Noteworthy Articles in 2015 for Cardiothoracic Critical Care

Abstract

In 2015, the demand for the presence of cardiothoracic anesthesiologists outside of the cardiac operating rooms continues to expand. Most notably, cardiothoracic anesthesiologists now find themselves called on to care for patients postoperatively in the cardiothoracic surgical intensive care unit. This article is the first in this annual series to review relevant contributions in postoperative cardiac critical care that may influence the cardiac anesthesiologist. We explore the use of extracorporeal membrane oxygenation, management of postoperative atrial fibrillation and coagulopathy, metabolic support of the critically ill cardiothoracic surgical patient, and new insights into delirium and acute kidney injury.

Keywords

critical care hyperglycemia intensive care unit perioperative glucose control postoperative care postoperative complications

Introduction

This article is the first in the annual series in Seminars in Cardiothoracic and Vascular Anesthesia highlighting important publications for cardiothoracic anesthesiologists. We would like to thank the editor-in-chief Dr Weitzel for the opportunity to review several important scientific areas related to the postoperative care of the cardiothoracic surgical patient in 2015. This article is not meant to serve as a comprehensive review of all facets of postoperative cardiac critical care but a discussion of selected, high-quality articles for reference for those caring for a cardiac surgery patient in the postoperative period. As cardiac anesthesiologists continue to expand their scope of services outside of the cardiac operating rooms, caring for patients in the intensive care unit remains a logical extension and the need to stay abreast of the latest knowledge remains paramount. In this yearly update, we focus on the latest trends in the use of extracorporeal membrane oxygenation, management of postoperative atrial fibrillation, approaches to managing coagulopathy, metabolic support of the critically ill cardiothoracic patient, and new insights into delirium and renal failure after cardiac surgery.

Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) has continued to increase in use, and the number of programs reportedly implementing ECMO is rapidly expanding.¹ Since the publication of the CESAR trial and other studies demonstrating favorable outcome in patients salvaged with ECMO, the number of studies reporting good outcomes for a variety of diagnosis continues to increase.^2,3 In addition to acute respiratory failure and failure to wean postcardiotomy, cardiopulmonary resuscitation in select candidates with the use of emergent veno-arterial (E-CPR) is gaining traction as a viable strategy to bridge patients to survival. Multiple centers have reported small series of patients with favorable outcomes with survival to discharge ranging from 20% to 34%.^4-6 The CHEER trial augmented the available case series with data on protocolized implementation of E-CPR with hypothermia therapy in patients with out-of-hospital or in-hospital arrest. This trial included patients aged 18 to 65 years with witnessed, refractory arrest, and rapid initiation of CPR. Although this observational trial only included 26 patients, the authors reported a survival with full neurologic recovery of 54% of the patients. This trial adds to the existing evidence suggesting that E-CPR may increase the chances of return of spontaneous circulation, neurologic recovery, and survival.^4,6 Although a randomized controlled trial has not been performed to date, the updated 2015 American Heart Association/American College of Cardiology guidelines for CPR and emergency cardiovascular care now state that E-CPR may be considered as an alternative to standard CPR in select patients with reversible causes of arrest.⁷

As ECMO results continue to improve, it is being considered in a wider range of diagnoses. Myocarditis is a disease state that can be associated with high mortality, and a standard therapy to bridge to recovery or transplant therapy has not been established because the only evidence published is in the form of small case series. Diddle and colleagues reviewed the Extracorporeal Life Support Organization database from 1995 to 2011 to characterize the outcomes of patients with myocarditis rescued with ECMO.⁸ The report included 147 patients, of which 31 patients had ECMO implemented as a component of E-CPR. The outcomes were favorable with 69% (101/147) of patients were weaned from ECMO and 61% (90/147) survived to discharge. Interestingly, the survival of patients cannulated as part of E-CPR was not significantly different from those cannulated for other indications (55% vs 63%).

