Hilary P. Grocott

Seizures following cardiac surgery: the impact of tranexamic acid and other risk factors

BackgroundSeizures after cardiac surgery are a serious complication. The antifibrinolytic agent tranexamic acid (TA), which has known proconvulsant properties, may be associated with postoperative seizures. We sought to determine the association between TA and other risk factors for seizures after cardiac surgery.Methods and resultsWe analyzed a database of consecutive cardiac surgery patients (April 2003 to December 2009) using multivariable logistic regression analysis to assess for seizure risk factors. Seizures occurred in 56 of 5,958 patients (0.94%). TA use was associated with an increased risk of seizures (odds ratio 7.4, 95% confidence interval 2.8–19.3; Pxa0<xa00.001). Multivariable logistic regression analysis revealed that the following factors were significantly associated with seizures: TA exposure; Acute Physiology, Age, and Chronic Health Evaluation (APACHE) II scorexa0>xa020; preoperative cardiac arrest; preoperative neurological disease; open chamber surgery; cardiopulmonary bypass timexa0>xa0150xa0min; and previous cardiac surgery. Seizures occurred at a median of 5.3 hr (interquartile range 2.4–15.1 hr) after the end of surgery. In all, 58.1% were grand mal, 14.5% were associated with a stroke, and 58.1% recurred in hospital. Altogether, 48.3% of the patients were able to discontinue anticonvulsant medications prior to discharge. Compared to the non-seizure group, seizure patients had an increased rate of postoperative neurological complications, defined as delirium and/or stroke (3.2% vs 19.6%, Pxa0<xa00.001), increased intensive care unit (ICU) length of stay (1.0 vs 4.7xa0days, Pxa0<xa00.001), and increased ICU mortality (1.4 % vs 9.7 %, Pxa0=xa00.001).ConclusionsOur data suggest that multiple risk factors, including TA, are associated with seizures after cardiac surgery. Thus, the TA dose may be a readily modifiable risk factor for postoperative seizures.RésuméContexteLa survenue de crises convulsives après chirurgie cardiaque peut être une complication grave. L’acide tranexamique (AT), un antifibrinolytique aux propriétés proconvulsivantes connues, peut être associé aux crises convulsives postopératoires. Nous avons cherché à déterminer s’il existait une association entre l’AT et les autres facteurs de risque de convulsions après chirurgie cardiaque.Méthodes et résultatsNous avons analysé une base de données de patients consécutifs ayant subi une chirurgie cardiaque (d’avril 2003 à décembre 2009) au moyen d’une analyse de régression logistique multifactorielle pour évaluer les facteurs de risque de crise convulsive. Des crises convulsives sont survenues chez 56 des 5958 patients (0,94xa0%). L’utilisation d’AT a été associée à une augmentation du risque de convulsions (rapport de cotes: 7,4; intervalle de confiance à 95xa0%: 2,8–19,3; Pxa0<xa00,001). L’analyse de régression logistique multifactorielle a révélé que les facteurs suivants étaient associés de façon significative aux crises convulsives: exposition à l’AT; score APACHE II (physiologie aiguë, âge et évaluation de la santé chronique ou Acute Physiology, Age, and Chronic Health Evaluation)xa0>xa020; arrêt cardiaque préopératoire; maladie du système nerveux avant l’intervention; chirurgie à cœur ouvert; durée de circulation extracorporellexa0>xa0150xa0min et antécédent de chirurgie cardiaque. Les crises convulsives sont survenues dans un délai médian de 5,3xa0h (intervalle interquartile: 2,4–15,1xa0h) après la fin de l’intervention chirurgicale. Parmi l’ensemble des cas, 58,1xa0% des crises ont été généralisées (grand mal), 14,5xa0% ont été associées à un accident vasculaire cérébral (AVC) et 58,1xa0% ont récidivé pendant l’hôpitalisation. Globalement, on a pu cesser le traitement anticonvulsivant avant le congé de l’hôpital chez 48,3xa0% des patients. Comparé au groupe sans crises convulsives, les patients ayant présenté des convulsions ont eu davantage de complications neurologiques postopératoires: delirium et/ou AVC (3,2xa0% contre 19,6xa0%, Pxa0<xa00,001), durée de séjour prolongée aux soins intensifs (1,0 contre 4,7 jours, Pxa0<xa00,001), et augmentation de la mortalité aux soins intensifs (1,4 % contre 9,7 %, Pxa0=xa00,001).ConclusionsNos données suggèrent que de multiples facteurs de risque, dont l’AT, sont associés aux crises convulsives après chirurgie cardiaque. La dose d’AT pourrait donc être un facteur de risque de convulsions facilement modifiable.

