ketamine, yet the soldier skills were largely resistant to performance decrements, suggesting that a trained task skill (autonomous phase) remains somewhat resilient to the drugged state at this dosage. The performance decrements with ketamine may represent the subjects' adoption of a cautious posture, as suggested by risk propensity testing whereby the subject is aware of impairment, trading speed for preservation of task accuracy. These results will help to inform the casualty care community regarding appropriate use of ketamine as an alternative or opioid-sparing battlefield analgesic.
Influences of limited resuscitation with plasma or plasma protein solutions on hemostasis and survival of rabbits with noncompressible hemorrhage
Dans ce travail et alors que l'albumine diluée n'est pas recommandée, les auteurs évoquent la possibilité que les effets favorables d'une réanimation basée sur l'apport de plasma serait lié à l'apport de protéine et en particulier d'albumine qui aurait un effet tampon élevé, réduisant l'acidose métabolique, un des facteurs de la triade létale.
Plasma infusion with or without red blood cells is the current military standard of care for prehospital resuscitation of combat casualties. We examined possible advantages of early and limited resuscitation with fresh plasma compared with a single plasma protein or crystalloid solutions in an uncontrolled hemorrhage model in rabbits.
Anesthetized spontaneously breathing rabbits (3.3 ± 0.1 kg) were instrumented and subjected to a splenic uncontrolled hemorrhage. Rabbits in shock were resuscitated at 15 minutes with Plasma-Lyte (PAL; 30 mL/kg), PAL + fibrinogen (PAL + F; 30 mL + 100 mg/kg), fresh rabbit plasma (15 mL/kg), or 25% albumin (ALB; 5 mL/kg) solution, all given in two bolus intravenous injections (15 minutes apart) to achieve a mean arterial pressure of 65 mm Hg, n = 8 to 9/group. Animals were monitored for 2 hours or until death, and blood loss was measured. Blood samples and tissues were collected and analyzed.
There were no differences among groups in baseline measures and their initial bleeding volume at 15 minutes. At 60 minutes after injury, mean arterial pressure was higher with ALB than with crystalloids (PAL or PAL + F), but shock indices were not different despite the large differences in resuscitation volumes. Fibrinogen addition to PAL only increased clot strength. Plasma resuscitation increased survival rate (75%) without significant improvement in coagulation measures. Albumin administration replenished total plasma protein and increased survival rate to 100% (p < .05 vs. crystalloids). No histological adverse events were identified in the vital organs.
Fibrinogen administration added to a compatible crystalloid did not improve hemostatic outcomes. Plasma resuscitation increased survival rate; however, its effects did not differ from those obtained with 25% ALB at one-third of the volume. The ALB advantage was consistent with our previous findings in which 5% ALB was used at a volume equal to plasma. The benefit of plasma for resuscitation may be mostly due to its ALB content rather than its coagulation proteins
The Myth of Rescue Reversal in “Can’t Intubate, Can’t Ventilate” Scenarios
Ce travail met en avant l'insuffisance des démarches d'antagonisation pour restaurer une ventilation adéquate dans les situations de CICV. En ce qui concerne la gestion des voies aériennes en situation tactique, le principe de la préservation de la ventilation spontanée lors de l'accès aux voies aériennes mérite d'être rappelé. Si la réalisation d'une induction en séquence rapide reste la référence, en cas de difficulté prévisible le recours à une anesthésie locale doit être préférée (lire ce post).
Ceci est parfaitement stipulé dans les RFE "Sédation et analgésie en structure d’urgence" dont on rappelle après la présentation de l'abstract les termes de la question N3.
An unanticipated difficult airway during induction of anesthesia can be a vexing problem. In the setting of can't intubate, can't ventilate (CICV), rapid recovery of spontaneous ventilation is a reasonable goal. The urgency of restoring ventilation is a function of how quickly a patient's hemoglobin oxygen saturation decreases versus how much time is required for the effects of induction drugs to dissipate, namely the duration of unresponsiveness, ventilatory depression, and neuromuscular blockade. It has been suggested that prompt reversal of rocuronium-induced neuromuscular blockade with sugammadex will allow respiratory activity to recover before significant arterial desaturation. Using pharmacologic simulation, we compared the duration of unresponsiveness, ventilatory depression, and neuromuscular blockade in normal, obese, and morbidly obese body sizes in this life-threatening CICV scenario. We hypothesized that although neuromuscular function could be rapidly restored with sugammadex, significant arterial desaturation will occur before the recovery from unresponsiveness and/or central ventilatory depression in obese and morbidly obese body sizes.
We used published models to simulate the duration of unresponsiveness and ventilatory depression using a common induction technique with predicted rates of oxygen desaturation in various size patients and explored to what degree rapid reversal of rocuronium-induced neuromuscular blockade with sugammadex might improve the return of spontaneous ventilation in CICV situations.