One of the main challenges to managing ECMO for cardiac insufficiency with poor ejection is the difficulty in preventing overdistension of the ventricles. Insufficient venous drainage, severe cardiac dysfunction, or significant afterload can impede effective unloading of the left ventricle (LV). Several methods to unload the ventricle exist including atrial septostomy, insertion of a ventricular assist device, direct apical LV venting, pulmonary artery catheter drains, and intraaortic balloon pump (IABP) insertion to unload the LV by decreasing LV afterload and aid ejection. Cheng and colleagues attempted to study the benefit of IABP use in patients on venoarterial (VA) ECMO by pooling the available studies.⁹ The authors pooled 16 studies comprising 1517 patients and found no difference in survival in patients maintained on VA ECMO compared with VA ECMO and concomitant IABP (risk ratio [RR] = 1.143; 95% confidence interval [CI] = 0.973-1.343; P = .10). Furthermore, VA ECMO with IABP did not improve outcome in patients with acute myocardial infarction (RR = 0.948; 95% CI = 0.718-1.252; P = .71). This study calls into the question the very common practice of placement of an IABP in patients with ECMO, which occurs in 55% of patients. For now the optimal way to vent an LV on ECMO remains in question.

The expansion of use of ECMO has brought questions of appropriate use and examination of experience to attempt to guide inclusion and exclusion criteria. Mortality remains high for patients placed on veno-arterial ECMO, and multiple institutions have reported varying ages as exclusion criteria.¹ The Mayo Clinic reported their experience with postcardiotomy ECMO in the elderly in a series of 45 patients ≥70 years of age.¹⁰ Although 53% (24/45) of patients were weaned off ECMO, only 24.4% (11/45) survived to hospital discharge. This poor rate of survival does call into question the appropriateness of a therapy that may prolong death. ECMO does remain a therapy of last resort in the situation of failure to wean from cardiopulmonary bypass.

The ability to predict survival in patients receiving ECMO remains problematic. Currently, there are at least 5 risk stratification scoring systems for candidates for ECMO for respiratory failure.^11-15 More recently, Schmidt and colleagues published a model to predict mortality for patients with refractory cardiogenic shock considered for VA-ECMO based on data from 3846 patients in the ESLO database from 2003 to 2013.¹⁶ In addition, the authors validated the model using patients who underwent VA-ECMO for refractory cardiogenic shock at Alfred Hospital in Melbourne, Australia, and reported an area under the receiver operating curve = 90 (95% CI = 0.85-0.95). This risk scoring system is easy to use and a web-based calculator is available to assist practitioners seeking to predict survival in candidates for ECMO (www.save-score.com).

Atrial Fibrillation

Atrial fibrillation continues to be a common complication following cardiac surgery. Despite the common use of β-blockers and maintenance of normal electrolytes, the aging population and increasing rates of surgery on the elderly has resulted in high rates of postoperative atrial fibrillation (POAF). The increase in cost associated with POAF has been estimated to range from $10 000 to $20 000 per patient.^17,18

It is clear that inflammation associated with cardiac surgery increases the risk of POAF, and multiple therapies to reduce inflammation have been proposed and studied. Steroids have been proposed and utilized as a preventive therapy, and been demonstrated to reduce POAF in multiple meta-analysis.^19,20 In 2012, the Dexamethasone for Cardiac Surgery Study Group attempted to analyze the incidence of adverse events in 4494 patients randomized to a single intraoperative dose of 1 mg/kg of dexamethasone versus placebo in patients undergoing cardiopulmonary bypass at 8 cardiac surgery centers.²¹ The investigators found that dexamethasone did not lower the risk of atrial fibrillation (dexamethasone group 33.1% vs placebo group 35.2%; RR = 0.94; 95% CI = 0.87-1.02; P = .14). More recently, the Steroids in Cardiac Surgery trial, which randomized 7507 patients undergoing cardiac surgery to 250 mg of methylprednisolone at induction and initiation of bypass or placebo, found no difference in the rate of new atrial fibrillation.²² The results of these 2 large randomized, placebo controlled trials may finally put to rest the debate over the role of steroids in the prevention of POAF.

During cardiac surgery, patients with atrial fibrillation frequently undergo surgical ablation but the evidence supporting this practice is poor. The Cardiac Surgical Trials Network recently published the results of a randomized controlled trial that randomized 260 patients with persistent or long-standing atrial fibrillation undergoing mitral valve surgery to ablation versus no ablation.²³ Furthermore, the patients randomized to the ablation therapy were randomized to pulmonary vein isolation or biatrial maze procedures. The 1-year mortality was not different in controls versus patients undergoing ablation, but the patients undergoing ablation had significantly higher rates of freedom from atrial fibrillation at 6 and 12 months (63.2% vs 29.4%, P < .001) In addition, there was no significant difference in the rate of freedom from atrial fibrillation in patients undergoing pulmonary vein isolation versus biatrial maze. It is important to note that the rate of permanent pacemaker implantation was significantly higher in the maze group (21.5% vs 8.1%, P = .01). This higher rate of permanent pacemaker implantation in patients undergoing surgical maze has since been confirmed in a large meta-analysis by El-Chami and colleagues.²⁴