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery

BACKGROUND The effect of a restrictive versus liberal red‐cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS In this multicenter, open‐label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red‐cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red‐cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non‐ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red‐cell transfusion and other clinical outcomes. RESULTS The primary outcome occurred in 11.4% of the patients in the restrictive‐threshold group, as compared with 12.5% of those in the liberal‐threshold group (absolute risk difference, ‐1.11 percentage points; 95% confidence interval [CI], ‐2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive‐threshold group and 3.6% in the liberal‐threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red‐cell transfusion occurred in 52.3% of the patients in the restrictive‐threshold group, as compared with 72.6% of those in the liberal‐threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between‐group differences with regard to the other secondary outcomes. CONCLUSIONS In patients undergoing cardiac surgery who were at moderate‐to‐high risk for death, a restrictive strategy regarding red‐cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898.)

Interrelationship of preoperative anemia, intraoperative anemia, and red blood cell transfusion as potentially modifiable risk factors for acute kidney injury in cardiac surgery: a historical multicentre cohort study

PurposeAcute kidney injury (AKI) is a potentially serious complication of cardiac surgery. Anemia and red blood cell (RBC) transfusion have individually been identified as potentially modifiable risk factors, but their interrelationship with AKI has not been clearly defined. The purpose of this study was to explore the interrelationship of preoperative anemia, intraoperative anemia, and RBC transfusion on the day of surgery with AKI in cardiac surgery.MethodsThis historical cohort study included 16 hospitals, each contributing data on approximately 100 consecutive patients who underwent cardiac surgery with cardiopulmonary bypass. Acute kidney injury was defined as a >xa050% increase in creatinine levels during the first postoperative week. Multivariable regression was used to identify the interrelationship between preoperative anemia (hemoglobinxa0<xa0130xa0g·L−1 in males andxa0<xa0120xa0g·L−1 in females), intraoperative anemia (hemoglobinxa0<xa080xa0g·L−1 during cardiopulmonary bypass), RBC transfusion on the day of surgery, and their interaction terms, after adjusting for site and baseline AKI risk.ResultsOf the 1,444 patients included in the study, 541 (37%) had preoperative anemia, 501 (35%) developed intraoperative anemia, 619 (43%) received RBC transfusions, and 238 (16%) developed AKI. After risk-adjustment, an individual with the combination of these three risk factors had a 2.6-fold (95% confidence interval 2.0 to 3.3) increase in the relative risk of AKI over an individual with none of these risk factors.ConclusionsPreoperative anemia, intraoperative anemia, and RBC transfusion on the day of surgery are interrelated risk factors for AKI after cardiac surgery. Targeting these risk factors may reduce the burden of AKI.RésuméObjectifLa lésion rénale aiguë (LRA) est une complication potentiellement grave de la chirurgie cardiaque. L’anémie et la transfusion de globules rouges ont individuellement été identifiées comme étant des facteurs de risque potentiellement modifiables, mais la relation entre ces facteurs et la LRA n’a pas été clairement établie. Le but de cette étude était d’explorer la relation entre l’anémie préopératoire, l’anémie peropératoire et la transfusion de globules rouges le jour de l’intervention avec la LRA en chirurgie cardiaque.MéthodesCette étude de cohorte historique a inclus 16xa0hôpitaux, chacun procurant les données d’environ 100xa0patients consécutifs ayant subi une chirurgie cardiaque avec circulation extracorporelle. La lésion rénale aiguë a été définie par une augmentation du taux de créatinine >xa050xa0% au cours de la première semaine postopératoire. Une analyse en régression multifactorielle a servi à identifier les rapports entre l’anémie préopératoire (hémoglobinexa0<xa0130xa0g·L−1 chez l’homme etxa0<xa0120xa0g·L−1 chez la femme), l’anémie peropératoire (hémoglobinexa0<xa080xa0g·L−1 pendant la circulation extracorporelle), la transfusion de globules rouges le jour de la chirurgie et leurs interactions, après ajustement pour le site et le risque de base de la LRA.RésultatsSur les 1xa0444 patients inclus dans l’étude, 541 (37xa0%) avaient une anémie préopératoire, 501 (35xa0%) ont développé une anémie peropératoire, 619 (43xa0%) ont reçu des transfusions de globules rouges et 238 (16xa0%) ont développé une LRA. Après ajustement pour le risque, la combinaison de ces trois facteurs de risque chez un même individu était associée à une augmentation du risque relatif de la LRA par un facteurxa0de 2,6 (intervalle de confiance à 95xa0%: 2,0 à 3,3) par rapport à un individu n’ayant aucun de ces facteurs de risque.ConclusionsL’anémie préopératoire, l’anémie peropératoire et la transfusion de globules rouges le jour de la chirurgie sont des facteurs de risque inter relié de la LRA après chirurgie cardiaque. La morbidité de la LRA pourrait possiblement être réduite en ciblant ces facteurs de risque.