Our simulations showed that the duration of neuromuscular blockade was longer with 1.0 mg/kg succinylcholine than with 1.2 mg/kg rocuronium followed 3 minutes later by 16 mg/kg sugammadex (10.0 vs 4.5 minutes). Once rocuronium neuromuscular blockade was completely reversed with sugammadex, the duration of hemoglobin oxygen saturation >90%, loss of responsiveness, and intolerable ventilatory depression (a respiratory rate of ≤4 breaths/min) were dependent on the body habitus and duration of oxygen administration. There is a high probability of intolerable ventilatory depression that extends well beyond the time when oxygen saturation decreases <90%, especially in obese and morbidly obese patients. If ventilatory rescue is inadequate, oxygen desaturation will persist in the latter groups, despite full reversal of neuromuscular blockade. Depending on body habitus, the duration of intolerable ventilatory depression after sugammadex reversal may be as long as 15 minutes in 5% of individuals.
The clinical management of CICV should focus primarily on restoration of airway patency, oxygenation, and ventilation consistent with the American Society of Anesthesiologist's practice guidelines for management of the difficult airway. Pharmacologic intervention cannot be relied upon to rescue patients in a CICV crisis.
Question 3 - Intubation sous ISR et sous AL : Quelles sont les modalités de réalisation d’une sédation et/ou d’une analgésie pour l’intubation trachéale ?
Les experts recommandent d’administrer une sédation pour toutes les indications de l’intubation trachéale, excepté chez le patient en arrêt cardiaque qui ne nécessite pas de sédation. Lorsque l’intubation trachéale est présumée diffi cile, il est possible d’effectuer une anesthésie locale réalisée de proche en proche, associée ou non à une sédation légère et titrée par voie générale
L’utilisation de médicaments anesthésiques lors de l’intubation trachéale a pour but de faciliter le geste et d’assurer le confort du patient. Cette sédation doit être rapidement réversible pour restaurer une ventilation effi cace en cas de diffi culté d’intubation. Le risque d’inhalation bronchique doit être minimisé au cours de la procédure et ce d’autant que les patients sont considérés comme ayant un estomac plein.
Les experts recommandent d’utiliser les techniques d’intubation en séquence rapide (ISR) associant un hypnotique d’action rapide (étomidate ou kétamine) et un curare d’action brève (succinylcholine) ........................................................
Lorsque l’intubation trachéale est présumée difficile, le protocole recommandé par les experts pour une intubation vigile est le suivant : - Lidocaïne entre 2 et 5% en pulvérisation de proche en proche - Complément de sédation intraveineuse pour intubation vigile : • midazolam : 1 mg par 1 mg IV • associé ou non à de la morphine : 2 mg par 2 mg IV
Les nouvelles modalités de transfusion mettent en avant le bénéfice de l'apport précoce de plasma. Les contraintes logistiques liées à l'emploi de plasma frais sont réelles. L'emploi de plasma lyophilisé permet de raccourcir ce délai et peut représenter dans certaines conditions d'isolement la seule source disponibles de fractions coagulantes. Le plasma lyophylisé est un vieux monsieur, mais dont la place est fondamentale. Largement utilisé notamment par l'armée française pendant la guerre d'indocchine, le SSA a maintenu sa production jusqu'à ce que l'épidémie de VIH ne survienne. Depuis les années 1980, le SSA a travaillé sans relâche pour sécuriser un produit qui retrouve la place qui lui est due dans la stratégie transfusionnelle du blessé de guerre (1) Il s'agit donc d'une redécouverte avec un emploi effectif en opération dès 1996 (2), plutôt que de révolution. Le document proposé à la lecture fait le point sur cette historique et les développements à venir. La lecture de ce document ne doit pas faire oublier la réflexion de plus en plus présente sur l'emploi en situation d'isolement de l'intérêt de la transfusion de sang total, seule source de plaquettes, associé au recours à des fractions coagulantes comme le fibrinogène et les complexes prothrombiques. Une telle association représente probablement l'avenir de la réanimation hémostatique préhospitalière (3, 4).
Historical dried plasma development Event Selected References
1930s Plasma lyophilization developed in the 1930s.
1940—Large scale production of pooled, lyophilized plasma by both the US and British established for war time use (to meet logistical constraints of whole blood and frozen/liquid plasma).ans les années
1941—Spray dried plasma produced for the Swedish Defense Department. 21 WWII Production 20-22 British produced >500,000 U lyophilized plasma during WWII. US produced >6,000,000 U lyophilized plasma during WWII. US/British distributed world-wide. Sweden produced approximately 17,000 U spray dried plasma for Sweden and Finland.
1945—Hepatitis 23 Hepatitis as a result of plasma transfusion recognized by the end of WWII. Believed that benefits outweighed the risk.
1945-1952—Hepatitis 24 Attempts at pathogen reduction and reducing pool size not successful. Several deaths in clinical studies of ultraviolet irradiated pooled plasma.
—Department of the Army (Circular 73) directed that, because of the risk of serum hepatitis, the higher cost, and the need to use it for the production of specific globulins, plasma would not be used “to support blood volume” unless dextran was not available.