Coagulation

Factor Concentrates

The body of literature supporting the use of factor concentrates in cardiac surgery patients continues to grow. There is potential benefit in using factor concentrates compared to allogeneic blood products because many transfusion risks (eg, lung injury, infection) are theoretically eliminated. In a double-blinded, placebo controlled trial (n = 116), Ranucci and colleagues evaluated fibrinogen concentrate in complex cardiac surgery patients with an expected cardiopulmonary bypass time longer than 90 minutes.²⁵ Dosing was based on FIBTEM measurements with a dosing algorithm that target a FIBTEM of 22 mm. Patients in the treatment arm also received 4-factor prothrombin complex (PCC; 7 IU/kg) if they had ongoing bleeding after fibrinogen repletion. The primary outcome was allogeneic transfusion during the 30 days after surgery. After controlling for transfusion risk and cardiopulmonary bypass duration, the treatment group had 0.43 as the odds of transfusion (95% CI = 0.19-0.98) when compared to the control group. The safety profile for fibrinogen and PCC was similar compared to controls. In a retrospective cohort study of patients who underwent pulmonary endarterectomy and were taking warfarin preoperatively, Ortmann and colleagues compared patients who were treated with fresh frozen plasma (FFP) and patients who were treated with 4-factor PCC.²⁶ The primary outcome variables were 12-hour postoperative blood loss and postoperative red blood cell transfusion. In estimates that included no adjustment for confounding, the PCC group had lower chest tube output at 1, 6, and 12 hours (650 mL vs 277 mL at 12 hours); however, there was no difference in the amount of allogeneic transfusion. Propensity score adjustment was used to compare duration of hospitalization, intensive care unit (ICU) length of stay, and adverse events. No differences were found between groups. One major limitation of this study is that adjusted estimates did appear to be performed when comparing bleeding and transfusion risks. Finally, in a randomized controlled trial comparing FFP and 4-factor PCC for warfarin reversal in patients requiring urgent surgery with outcomes of bleeding and international normalized ratio reversal, Goldstein and colleagues demonstrated that 4-factor PCC reduced the international normalized ratio more rapidly than FFP and bleeding was comparable.²⁷ There were no differences in adverse events between groups. As a limitation, this study only included 3 cardiac patients, but included a number of other surgical patients.

Coagulation Testing and Monitoring

The utility of viscoelastic tests for monitoring perioperative coagulation in cardiac surgery continues to be validated. In a study that included 52 adult patients having cardiac surgery, Ortmann and colleagues demonstrated that both TEG and ROTEM clot strength values (both intrinsically and extrinsically activated) measured on bypass (MA and MCF) have strong agreement with postprotamine values(<20% difference).²⁸ For clotting time values (R and CT) on cardiopulmonary bypass ROTEM values were consistent with postprotamine values in both intrinsically and extrinsically activated assays, while TEG values were not (>20% difference in intrinsically activated TEG). Heparin and protamine dosing varies between centers and its impact on bleeding continues to be controversial. Two studies evaluated individualized heparin management in comparison with “conventional” management (weight based with an ACT target). Radulovic and colleagues performed a prospective randomized trial that included 60 coronary artery bypass grafting (CABG) patients.²⁹ Patients received either individualized heparin and protamine management (IHM) based on heparin dose-response curves and heparin protamine titration (using Hepcon HMS plus) or conventional dosing as previously described. Protamine dosing in the control group was 1 mg/100 U heparin. The primary endpoint was endogenous thrombin potential 2 hours after surgery. Secondary outcomes were bleeding, drug doses, and ROTEM values. There were no differences between the 2 groups in any outcome, suggesting that individualized heparin management offers little benefit in terms of bleeding. In a similar study, Hoenicka and colleagues suggested that IHM might actually be harmful in CABG patients. In their randomized trial that included 120 patients, IHM was associated with more bleeding in the first 12 hours (420 vs 345 mL) and higher activated partial thromboplastin time and INTEM CT values after surgery.³⁰

Transfusion Algorithms

Transfusion algorithms based on viscoelastic tests and point of care platelet function tests continue to demonstrate efficacy in reducing total transfusion and bleeding. Two quasi-experimental studies comparing transfusion prior to a ROTEM-based algorithm and after demonstrated significant reductions in overall transfusion.^31,32 The algorithm published by Pearse and colleagues³¹ also incorporated impedance aggregometry using Multiplate to determine platelet function, while the algorithm published by Karkouti and colleagues³² used Plateletworks. Both studies are obviously limited by their observational nature despite attempts to control for confounding.