Effect of intensive care unit environment on in-hospital delirium after cardiac surgery

OBJECTIVESnThe etiology of postcardiac surgery delirium is complex. Our primary objective was to determine the effect of the postoperative environment on the prevalence of delirium by examining the in-hospital delirium rates in 2 postoperative intensive care units with differing physical infrastructure. We further sought to identify other risk factors associated with in-hospital delirium.nnnMETHODSnThe rates of postoperative delirium were retrospectively examined in consecutive cardiac surgery patients during 2 separate 6-month periods. Environment 1 was characterized by a lack of physical barriers between bed spaces and was windowless, and environment 2 consisted of private rooms with physical barriers for each patient and with wall-to-wall exterior windows. Univariate and multivariate analyses to determine the risk factors associated with in-hospital delirium, including the effect of environment, were undertaken.nnnRESULTSnOf the 1010 patients studied, 148 (14.7%) experienced in-hospital delirium after cardiac surgery. The prevalence of delirium was not significantly different between environments 1 and 2 (16.1% vs 13.5%; Pxa0=xa0.25). However, in patients younger than 65 years, the proportion of intensive care unit days on which delirium occurred was greater in environment 1 than in environment 2 (5.4% vs 1.7%; Pxa0=xa0.006). Postoperative stroke or transient ischemic attack, mechanical ventilation longer than 24 hours, age 65 years or older, concomitant coronary artery bypass grafting and valve surgery, prehospital admission benzodiazepine use, a requirement for any postoperative blood product transfusion, and postoperative renal insufficiency were identified as risk factors.nnnCONCLUSIONSnThe intensive care unit environment did not have a significant effect on the overall prevalence of delirium. However, that does not preclude the possibility that the intensive care unit environment might interact with other factors, such as age, in a complex manner. Attempts to reduce delirium by adjusting the intensive care unit environment alone will likely not be sufficient, and instead will require a more comprehensive multimodal approach.