—Serum albumin replaced plasma as primary resuscitative product for US Forces in Korea.
1968—National Research Council Committee on Plasma and Plasma Substitutes recommended that “the use of whole, pooled human plasma be discouraged and even discontinued unless a clear cut case can be made for its unique requirements.”
The French Military Blood Institute produced dried plasma from 1949 to 1984, and provided over 40,000 units to French military forces during the Indochina War. In 1985, production was discontinued due to risk of HIV infection.
Acute Fibrinolysis Shutdown after Injury Occurs Frequently and Increases Mortality: A Multicenter Evaluation of 2,540 Severely Injured Patients
La recommandation n°15 de la RFE Portant sur la réanimation du choc hémorragique stipule qu' il est recommandé d'administrer de l'acide tranexamique dès que possible chez les patients traumatisés à la dose de 1 g en bolus intraveineux en 10 min suivi de 1 g perfusé sur 8 h chez les patients traumatisés. Cette administration ne doit pas être initiée au delà de la 3e heure suivant la survenue d'un traumatisme avec choc hémorragique. Si l'étude CRASH-2 a montré que l'acide tranexamique réduisait significativement la mortalité. De nouvelles données disponibles depuis alimentent la discussion (1). Trois états du système de fibrinolyse peuvent être retrouvés: normal, hyperfibrinolyse, inhibition Les deux derniers sont associés à une surmortalité mais la fréquence des états d'inhibition de l'inhibition ne plaiderait pas pour une administration systématique mais ciblée d'exacyl. En qui nous concerne il faut à nouveau insister sur la précocité de l'administration d'exacyl dans l'heure chez les blessés sévères, pour lesquels le bénéfice en terme de mortalité est le plus grand (2). Une réflexion pour un emploi optimisé est en MARCHE (3, 4)
Fibrinolysis is a physiologic process that maintains microvascular patency by breaking down excessive fibrin clot. Hyperfibrinolysis is associated with a doubling of mortality. Fibrinolysis shutdown, an acute impairment of fibrinolysis, has been recognized as a risk factor for increased mortality. The purpose of this study was to assess the incidence and outcomes of fibrinolysis phenotypes in 2 urban trauma centers.
Injured patients included in the analysis were admitted between 2010 and 2013, were 18 years of age or older, and had an Injury Severity Score (ISS) > 15. Admission fibrinolysis phenotypes were determined by the clot lysis at 30 minutes (LY30): shutdown ≤ 0.8%, physiologic 0.9% to 2.9%, and hyperfibrinolysis ≥ 3%. Logistic regression was used to adjust for age, arrival blood pressure, ISS, mechanism, and facility.
There were 2,540 patients who met inclusion criteria. Median age was 39 years (interquartile range [IQR] 26 to 55 years) and median ISS was 25 (IQR 20 to 33), with a mortality rate of 21%. Fibrinolysis shutdown was the most common phenotype (46%) followed by physiologic (36%) and hyperfibrinolysis (18%). Hyperfibrinolysis was associated with the highest death rate (34%), followed by shutdown (22%), and physiologic (14%, p < 0.001). The risk of mortality remained increased for hyperfibrinolysis (odds ratio [OR] 3.3, 95% CI 2.4 to 4.6, p < 0.0001) and shutdown (OR 1.6, 95% CI 1.3 to 2.1, p = 0.0003) compared with physiologic when adjusting for age, ISS, mechanism, head injury, and blood pressure (area under the receiver operating characteristics curve 0.82, 95% CI 0.80 to 0.84).
Fibrinolysis shutdown is the most common phenotype on admission and is associated with increased mortality. These data provide additional evidence of distinct phenotypes of coagulation impairment and that individualized hemostatic therapy may be required.