ECMO Bleeding

Bleeding and coagulopathy continues to be a major issue during ECMO with limited trials to support best practice. Anselmi and colleagues described the use of recombinant activated factor VII (rFVIIa) in 30 ECMO patients with severe bleeding.³³ They compared patients receiving rFVIIa against a matched group who did not receive the drug and found no increased rate of complications (including thrombosis). They also described a high rate of treatment success in stopping refractory hemorrhage with rFVIIa (93.3%). The mechanisms of ECMO-induced coagulopathy remain poorly described. In 20 patients receiving ECMO, Mutlak and colleagues used Multiplate impedance aggregometry to measure ADP-induced aggregation at various time points (baseline, 90, 120, 150, and 180 minutes).³⁴ ECMO patients appeared to have a decrease in platelet aggregation within 90 minutes of starting therapy.

Reversal of Novel Oral Anticoagulants

Novel oral anticoagulants are changing anticoagulation practices in patients with thromboembolic disease and atrial fibrillation. Reversal strategies have been a “hot” topic in recent years. In a landmark study by Pollack and colleagues, the first clinical experience with dabigatran reversal using a monoclonal antibody, idarucizumab, was described.³⁵ The drug was administered in 2 doses (each 2.5 g) 15 minutes apart. Dabigatran reversal was performed in both medical and surgical patients. Although the study was small (N = 90), the drug provided 100% reversal based on dilute thrombin time or ecarin clotting time in nearly all patients within minutes. In patients having surgery, normal hemostasis was reported in all patients except for 3 of 36. Furthermore, the safety of the drug appeared to be excellent with only 5 patients experiencing thrombotic events (1 early, 4 late).

Metabolic Support of the Critically Ill Cardiothoracic Patient

Glycemic Control

The importance of satisfactory serum glucose control cannot be understated as failure to do so is associated with increased postsurgical complications, length of hospital stay, and mortality. In the cardiac surgery population, achievement of tight glucose control can prove difficult as the use of cardiopulmonary bypass and intentional hypothermia encourage a state of insulin resistance. Omar et al published the results of a prospective, descriptive, single-center study evaluating the importance of time duration spent in a target glucose range following cardiac surgery with respect to outcomes.³⁶ In addition, the study sought to identify factors related to poor glucose control in the postoperative period. Two hundred twenty-seven consecutive patients undergoing cardiac surgery were enrolled in the study (of which 100 were diabetic). Patients were maintained on a continuous insulin infusion for greater than 12 hours with target serum glucose between 6.0 and 8.1 mmol/L (108-144 mg/dL). Hourly arterial blood samples were obtained for the first 6 hours to assess serum glucose with capillary finger-stick analysis carried out thereafter. The time in target glucose range (TIR) was determined and used to divide patients into 2 groups. Group I was composed of individuals with TIR > 80%, and Group II was made up of individuals with TIR < 80%. Complications and outcomes including acute kidney injury (AKI), POAF, infection, stroke, wound infection, and death were recorded for each patient. Outcomes were analyzed between diabetics and nondiabetics, and factors associated with poor glycemic control were analyzed. Groups I and II were similar with respect to age, gender, body mass index (BMI), hypertension, and Euro score. Hemoglobin A1C was significantly higher in Group II (8.0 ± 2.2 vs 6.6 ± 1.7; P = .01). Poorer glucose control was noted in patients undergoing CABG (68.5% [Group I] vs 83.3% [Group II]; P = .04), whereas patients undergoing valve surgery had better blood glucose control (27.5% [Group I] vs 11.3% [Group II]; P = .03). Those requiring infusions of either epinephrine (11.1% [Group I] vs 23% [Group II]; P = .04) or dopamine (13.8% [Group I] vs 24.7% [Group II]; P = .03) displayed worse glucose control as well. Aortic cross clamp time (64.8 ± 37 minutes [Group I] vs 75.5 ± 23 minutes [Group II]); P = .04) and total anesthesia time (318 ± 103 minutes [Group I] vs 349 ± 81 minutes [Group II]; P = .05) were higher in Group II in addition to lengths of hospital (7.5 ± 3.7 days [Group I] vs 9.9 ± 11 days [Group II]) and ICU stay (203 ± 142 hours [Group I] vs 256 ± 411 hours [Group II]). The incidence of POAF (6.8% [Group I] vs 14.8% [Group II]; P = 0.04), wound infection (2.1% [Group I] vs 8.6% [Group II]; P = .05), and overall in-hospital mortality (1.3% [Group I] vs 3.7% [Group II]) were higher in Group II as well. Multivariate analysis revealed that diabetes was the only independent predictor of poor glycemic control (odds ratio [OR] = 0.3; CI = 0.12-0.75; .01) and TIR < 80% was significantly associated with longer ICU stay (OR = 0.668; CI = 0.159-0.647; .001). In comparing diabetics to nondiabetics, TIR < 80% was associated with increased incidence of POAF and longer lengths of stay in both groups. The authors advocate enhancing TIR in post–cardiac surgery patients admitted to the ICU and utilizing hemoglobin A1C as a screening tool prior to cardiac surgery. Last, tight glucose control was achieved in part through frequent arterial measurements, which the authors view as a reasonable approach to fine-tuning an insulin regimen in the cardiac surgery population.