Protocol for the PREHAB study—Pre-operative Rehabilitation for reduction of Hospitalization After coronary Bypass and valvular surgery: a randomised controlled trial

Introduction Frailty is a geriatric syndrome characterised by reductions in muscle mass, strength, endurance and activity level. The frailty syndrome, prevalent in 25–50% of patients undergoing cardiac surgery, is associated with increased rates of mortality and major morbidity as well as function decline postoperatively. This trial will compare a preoperative, interdisciplinary exercise and health promotion intervention to current standard of care (StanC) for elective coronary artery bypass and valvular surgery patients for the purpose of determining if the intervention improves 3-month and 12-month clinical outcomes among a population of frail patients waiting for elective cardiac surgery. Methods and analysis This is a multicentre, randomised, open end point, controlled trial using assessor blinding and intent-to-treat analysis. Two-hundred and forty-four elective cardiac surgical patients will be recruited and randomised to receive either StanC or StanC plus an 8-week exercise and education intervention at a certified medical fitness facility. Patients will attend two weekly sessions and aerobic exercise will be prescribed at 40–60% of heart rate reserve. Data collection will occur at baseline, 1–2u2005weeks preoperatively, and at 3 and 12u2005months postoperatively. The primary outcome of the trial will be the proportion of patients requiring a hospital length of stay greater than 7u2005days. Potential impact of study The healthcare team is faced with an increasingly complex older adult patient population. As such, this trial aims to provide novel evidence supporting a health intervention to ensure that frail, older adult patients thrive after undergoing cardiac surgery. Ethics and dissemination Trial results will be published in peer-reviewed journals, and presented at national and international scientific meetings. The University of Manitoba Health Research Ethics Board has approved the study protocol V.1.3, dated 11 August 2014 (H2014:208). Trial registration number The trial has been registered on ClinicalTrials.gov, a registry and results database of privately and publicly funded clinical studies (NCT02219815).

A phase 2 prospective, randomized, double-blind trial comparing the effects of tranexamic acid with ecallantide on blood loss from high-risk cardiac surgery with cardiopulmonary bypass (CONSERV-2 Trial)

OBJECTIVEnEcallantide is a recombinant peptide in the same class as aprotinin that inhibits plasma kallikrein, a major component of the contact coagulation and inflammatory cascades. Therefore, ecallantide was expected to reduce blood loss associated with cardiac surgery requiring cardiopulmonary bypass.nnnMETHODSnThis prospective multinational, randomized, double-blind trial enrolled patients undergoing cardiac surgery using cardiopulmonary bypass for procedures associated with a high risk of bleeding. Patients were randomly assigned to ecallantide (n = 109) or tranexamic acid (high dose, n = 24; low dose, n = 85). Efficacy was assessed from the volume of packed red blood cells administered within the first 12 hours after surgery.nnnRESULTSnThe study was terminated early after the independent data safety and monitoring board observed a statistically significantly higher 30-day mortality in the ecallantide group (12%) than in the tranexamic acid groups (4%, P = .041). Patients receiving ecallantide received more packed red blood cells within 12 hours of surgery than tranexamic acid-treated patients: median = 900 mL (95% confidence interval, 600-1070) versus 300 mL (95% confidence interval, 0-523) (P < .001). Similar differences were seen at 24 hours and at discharge. Patients treated with the higher tranexamic acid dose received less packed red blood cells, 0 mL (95% confidence interval, 280-600), than the group treated with the lower dose, 400 mL (95% confidence interval, 0-400) (P = .008). No deaths occurred in the higher dose tranexamic acid group.nnnCONCLUSIONSnEcallantide was less effective at reducing perioperative blood loss than tranexamic acid. High-dose tranexamic acid was more effective than the low dose in reducing blood loss.