Froid et suxaméthonium : une recommandation non fondée
L’Agence nationale de sécurité du médicament et des produits de santé (ANSM) a publié en 2012 une recommandation destinée aux médecins anesthésistes-réanimateurs et urgentistes décrivant les conditions d’utilisation du chlorure de suxaméthonium. .......Cette recommandation faisait suite à une enquête rétrospective de pharmacovigilance sur les réactions allergiques induites par les curares qui mettait en évidence une augmentation des notifications de réactions allergiques attribuées au suxaméthonium........Néanmoins, l’hypothèse émise par l’ANSM ne résiste pas à l’évaluation scientifique. En effet, aucune étude n’a démontré que le suxaméthonium conservé à température ambiante favorise la survenue d’une réaction allergique, ce qui avait déjà été souligné lors de la publication de cette recommandation..........................En revanche, depuis 20 ans, plusieurs équipes européennes et nord-américaines ont confirmé la stabilité des solutions de chlorure de suxaméthonium à température ambiante ou lors de variations extrêmes de température................... La succinylcholine (50 mg/mL) préservée dans l’ampoule est stable pendant deux mois à température ambiante (25°C)  alors que la solution à 20 mg/mL reste stable au moins sept jours après exposition à des variations extrêmes de température (de -6°C à +54°C).......................Par ailleurs, la solution de succinylcholine (20 mg/mL) conservée dans une seringue en plastique est stable trois mois à 25°C et deux mois à 40°C . Enfin, la stabilité de la succinylcholine stockée à bord d’ambulances, respectivement pendant sept mois  et un an , a été évaluée après exposition aux variations climatiques auxquelles ces équipes sont exposées. La succinylcholine (20 mg/mL) est stable pendant environ trois mois quand elle est soumise à des températures moyennes variant de -9°C à +32°C  alors que la solution à 100 mg/mL est stable pendant un peu plus d’un mois quand elle est exposée de -8°C à +36°C. D’autres études ont également confirmé la stabilité de la succinylcholine (10 mg/ml) dans une seringue en plastique pendant sept jours  et pendant au moins cinq mois, quand celle-ci est conservée dans l’ampoule (20 et 50 mg/ml) ..........Plus récemment, la stabilité de la succinylcholine à température ambiante (25°C) a été confirmée par l’ANSM pour qui les résultats obtenus sont « conformes aux spécifications à péremption décrites dans le dossier d’AMM................Ce rapport de conclure que « les données relatives à la qualité ne semblent donc pas être en mesure d’expliquer l’augmentation des réactions anaphylactiques sur la période étudiée............Le turn-over prévisible de l’utilisation du suxaméthonium stocké à température ambiante rend ainsi son utilisation possible par les équipes de Samu. En effet, l’éventuelle morbidité – voire mortalité – induite par cette recommandation ne peut être occultée. Nombreux sont les patients qui devant bénéficier d’une induction à séquence rapide, ont été intubés sans curare par les équipes qui ne disposaient pas d’un réfrigérateur à bord alors que l’appréciation de la balance risque/ bénéfice penche en faveur de l’utilisation du suxaméthonium dans cette situation clinique
Gammon DL, et al (2008) Alteration in prehospital drug concentration after thermal exposure. Am J Emerg Med 26:566–73.
Agence Nationale de Sécurité du Médicament et des Produits de Santé (2013) Enquête officielle de pharmacovigilance relative aux réactions anaphylactiques liées à l’utilisation des curares. 21 mai 2013.
Thrombosomes: a platelet-derived hemostatic agent for control of noncompressible hemorrhage
Un thrombosome est en quelque sorte une plaquette lyophilisée dans laquelle l'eau est remplacée par un sucre particulier: le trehalose. Ré exposé à une atmosphère humide, il se réhydrate pour retrouver toutes ses propriétés. Cela ne semble pas être une simple théorie car il initierait une génération de thrombine permettant la formation d'un caillot de manière satisfaisante. Des thrombosmes, du fibrinogène et du PLyo, on peut espérer !
BACKGROUND: Uncontrolled hemorrhage is responsible for ~80% of the potentially survivable deaths in combat and over 40% of early mortality in the under 65 age group in the United States. Providing an easily used infusible hemostatic agent to first responders could significantly reduce these fatalities. We report on an infusible lyophilized platelet-derived hemostatic agent stabilized with trehalose and polysucrose prior to and during lyophilization.
STUDY DESIGN AND METHODS: Characterization included determining the particle population size range, surface marker expression GPIb, GPIIbIIIa, and Annexin V binding. Function was assessed by aggregation, thromboelastography, and thrombin generation. Pharmacokinetics, biodistribution, and immunogenicity established using Indium111 labeled Thrombosomes in healthy New Zealand white rabbits (NZWRs), efficacy in thrombocytopenic NZWR, and safety in NZWRs, canines, and nonhuman primates.
RESULTS: Thrombosomes retained GPIIbIIIa expression (98.71% 0.18 of the rehydrated particles), a reduced expression of GPIb (47.77% 6.65), and Annexin V binding (86.05% 2.65). Aggregation to all agonists except thrombin in buffer (78.15% 2.5) was <50%. Thrombin generation and thromboelastography results demonstrated a concentration gradient that was consistent from lot to lot. There were no observed adverse events in any safety study and blood loss was reduced by >80% in the thrombocytopenic ear bleed model.
CONCLUSION: Our in vitro characterization studies in conjunction with preclinical animal safety and efficacy studies demonstrated lot consistency in manufacturing, maintenance of hemostatic functions of Thrombosomes, safety at high dose concentrations, and the potential to provide an effective hemostatic agent at the site of injury.