Nutritional Assessment

Optimization of nutritional status in patients undergoing cardiac surgery is seen as an avenue by which outcomes can be improved. Integral to attainment of this goal is the identification of reliable markers of overall nutrition. Yu et al investigated the efficacy of prealbumin as a diagnostic marker of nutritional status as well as its potential use as a predictor of outcomes following cardiac surgery.³⁷ In the prospective study, serum prealbumin was obtained from 69 patients within 24 hours of undergoing cardiac surgery. Demographic data were obtained as was information related to preoperative risk factors, cardiac function, transfusion requirements, glucose control, and operative management. Study end points included infectious and noninfectious complications, length of intubation, total hours in the ICU, and total length of hospital stay. Patients were separated into 2 groups according to preoperative prealbumin levels with group one comprising those with prealbumin >20 mg/dL and the other including patients with prealbumin ≤20 mg/dL. No differences in demographic data existed between the groups. Prealbumin levels did not correlate with serum albumin levels or BMI. Univariate analysis demonstrated an association between low prealbumin levels and incidence of postoperative infection (9 vs 2; P = .010) as well as likelihood to remain intubated for greater than 12 hours postoperatively (13 vs 5; P = .10). No significant differences were noted regarding noninfectious postoperative complications, length of ICU stay, and length of hospital stay. Of note, neither serum albumin nor BMI was associated with postoperative infections (P = .470 and .161, respectively). Results of the study suggest that prealbumin may be a useful tool in identifying patients with a potentially correctable nutritional deficit that may affect cardiac surgery outcomes. As opposed to serum albumin and BMI, the relatively short half-life of prealbumin reflects short-term nutritional status, thus making it a sounder choice in nutritional assessment in the preoperative period.

Considerable debate exists regarding the optimal nutritional regimen in patients admitted to ICUs. Recent studies are at times contradictory, and the dichotomy of recommendations can prove troublesome when deciding on the appropriate course of management. The retrospective cohort study by Wei et al examines the influence of nutritional status on both short- and long-term outcomes in patients requiring prolonged mechanical ventilation.³⁸ A total of 475 patients were enrolled in which nutritional adequacy was determined by summing the amount of calories administered to individual patients over the first 8 days of ICU admission and dividing by the number of calories prescribed to arrive at a percentage. Patients were then arranged in low (<50%), moderate (≥50% and <80%), and high (≥80%) nutritional adequacy subsets. Study analysis revealed a higher mortality rate in the low nutritional adequacy group when compared to the high nutritional adequacy group (adjusted hazard ratio = 1.7; 95% CI = 1.1-2.6) within the first week of ICU admission, calling attention to the risks of underfeeding during this time period.