A novel survival model of cardioplegic arrest and cardiopulmonary bypass in rats: a methodology paper

BackgroundGiven the growing population of cardiac surgery patients with impaired preoperative cardiac function and rapidly expanding surgical techniques, continued efforts to improve myocardial protection strategies are warranted. Prior research is mostly limited to either large animal models or ex vivo preparations. We developed a new in vivo survival model that combines administration of antegrade cardioplegia with endoaortic crossclamping during cardiopulmonary bypass (CPB) in the rat.MethodsSprague-Dawley rats were cannulated for CPB (n = 10). With ultrasound guidance, a 3.5 mm balloon angioplasty catheter was positioned via the right common carotid artery with its tip proximal to the aortic valve. To initiate cardioplegic arrest, the balloon was inflated and cardioplegia solution injected. After 30 min of cardioplegic arrest, the balloon was deflated, ventilation resumed, and rats were weaned from CPB and recovered. To rule out any evidence of cerebral ischemia due to right carotid artery ligation, animals were neurologically tested on postoperative day 14, and their brains histologically assessed.ResultsThirty minutes of cardioplegic arrest was successfully established in all animals. Functional assessment revealed no neurologic deficits, and histology demonstrated no gross neuronal damage.ConclusionThis novel small animal CPB model with cardioplegic arrest allows for both the study of myocardial ischemia-reperfusion injury as well as new cardioprotective strategies. Major advantages of this model include its overall feasibility and cost effectiveness. In future experiments long-term echocardiographic outcomes as well as enzymatic, genetic, and histologic characterization of myocardial injury can be assessed. In the field of myocardial protection, rodent models will be an important avenue of research.

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial

Introduction Postoperative delirium is one of the most common complications of major surgery, affecting 10–70% of surgical patients 60u2005years and older. Delirium is an acute change in cognition that manifests as poor attention and illogical thinking and is associated with longer intensive care unit (ICU) and hospital stay, long-lasting cognitive deterioration and increased mortality. Ketamine has been used as an anaesthetic drug for over 50u2005years and has an established safety record. Recent research suggests that, in addition to preventing acute postoperative pain, a subanaesthetic dose of intraoperative ketamine could decrease the incidence of postoperative delirium as well as other neurological and psychiatric outcomes. However, these proposed benefits of ketamine have not been tested in a large clinical trial. Methods The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study is an international, multicentre, randomised controlled trial. 600 cardiac and major non-cardiac surgery patients will be randomised to receive ketamine (0.5 or 1u2005mg/kg) or placebo following anaesthetic induction and prior to surgical incision. For the primary outcome, blinded observers will assess delirium on the day of surgery (postoperative day 0) and twice daily from postoperative days 1–3 using the Confusion Assessment Method or the Confusion Assessment Method for the ICU. For the secondary outcomes, blinded observers will estimate pain using the Behavioral Pain Scale or the Behavioral Pain Scale for Non-Intubated Patients and patient self-report. Ethics and dissemination The PODCAST trial has been approved by the ethics boards of five participating institutions; approval is ongoing at other sites. Recruitment began in February 2014 and will continue until the end of 2016. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement and popular media. Registration details The study is registered at clinicaltrials.gov, NCT01690988 (last updated March 2014). The PODCAST trial is being conducted under the auspices of the Neurological Outcomes Network for Surgery (NEURONS). Trial registration number NCT01690988 (last updated December 2013).

Preoperative stroke and outcomes after coronary artery bypass graft surgery.

Background:Data are lacking on the optimal scheduling of coronary artery bypass grafting (CABG) surgery after stroke. The authors investigated the preoperative predictors of adverse outcomes in patients undergoing CABG, with a focus on the importance of the time interval between prior stroke and CABG. Methods:The Hospital Episode Statistics database (April 2006–March 2010) was analyzed for elective admissions for CABG. Independent preoperative patient factors influencing length of stay, postoperative stroke, and mortality, were identified by logistic regression and presented as adjusted odds ratios (OR). Results:In all, 62,104 patients underwent CABG (1.8% mortality). Prior stroke influenced mortality (OR 2.20 [95% CI 1.47–3.29]), postoperative stroke (OR 1.99 [1.39–2.85]), and prolonged length of stay (OR 1.31 [1.11–1.56]). The time interval between stroke and CABG did not influence mortality or prolonged length of stay. However, a longer time interval between stroke and CABG surgery was associated with a small increase in risk of postoperative stroke (OR per month elapsed 1.02 [1.00–1.04]; P = 0.047). An interaction was evident between prior stroke and myocardial infarction for death (OR 5.50 [2.84–10.8], indicating the importance of the combination of comorbidities. Prominent effects on mortality were also exerted by liver disease (OR 20.8 [15.18–28.51]) and renal failure (OR 4.59 [3.85–5.46]). Conclusions:The authors found no evidence that more recent preoperative stroke predisposed patients undergoing CABG surgery to suffer postoperative stroke, death, or prolonged length of stay. The combination of prior stroke and myocardial infarction substantially increased perioperative risk.