A prospective, randomized trial of intravenous hydroxocobalamin versus whole blood transfusion compared to no treatment for class III hemorrhagic shock resuscitation in a prehospital swine model
La prise en charge des hémorragies traumatiques en préhospitalier est basée sur la miseen oeuvre des moyens d'arrêts de ces dernières et l'initiation d'une stratégie raisonnée de remplissage vasculaire et de transfusion. L'apport équilibrée de CGR, de plasma,de fractions coagulantes et même de plaquettes fait partie de cette démarche de damage control resuscitation de même que l'apport d'acide tranexaminique pour s'opposer à une fibrinolyse précoce souvent présente. D'autres axes de recherches sont proposés. AInsi l'hydroxocobalamine, connue en tant qu'antidote de l'acide cynahydrique permettrait sur des cochons auxquels on aurait soustrait 20 ml/kg de sang de préserver la pression artérielle et la lactatémie de manière identique à celle obtenue par l'apport de sang total.
The objective was to compare systolic blood pressure (sBP) over time in swine that have had 30% of their blood volume removed (Class III shock) and treated with intravenous (IV) whole blood or IV hydroxocobalamin, compared to nontreated control animals.
Thirty swine (45 to 55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Animals were hemorrhaged a total of 20 mL/kg over a 20-minute period. Five minutes after hemorrhage, animals were randomly assigned to receive 150 mg/kg IV hydroxocobalamin solubilized in 180 mL of saline, 500 mL of whole blood, or no treatment. Animals were monitored for 60 minutes thereafter. A sample size of 10 animals per group was determined based on a power of 80% and an alpha of 0.05 to detect an effect size of at least a 0.25 difference (>1 standard deviation) in mean sBP between groups. sBP values were analyzed using repeated-measures analysis of variance (RANOVA). Secondary outcome data were analyzed using repeated-measures multivariate analysis of variance (RMANOVA).
There were no significant differences between hemodynamic parameters of IV hydroxocobalamin versus whole blood versus control group at baseline (MANOVA; Wilks' lambda; p = 0.868) or immediately posthemorrhage (mean sBP = 47 mm Hg vs. 41 mm Hg vs. 37 mm Hg; mean arterial pressure = 39 mm Hg vs. 28 mm Hg vs. 34 mm Hg; mean serum lactate = 1.2 mmol/L vs. 1.4 mmol/L vs. 1.4 mmol/L; MANOVA; Wilks' lambda; p = 0.348). The outcome RANOVA model detected a significant difference by time between groups (p < 0.001). Specifically, 10 minutes after treatment, treated animals showed a significant increase in mean sBP compared to nontreated animals (mean sBP = 76.3 mm Hg vs. 85.7 mm Hg vs. 51.1 mm Hg; p < 0.001). RMANOVA modeling of the secondary data detected a significant difference in mean arterial pressure, heart rate, and serum lactate (p < 0.001). Similar to sBP, 10 minutes after treatment, treated animals showed a significant increase in mean arterial pressure compared to nontreated animals (mean arterial pressure = 67.7 mm Hg vs. 61.4 mm Hg vs. 40.5 mm Hg). By 10 minutes, mean heart rate was significantly slower in treated animals compared to nontreated animals (mean heart rate = 97.3 beats/min vs. 95.2 beats/min vs. 129.5 beats/min; p < 0.05). Serum lactate, an early predictor of shock, continued to rise in the control group, whereas it did not in treated animals. Thirty minutes after treatment, serum lactate values of treated animals were significantly lower compared to nontreated animals (p < 0.05). This trend continued throughout the 60-minute observation period such that 60-minute values for lactate were 1.4 mmol/L versus 1.1 mmol/L versus 3.8 mmol/L. IV hydroxocobalamin produced a statistically significant increase in systemic vascular resistance compared to control, but not whole blood, with a concomitant decrease in cardiac output.
Intravenous hydroxocobalamin was more effective than no treatment and as effective as whole blood transfusion, in reversing hypotension and inhibiting rises in serum lactate in this prehospital, controlled, Class III swine hemorrhage model.
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
La reconnaissance et la mise en place de la meilleure stratégie thérapeutique du choc hémorragique traumatique sont des enjeux fondamentaux qui se posent aux équipes de réanimation préhospitalières et hospitalières. L'application du concepts du damage control resuscitation (1) vise par la mise en place d'un stratégie raisonnée d'arrêt des hémorragies (2), d'un remplissage vasculaire mesuré (3) et d'une politique transfusionnelle spécifique (4). Parmi ces mesures, il apparaît important de garantir l'apport équilibré de plasma, de plaquettes et de CGR dans un ration élevé 1/1/1 ou 1/1/2. Deux études se sont attachées à ce point: L'étude PROMMTT et l'étude PROPPR ici présentée. La première confirme le bénéfice d'une telle stratégie avec une moindre mortalité chez les patients bénéficiant de rapport élevé supérieur mais uniquement dans les 6 premières heures. L'étude PROPPR semble confirmer ces données avec une moindre mortalité précoce par hémorragie mais ne réussit pas à confirmer l'intérêt d'un ratio 1/1/1 par rapport à un ratio 1/1/2 sur la mortalité à long terme.
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.
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.
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.
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 < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications.
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.
Is ketamine ready to be used clinically for the treatment of depression ?