Nutritional Supplementation

In 2015, there remained considerable interest in studying the use of vitamins and nutritional supplements as an adjunct to conventional supports of nutrition. Elevated serum lactate in those with thiamine deficiency serves as evidence of the vitamin’s role as a cofactor in its biochemical processing. Sustained increases in serum lactate, in turn, serve as an indicator of poor outcomes. Luger et al hypothesized that thiamine supplementation prior to cardiac surgery would correct a surgery-induced deficiency and allow for reduced serum lactate levels.³⁹ In addition, the authors analyzed demographic data to identify risk factors for increased serum lactate. Thirty-nine patients undergoing elective cardiac surgery with cardiopulmonary bypass were recruited for the randomized controlled pilot study. Patients received a one-time dose of intravenous thiamine (300 mg) immediately before surgery or placebo. Serum thiamine concentration was measured before and after intervention, and arterial blood gas analysis was carried out at multiple time points to determine serum lactate. Thiamine excretion was determined via urine studies. No significant difference in preoperative thiamine levels was observed between groups. However, thiamine levels were significantly higher in the treatment group 48 hours after surgery as was thiamine excretion. By postoperative hour 24, all patients in the treatment group had normal thiamine levels compared to 53% of the placebo population. Blood lactate concentration differed between groups at different points, but the differences were never significant.

Sriram et al investigated the relationship between vitamin D levels and outcomes in patients undergoing either coronary artery bypass grafting or valve replacement.⁴⁰ Sixty-four individuals were enrolled in the prospective observational study in which patients were divided into 2 groups according to preoperative vitamin D level. Univariate analysis of demographic data revealed that seasonal timing of surgery was associated with vitamin D level (P < .05). A statistically significant decline in vitamin D levels postoperatively was observed in >90% of patients (P < .001). Preoperative vitamin D levels did not influence the incidence of postoperative arrhythmias, respiratory failure (ventilatory support > 24 hours), or need for prolonged inotropic support (>48 hours). Neither glycemic control nor postoperative cardiac function was correlated with preoperative vitamin D levels. However, statistical analysis revealed that a 1 ng/mL increase in preoperative vitamin D would reduce ICU and hospital stay by a factor of 0.98 (P < .018) and 0.98 (P < .001), respectively, after adjusting for BMI, smoking, diabetes, and age, whereas postoperative vitamin D had no such effect. While more studies are required to confirm the positive effects of vitamin D on hospital length of stay, the results point to an uncomplicated, inexpensive intervention with the potential to reduce length of stay and thus cost in the care of patients undergoing cardiac surgery.

Sadeghpour et al conducted a single-center, double-blinded, placebo-controlled trial to explore the potential benefits of vitamin C administration to patients undergoing cardiac surgery.⁴¹ Two hundred and ninety patients set to undergo cardiac surgery were randomized into the intervention group (n = 113) and control group (n = 177). Inclusion criteria included ASA class II-III patients >18 years of age undergoing coronary artery bypass grafting or surgery for congenital valvular disease. Individuals with significant comorbidities, patients who died during the first postoperative day, and those undergoing emergent surgeries were excluded. Patients in the intervention group received ascorbic acid 2 g intravenously prior to surgery followed by 1 g oral daily doses for the first 4 postoperative days. Statistically significant findings included decreased hospital length of stay (10.17 ± 4.63 [intervention] vs 12 ± 4.51 [placebo]; P = .01), intubation time (11.83 ± 3.91 vs 14.14 ± 9.52 hours), and surgical site drainage in the first 24 hours (262.21 ± 190.91 vs 348.50 ± 262.17 mL). Length of ICU stay and total surgical site drainage were not statistically significant. Given its ease of administration, minimal side effect profile, low cost, and evidence of appreciable benefit, the authors advocate for vitamin C supplementation in those undergoing cardiac surgery.

The profound oxidative stress precipitated by cardiac surgery with cardiopulmonary bypass necessitates an equally robust response to such an insult. The trace element selenium has been identified as a major component of antioxidant defense, and low levels of the element in the postoperative period have been correlated with adverse cardiac surgical outcomes. The SUSTAIN-CSX trial is a multicenter, randomized, placebo-controlled trial that will investigate the effects of perioperative selenium supplementation on postoperative organ dysfunction.⁴² The multinational study will be carried out in both Europe (Germany, Belgium, and Switzerland) and North America (Canada and the United States) on completion of a pilot study begun in August 2014 at 6 medical centers in Canada and Germany. The trial aims to enroll 1400 adult patients undergoing elective high-risk complex cardiac surgery with cardiopulmonary bypass (left ventricular assist device and heart transplantation patients are excluded). Intraoperatively, patients in the treatment group will receive 2000 µg sodium selenite intravenously and a second 2000 µg bolus on admission to the ICU. A daily bolus of 1000 µg will be administered throughout the patient’s ICU stay beginning on postoperative day 1 for a maximum of 10 days. The primary endpoint will be the number of days alive and persistent organ dysfunction free within the first 30 days of surgery. The SUSTAIN-CSX is the largest study to date that will investigate the effects of selenium supplementation on cardiac surgical outcomes.