Avoid hypotension and hypoxia: an old anesthetic adage with renewed relevance from cerebral oximetry monitoring.

In this freestanding editorial, issues are discussed regarding advancements in patient monitoring modalities and how they are poised to continue the evolution of perioperative management. Innovations in cerebral oximetry technologies using near infrared spectroscopy (NIRS) is utilized may allow us to reconsider how we define and manage both hypotension and hypoxemia. With the exception of cardiac anesthesia where cerebral oximetry had early (though arguably still sporadic) clinical adoption, its dispersion into other perioperative disciplines has been somewhat limited. However, the information this technology provides could significantly alter how we manage many physiologic perturbations seen during anesthesia. As a corollary to the scrutiny directed at pulse oximetry when it first came into clinical practice, cerebral oximetry is on the precipice of an increasingly steeper adoption curve which demands a similar evaluation of its uses and potential efficacy. The purpose of this editorial is to discuss how the use of NIRS cerebral oximetry may require clinicians to re-examine their understanding of perioperative physiologic management, particularly that related to blood pressure and oxygenation. In days gone by, the phrase, ‘‘avoid hypotension and hypoxia’’, was a remark appearing frequently in the preoperative medical consultations requested by surgeons for seemingly higher-risk patients. This cautionary statement seemed so obvious that many anesthesiologists caring for these patients viewed it as downright insulting. Indeed, the consequent seething criticism of our medical colleagues was frequent fodder for breakroom chatter. No one could argue that this suggestion was in any way erroneous, yet avoiding these two clinical situations was seen as so obvious and basic a tenet that even the most junior anesthetic trainee could be counted on to avoid these situations – or, at the very least, to identify them and take counteractive measures. However, in the ensuing decades, a time during which technologic advances have reassured us – perhaps falsely – that we are detecting these occurrences accurately and preventing them as much as possible, it is increasingly becoming apparent that our confidence in doing so may be misplaced. Indeed, to avoid these situations assumes our competence both to detect them and to intervene accordingly. However, detection is, in part, critically dependent upon how hypotension and hypoxia are defined. For example, hypotension should be determined according to the patient’s baseline blood pressure status and, as such, should be individualized. Instead, it is placed too often in the context of the somewhat arbitrarily defined normal limits of autoregulation-dependent tissue perfusion. The cerebral autoregulatory curve outlines the relationship between blood pressure and cerebral blood flow (CBF). The pressure independent central plateau (though even under normal conditions it has a slightly positive slope) is bordered by pressure dependent steeply sloped regions at both low and high pressure thresholds (i.e., knees of the curve). A number of pathologic conditions and perioperative situations encountered relatively routinely (e.g., hypercarbia or volatile anesthesia levels [ 1 MAC) can alter the slope and/or the knees of the plateau. Although the lower threshold for cerebral autoregulation has traditionally been defined as approximately 50 mmHg, this is variable and may be influenced in particular by the presence of pre-existing hypertension. Even in the absence H. P. Grocott, MD (&) Departments of Anesthesia and Surgery, University of Manitoba, CR3008-369 Tache Avenue, Winnipeg, MB R2H 2A6, Canada e-mail: hgrocott@sbgh.mb.ca