A single dose of ketamine produces rapid antidepressant effects, but attaining lasting remission remains a challenge
Il existe un engouement très important pour l'emploi de kétamine pour la prise en charge de la dépression (1,2). Pour autant il ne faut pas oublier les effets secondaires de cette dernière lorsqu'elle est administrée de manière chronique. De nombreuses données issues de l'emploi récréatif de la kétamine mettent en avant de nombreux effets secondaires comme l'hépatotoxicité, les dysfonctions vésicales et, possiblement des troubles cognitifs. Même si aucun effets de ce type n'est retrouvé lors d'emploi encadré médicalement, la prudence reste de mise.
Anesthesiologists Take Lead As Ketamine Clinics Proliferate
A growing number of anesthesiologists are opening private clinics that provide off-label infusions of ketamine to patients suffering from treatment-resistant unipolar and bipolar depression, post-traumatic stress disorder (PTSD), anxiety, suicidality and other disorders. Psychiatrists and other physicians have also recently opened clinics.
The cost per infusion ranges from $400 to $1700, with most clinics charging about $500. Patients pay out-of-pocket since most health insurance plans do not cover the off-label procedure.
Despite the cost, patients seek the treatments after their antidepressants and other therapies prove ineffective. Proponents claim that, when administered as an IV infusion in a subanesthetic dose (typically 0.5 mg/kg body weight) over 40 to 45 minutes, ketamine begins reversing symptoms of depression for two of three patients in less than 24 hours, with effects persisting for a week or more. Nearly three of four patients suffering from suicidality experience an almost immediate reversal in thinking.
“The results are amazing,” said anesthesiologist Glen Z. Brooks, MD, founder and medical director of New York Ketamine Infusions LLC, in New York City, and one of the pioneers in the field. His success rate averages about 65% when measured by standardized mood and function surveys, and is even greater for younger adults, he said. The typical course of treatment is six infusions administered every other day for two weeks followed by “maintenance” or “booster” infusions as needed, typically every six weeks afterward.
“The procedure is very well tolerated. We have seen no complications during or after the 45-minute infusions in now close to 8,000 treatments,” Dr. Brooks told Anesthesiology News. “I have been treating some patients for as long as three years with ongoing remission of their symptoms, so efficacy can be very long term.”
Ketamine Can Work Quickly
Ketamine was synthesized in the early 1960s and approved for human anesthesia a decade later. It has been administered to millions of patients worldwide, and continues to be an anesthetic of choice for pediatric patients who may experience adverse reactions to other agents. It also is used in pain clinics and when changing dressings of severe burn victims.
For treating depression, it only takes two ketamine infusions to determine whether a patient will respond favorably, whereas traditional antidepressants can take four to six weeks and will work about 30% of the time. During the ketamine infusion, patients remain awake or in a twilight state. Dizziness or a sensation of dissociation is common, and generally disappears shortly after the infusion. “We notice a 50% improvement in depression scores within the first three infusions, which take six days,” said anesthesiologist Enrique Abreu, MD, medical director at Portland Ketamine Clinic in Oregon. “Overall, 75% to 80% of patients see improvement in depression, mood and anxiety after six treatments,” he told Anesthesiology News.
Some experts in depression research have called ketamine’s “rapid and robust” antidepressant properties “arguably the most important discovery in half a century” (Science 2012;338:68-72). Others urge caution, citing concerns over long-term side effects and potential for abuse. The latter concern stems from ketamine being an illicit “rave” drug (nicknamed “Special K” or “Vitamin K”) that creates intense, short-term hallucinations, dissociation and psychotomimetic effects. Ketamine also is pharmacologically similar to PCP (phencyclidine), a powerful psychotomimetic drug.
While the World Health Organization has long included ketamine on its model list of essential medicines for anesthesia, the drug also has been placed under national control in more than 60 countries, especially in Asia, where abuse is common. Bladder problems and cognitive declines have been observed in long-term recreational ketamine abusers, but none of these effects has been observed in clinical trials.
The anesthesiologists and psychiatrists who administer ketamine infusions for severe depression report overwhelmingly positive outcomes. New Jersey psychiatrist Steven Levine, MD, decided to explore ketamine after reading reports of clinical studies conducted at the National Institute of Mental Health (NIMH). “The results were unlike anything we had seen before, with positive outcomes emerging within days or weeks,” Dr. Levine said. “Some really sick people were getting significantly better within hours. I couldn’t convince myself to not do it.”
Dr. Levine quizzed several anesthesiologist friends about potential dangers before opening his clinic. “They were totally nonplussed about the low dosage used in the infusion, unconcerned about any potential for bad side effects,” Dr. Levine told Anesthesiology News. “They were used to giving it in much higher doses for anesthesia and even higher doses in burn units when changing dressings.” Dr. Levine opened Ketamine Treatment Centers of Princeton LLC, in New Jersey, in 2011 and has since treated about 500 patients. He plans to open clinics in Baltimore, Florida and Denver in early 2016.