Delirium

Postoperative delirium (POD) is a common occurrence after surgery in general and cardiac surgery in particular.⁴³ In 2015, the American Geriatrics Society (AGS) released guidelines for postoperative delirium and in older adults.⁴⁴ Prevention of delirium remains elusive. The AGS expert panel found insufficient evidence to consider depth of anesthesia a risk factor for POD or preoperative antipsychotic therapy protective against delirium. However, adequate pain control, especially with nonopioid medications, was cited as an important method of delirium prevention. Some drugs were associated with increased POD including anticholinergics, meperidine, and benzodiazepines, as well as the use of 5 or more medications. The AGS expert panel concluded that antipsychotics are best used to treat agitated and distressed patients but at the lowest dose and for the shortest duration possible.

Researchers continued to explore the topic of delirium in the cardiac surgery population. Intraoperative hyperglycemia has been linked to POD.⁴⁵ Saager et al sought to examine the relationship between hyperglycemia and delirium.⁴⁶ They designed their study on the basis that hyperglycemia is both the result of an inflammatory response and also induces further inflammation. Therefore, the authors proposed that treatment with insulin would decrease perioperative inflammation, and have a favorable impact on delirium. A hyperinsulinemic-normoglycemic clamp technique was chosen due to the inherent anti-inflammatory properties of insulin. The study was designed to test 2 hypotheses: (a) tight glucose control decreases incidence of postoperative delirium as detected by Confusion Assessment Method (CAM) and (b) the normoglycemic clamp technique reduces severity of delirium based on Memorial Delirium Assessment Scale (MDAS). Two hundred and three patients were randomized to either a hyperinsulinemic-normoglycemic clamp group or standard therapy of glucose <150 mg/dL. The insulin clamp group had an intraoperative glucose target of 80 to 100 mg/dL. Postoperatively glycemic goal was the same for all patients: 80 to 150 mg/dL on day of surgery and 80 to 120 mg/dL thereafter. Intraoperative management was similar between the 2 groups. Postoperatively blinded clinicians, trained in the CAM and MDAS tools, assessed delirium. To the surprise of the investigators, the hyperinsulinemic-normoglycemic clamp resulted in an increased risk of postoperative delirium without any reduction in severity. The incidence of delirium in the clamp group was significantly higher at 28% versus 14% in the control group (unadjusted RR = 1.96; 95% CI = 1.06-3.37; P = .02). However, MDAS assessments of delirium severity in the 42 effected patients were similar regardless of glucose management strategy (4.9 vs 4.1, P = .43). The investigators conceded that perhaps hyperglycemia is a normal response to stress and that some organs including the brain may benefit from high glucose concentrations during periods of stress. Clearly, we have more to learn about both perioperative glycemic control and delirium.

Acute Kidney Injury and Cardiac Surgery

Remote ischemic preconditioning (RIPC) has been shown to prevent AKI following both major vascular and cardiac surgery.^47,48 However, its effect on those at particularly high risk for renal injury after cardiac surgery had not previously been examined but was important enough to warrant 2 publications in very high impact journals this past year. Zarbock and the RenalRIPC Investigators reported in JAMA the results of a double-blind, prospective, randomized trial of cardiac surgery patients at high risk for postoperative AKI (Cleveland Clinic Renal Score > 6).⁴⁹ Two hundred forty patients from 4 centers were enrolled. Patients in both groups received protocolized anesthetics and had similar surgical profiles with respect to type of surgery and periods of both myocardial ischemia and cardiopulmonary bypass. During the period between induction and surgical start, patients randomized to RIPC were treated on one arm with 3 cycles of 5-minute inflation of a blood pressure cuff to 200 mm Hg (or 50 mm Hg higher than systolic blood pressure). A 5-minute period of reperfusion was allowed between the inflations. The control group was treated with the same inflation and reperfusion protocol; however, the cuff was only inflated to 20 mm Hg.