Mechanisms of Action
Typical FDA-approved antidepressants target neurons that inhibit the reuptake of serotonin, norepinephrine and dopamine. Ketamine works more broadly by blocking the N-methyl-D-aspartate (NMDA) receptor, a component of the fast-signaling glutamate system that affects nearly all neurons. Brain scans reveal that ketamine rapidly induces synaptogenesis, repairing damage caused by chronic stress.
Many clinical trials of ketamine for depression have been, and continue to be, conducted at NIMH. A seminal study published in 2006 was a randomized, placebo-controlled, double-blind crossover trial led by Carlos A. Zarate Jr., MD, chief of NIMH’s neurobiology and mood disorders treatment section. In this year-long study, patients receiving ketamine showed significant improvement in depression compared with placebo after 24 hours, with effects remaining “moderate to large” after one week (Arch Gen Psych 2006;63:856-864). “This line of research holds considerable promise for developing new treatments for depression with the potential to alleviate much of the morbidity and mortality associated with the delayed onset of action of traditional antidepressants,” Dr. Zarate and colleagues wrote, citing the need to improve the drug’s long-term effectiveness.
Since then, studies at NIMH and elsewhere have demonstrated ketamine’s efficacy for rapidly diminishing suicidal ideation (Drugs R D 2015;15:37-43), unipolar and bipolar depression (Cochrane Database Syst Rev 2015;23:CD011612; Cochrane Database Syst Rev 2015;29:CD-011611), and for PTSD and other anxiety disorders (JAMA Psychiatry 2014;71:681-688).
The American Psychiatric Association’s Task Force on Novel Biomarkers and Treatments urges caution when it comes to clinical use of ketamine. In a systematic review and meta-analysis of randomized clinical trials of ketamine and other NMDA receptor antagonists (Am J Psych 2015;172:950-966), the task force concluded: “The antidepressant efficacy of ketamine … holds promise for future glutamate-modulating strategies.” However, the “fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.”
When asked to comment on anesthesiologists performing off-label ketamine infusions, the American Society of Anesthesiologists (ASA) provided this statement to Anesthesiology News: “The American Society of Anesthesiologists is committed to promoting the highest standards of care for the patients they serve. This new practice area has been brought to ASA’s attention and will be carefully reviewed.”
According to ketamine advocate Dennis Hartman, at least 60 private clinics in the United States offer off-label infusions, and the number is growing. The former business executive says ketamine infusions rescued him from suicide in 2012, and ongoing treatments have brought his depression into remission. As founder and CEO of the nonprofit Ketamine Advocacy Network, Mr. Hartman now works full time with practitioners and patients to help gain legitimacy for the field. His website lists 18 ketamine practitioners in the United States, most of them anesthesiologists, with a smaller number of psychiatrists and neurologists, plus one emergency medicine physician and one family physician.
“There are others that we have not vetted and others that we’ve purposefully chosen not to include,” Mr. Hartman explained, most often because they charge too much money or require expensive additional tests or medical procedures for which clinical evidence is lacking. “There are still others who offer the treatment but want to be under the radar,” Mr. Hartman told Anesthesiology News.
Anesthesiologists generally believe they are uniquely qualified to administer ketamine infusions because of their expertise with anesthetics. “I want this to stay as something for anesthesiologists,” said Steven Mandel, MD, founder of Ketamine Clinics of Los Angeles. “Nevertheless, I don’t want there to be a conflict between anesthesiology and psychiatry, because ketamine definitely needs an anesthesiologist to administer it and definitely needs a psychiatrist or psychologist involved because they know about psychopathology,” he said. But ketamine does take “considerable vigilance and finesse” to infuse properly, he added, even for those with years of operating room experience. “This is different because the ‘sweet spot’ for treatment is this side of unconsciousness in the moderate- to deep-sedation range,” Dr. Mandel explained.
Many psychiatrists, on the other hand, believe they are best suited to oversee ketamine therapy because of their expertise in treating patients with depression, PTSD and other conditions. In those ketamine clinics run by psychiatrists, the IV insertion is generally performed by a nurse, not an anesthesiologist, and the infusion is overseen by a psychiatrist and a nurse. Clinics led by anesthesiologists generally do not employ a staff psychiatrist but coordinate with the patients’ mental health practitioners.
Virtually all practitioners—anesthesiologists and psychiatrists alike—recognize the importance of cooperation. Nearly all ketamine clinics require a referral from a psychiatrist or other mental health professional, with few accepting walk-ins. “Three years ago, the relationships [between psychiatrists and anesthesiologists] were difficult, to say the least,” said anesthesiologist Mark Murphy, MD, who established Ketamine Wellness Centers in Phoenix, in 2013. “However, the momentum is shifting. Now we regularly receive referrals from mental health professionals.”
Those patients who do best tend to have psychiatrists or therapists supporting them throughout the treatment course and are engaged in a team approach, said anesthesiologist Isabel Legarda, MD, medical director at Boston MindCare LLC. “I believe anesthesiologists and psychiatrists must work collaboratively when it comes to ketamine infusion therapy; anything less shortchanges patients,” she said.