Postoperative kidney dysfunction was diagnosed according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. AKI in the first 72 hours postoperatively was the primary endpoint. Secondary endpoints included incidence of severe kidney injury (stage 2-3) in first 72 hours, 30-day mortality, need for renal replacement therapy during index hospitalization, time on the ventilator, ICU and hospital length of stay (LOS), various urinary biomarkers 24 hours after surgery, myocardial infarction, stroke, and in-hospital death. Those treated with RIPC experienced a 15% absolute risk reduction in the incidence of any degree of AKI during the 72 hours after surgery (37.5% vs 52.5%, P = .02). They also found that in the preconditioning group, significantly fewer patients developed moderate or severe kidney injury (12.5% vs 25.8%; P = .02; RR = 85%; 95% CI = 75% to 97%). The incidence of mild AKI (25% vs 26.7%, P = .77) was not affected by the addition of RIPC. Among the secondary endpoints, the use of renal replacement therapy (5.8% vs 15.8%; P = .01; adjusted RR = 10%; 95% CI = 2.25% to 17.75%) was significantly reduced in the RIPC group, as was ICU LOS (3 days vs 4 days; 95% CI = 0.2 days, median difference; P = .04). Furthermore, while baseline urinary biomarkers were similar between the treatment groups, the “alarm markers” TIMP-2 and IGFBP7 as well as urinary NGAL, a marker for renal damage, were significantly lower post-bypass in the RIPC group, and highly predictive of less AKI on multivariate analysis.⁵⁰ High-mobility group box 1 (HMGB-1), a molecular pattern associated with cellular protection, was substantially higher after RIPC and also significantly predictive of less AKI on multivariate logistic regression analysis (OR = 0.75; P < .03). The authors postulate that these results suggest RIPC may be an inexpensive, simple, and effective renal protective strategy in patients at high risk for AKI following cardiac surgery. The molecular mechanisms responsible for the benefits of RIPC may be enhanced production of important renal cellular protective molecules like HMGB-1, which arrest cells in the G1 phase of the cell cycle before being exposed to the effects of cardiopulmonary bypass.

Additional interest in RIPC affecting outcomes after cardiac surgery was demonstrated by 2 studies published in the same issue of The New England Journal of Medicine. Meybohm and the RIPHeart Study collaborators reported on a prospective, randomized, double-blind, multicenter trial involving 1385 patients undergoing elective cardiac surgery at 14 German centers.⁵¹ The protocol for RIPC use was quite similar to that in the JAMA publication. Although 10% of the study population did not receive adequate RIPC therapy, a subgroup analysis of the remaining 1167 found no difference in the incidence of AKI (6.1% vs 5.1%, P = .45) contradictory to the findings by Zarbock et al. Hausenloy and the ERICCA Trial investigators randomized 1612 patients at 30 centers in the United Kingdom with the primary outcome of the study being clinical outcomes at 12 months.⁵² The authors failed to find any difference in survival, myocardial infarction, cerebrovascular accident, or need for coronary re-intervention at 12 months. They examined a secondary endpoint of AKI and similarly failed to note any reduction in the incidence of AKI with RIPC (38% vs 38.3%, P = .98). However, there were significant methodological flaws in this study that perhaps diminish the importance of these findings. In their secondary analysis of AKI, 55% of the entire cohort was left out of this analysis because of inadequate data. While they compensated for the lost data by using multiple imputation analysis, the authors acknowledge that this may have influenced outcomes substantially. In addition, the authors failed to control for either anesthetic technique, including the use of propofol, a known attenuator of the effects of RIPC, or postoperative management, further clouding these results. Similar criticisms regarding heterogeneity in anesthetic and postoperative care could also be leveled at the Meybohm study.

Clearly the conflicting results of these 3 trials mandate further attention to the role of RIPC in preventing AKI in patients undergoing cardiac surgery. Given the profoundly negative effect acute renal failure has on outcomes after cardiac surgery, more investigation into this fascinating area of translational research seems warranted.

Conclusion

The past year has seen significant advances in the management of the patients undergoing cardiovascular surgery. Expanded indications for the use of ECMO, refinement in the treatment of atrial fibrillation and coagulopathy, emerging data on optimization of metabolic support, delirium, and potential kidney injury should further improve perioperative outcomes for this population.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

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