Because ketamine is generic, pharmaceutical companies have no financial incentive to sponsor the costly clinical trials needed to win FDA approval, generally a prerequisite for insurance coverage. Recognizing this, there is a movement in the ketamine community to gather and publish retrospective chart data and promulgate best practice guidelines. “There’s never going to be an FDA label for ketamine to treat depression,” said Dr. Levine. “But once more guidelines and protocols for using ketamine in clinical practice are published, it is very likely that insurers will consider covering it,” he predicted.
At least two drug companies are developing new ketamine variants that might be easier to administer and which lack some of the generic’s less-favorable short-term side effects, such as dissociation, and which insurers may be willing to cover. Johnson & Johnson’s subsidiary Janssen Pharmaceuticals is conducting late-stage clinical trials of esketamine, a variant that can be administered via a nasal spray. The FDA granted the drug “breakthrough” status in 2013, which streamlines the regulatory approval process. Allergan’s subsidiary Naurex Inc. is testing GLYX-13, an IV NMDA receptor variant that reportedly is effective in about half of patients in 24 hours, but without ketamine’s dissociative side effects. NeuroRx Inc. is testing a drug, Cyclurad, whose ingredients include D-cycloserine, an NMDA receptor modulator.
Dr. Levine and other physicians caution colleagues against starting a ketamine clinic to make quick money. “If someone is thinking of doing this part time to pad their income, there could be bad outcomes because these patients are very vulnerable,” Dr. Levine said. “This is an area that could use some regulation and standardization so that patients don’t get hurt, and what is a very important treatment becomes lost.”
Most ketamine practitioners say their motivation stems from having had patients or family members who were treatment resistant and, in some cases, even committed suicide. For them, money is secondary to the satisfaction they gain. “For me, this has been a much more demanding and professionally rewarding practice than being in a hospital operating room,” said Dr. Brooks. “It requires a special dedication and availability.”
Trauma-induced coagulopathy: impact of the early coagulation support protocol on blood product consumption, mortality and costs
Le damage control resuscitation fait largement appel à l'apport de plasma, concentrés de globules rouges et de plaquettes dans un rapport de 1/1/1 (1). Malgré la relative correction de la coagulopathie la survie à long terme ne semble pas être améliorée (2). Aussi certains proposent d'avoir plutôt recours à l'administration précoce de fibrinogène plutôt que l'administration de plasma. Le travail suivant qui propose l'apport précoce de 2g de fibrinogène est en faveur d'une telle démarche.
Hemorrhage is the principal cause of death in the first few hours following severe injury. Coagulopathy is a frequent complication of critical bleeding. A network of Italian trauma centers recently developed a protocol to prevent and treat trauma-induced coagulopathy. A pre-post cohort multicenter study was conducted to assess the impact of the early coagulation support (ECS) protocol on blood products consumption,mortality and treatment costs.
We prospectively collected data from all severely injured patients (Injury Severity Score (ISS) >15) admitted to two trauma centers in 2013 and compared these findings with the data for 2011. Patients transfused with at least 3 units of packed red blood cells (PRBCs) within 24 hours of an accident were included in the study. In 2011, patients with significant hemorrhaging were treated with early administration of plasma with the aim of achieving a high (≥1:2) plasma-to-PRBC ratio. In 2013, the ECS protocol was the treatment strategy. Outcome data, blood product consumption and treatment costs were compared between the two periods.
The two groups were well matched for demographics, injury severity (ISS: 32.9 in 2011 versus 33.6 in 2013) and clinical and laboratory data on admission. In 2013, a 40% overall reduction in PRBCs was observed, together with a 65% reduction in plasma and a 52% reduction in platelets. Patients in the ECS group received fewer blood products: 6.51 units of PRBCs versus 8.14 units. Plasma transfusions decreased from 8.98 units to 4.21 units (P <0.05), and platelets fell from 4.14 units to 2.53 units (P <0.05). Mortality in 2013 was 13.5% versus 20% in 2011 (13 versus 26 hospital deaths, respectively) (nonsignificant). When costs for blood components, factors and point-of-care tests were compared, a €76,340 saving in 2013 versus 2011 (23%) was recorded.
The introduction of the ECS protocol in two Italian trauma centers was associated with a marked reduction in blood product consumption, reaching statistical significance for plasma and platelets, and with a non-significant trend toward a reduction in early and 28-daymortality. The overall costs for transfusion and coagulation support (including point-of-care tests) decreased by 23% between 2011 and 2013.
Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder. A Randomized Clinical Trial
Importance Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition.
Objective To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD.
Design, Setting, and Participants Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements.
Interventions Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg).
Main Outcomes and Measures The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale–Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression–Severity and –Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.
Results Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale–Revised score, 12.7 [95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms.
Conclusions and Relevance This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition.