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Interest in developing and using novel biomarkers in critical care and perioperative medicine is increasing. Biomarkers studies are often presented with flaws in the statistical analysis that preclude them from providing a scientifically valid and clinically relevant message for clinicians. To improve scientific rigor, the proper application and reporting of traditional and emerging statistical methods (e.g., machine learning) of biomarker studies is required. This Readers' Toolbox article aims to be a starting point to nonexpert readers and investigators to understand traditional and emerging research methods to assess biomarkers in critical care and perioperative medicine., (Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

Background: Initial blood lactate and base deficit have been shown to be prognostic biomarkers in trauma, but their respective performances have not been compared., Methods: Blood lactate levels and base deficit were measured at admission in trauma patients in three level 1 trauma centers. This was a retrospective analysis of prospectively acquired data. The association of initial blood lactate and base deficit with mortality was tested using receiver operating characteristics curve, logistic regression using triage scores (Revised Trauma Score and Mechanism Glasgow scale and Arterial Pressure score), and Trauma Related Injury Severity Score as a reference standard. The authors also used a reclassification method., Results: The authors evaluated 1,075 trauma patients (mean age, 39 ± 18 yr, with 90% blunt and 10% penetrating injuries and a mortality of 13%). At admission, blood lactate was elevated in 425 (39%) patients and base deficit was elevated in 725 (67%) patients. Blood lactate was correlated with base deficit (R = 0.54; P < 0.001). Using logistic regression, blood lactate was a better predictor of death than base deficit when considering its additional predictive value to triage scores and Trauma Related Injury Severity Score. This result was confirmed using a reclassification method but only in the subgroup of normotensive patients (n = 745)., Conclusions: Initial blood lactate should be preferred to base deficit as a biologic variable in scoring systems built to assess the initial severity of trauma patients.

Background: The effect on cardiovascular outcomes of withholding angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in chronic users before noncardiac surgery is unknown., Methods: In this international prospective cohort study, the authors analyzed data from 14,687 patients (including 4,802 angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users) at least 45 yr old who had in-patient noncardiac surgery from 2007 to 2011. Using multivariable regression models, the authors studied the relationship between withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and a primary composite outcome of all-cause death, stroke, or myocardial injury after noncardiac surgery at 30 days, with intraoperative and postoperative clinically important hypotension as secondary outcomes., Results: Compared to patients who continued their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, the 1,245 (26%) angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users who withheld their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the 24 h before surgery were less likely to suffer the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1,245 [12.0%] vs. 459/3,557 [12.9%]; adjusted relative risk, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and intraoperative hypotension (adjusted relative risk, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The risk of postoperative hypotension was similar between the two groups (adjusted relative risk, 0.92; 95% CI, 0.77 to 1.10; P = 0.36). Results were consistent across the range of preoperative blood pressures. The practice of withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was only modestly correlated with patient characteristics and the type and timing of surgery., Conclusions: Withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers before major noncardiac surgery was associated with a lower risk of death and postoperative vascular events. A large randomized trial is needed to confirm this finding. In the interim, clinicians should consider recommending that patients withhold angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 24 h before surgery.

Background: An accurate risk score able to predict in-hospital mortality in patients undergoing surgery may improve both risk communication and clinical decision making. The aim of the study was to develop and validate a surgical risk score based solely on preoperative information, for predicting in-hospital mortality., Methods: From January 1, 2010, to December 31, 2010, data related to all surgeries requiring anesthesia were collected from all centers (single hospital or hospitals group) in France performing more than 500 operations in the year on patients aged 18 yr or older (n = 5,507,834). International Statistical Classification of Diseases, 10th revision codes were used to summarize the medical history of patients. From these data, the authors developed a risk score by examining 29 preoperative factors (age, comorbidities, and surgery type) in 2,717,902 patients, and then validated the risk score in a separate cohort of 2,789,932 patients., Results: In the derivation cohort, there were 12,786 in-hospital deaths (0.47%; 95% CI, 0.46 to 0.48%), whereas in the validation cohort there were 14,933 in-hospital deaths (0.54%; 95% CI, 0.53 to 0.55%). Seventeen predictors were identified and included in the PreOperative Score to predict PostOperative Mortality (POSPOM). POSPOM showed good calibration and excellent discrimination for in-hospital mortality, with a c-statistic of 0.944 (95% CI, 0.943 to 0.945) in the development cohort and 0.929 (95% CI, 0.928 to 0.931) in the validation cohort., Conclusion: The authors have developed and validated POSPOM, a simple risk score for the prediction of in-hospital mortality in surgical patients.

Background: It is unclear whether postoperative B-type natriuretic peptides (i.e., BNP and N-terminal proBNP) can predict cardiovascular complications in noncardiac surgery., Methods: The authors undertook a systematic review and individual patient data meta-analysis to determine whether postoperative BNPs predict postoperative cardiovascular complications at 30 and 180 days or more., Results: The authors identified 18 eligible studies (n = 2,051). For the primary outcome of 30-day mortality or nonfatal myocardial infarction, BNP of 245 pg/ml had an area under the curve of 0.71 (95% CI, 0.64-0.78), and N-terminal proBNP of 718 pg/ml had an area under the curve of 0.80 (95% CI, 0.77-0.84). These thresholds independently predicted 30-day mortality or nonfatal myocardial infarction (adjusted odds ratio [AOR] 4.5; 95% CI, 2.74-7.4; P < 0.001), mortality (AOR, 4.2; 95% CI, 2.29-7.69; P < 0.001), cardiac mortality (AOR, 9.4; 95% CI, 0.32-254.34; P < 0.001), and cardiac failure (AOR, 18.5; 95% CI, 4.55-75.29; P < 0.001). For greater than or equal to 180-day outcomes, natriuretic peptides independently predicted mortality or nonfatal myocardial infarction (AOR, 3.3; 95% CI, 2.58-4.3; P < 0.001), mortality (AOR, 2.2; 95% CI, 1.67-86; P < 0.001), cardiac mortality (AOR, 2.1; 95% CI, 0.05-1,385.17; P < 0.001), and cardiac failure (AOR, 3.5; 95% CI, 1.0-9.34; P = 0.022). Patients with BNP values of 0-250, greater than 250-400, and greater than 400 pg/ml suffered the primary outcome at a rate of 6.6, 15.7, and 29.5%, respectively. Patients with N-terminal proBNP values of 0-300, greater than 300-900, and greater than 900 pg/ml suffered the primary outcome at a rate of 1.8, 8.7, and 27%, respectively., Conclusions: Increased postoperative BNPs are independently associated with adverse cardiac events after noncardiac surgery.

Background: Cardiac output (CO) is rarely monitored during surgery, and arterial pressure remains the only hemodynamic parameter for assessing the effects of volume expansion (VE). However, whether VE-induced changes in arterial pressure accurately reflect changes in CO has not been demonstrated. The authors studied the ability of VE-induced changes in arterial pressure and in pulse pressure variation to detect changes in CO induced by VE in the perioperative period., Methods: The authors studied 402 patients in four centers. Hemodynamic variables were recorded before and after VE. Response to VE was defined as more than 15% increase in CO. The ability of VE-induced changes in arterial pressure to detect changes in CO was assessed using a gray zone approach., Results: VE increased CO of more than 15% in 205 patients (51%). Areas under the receiver operating characteristic curves for VE-induced changes in systolic, diastolic, means, and pulse pressure ranged between 0.64 and 0.70, and sensitivity and specificity ranged between 52 and 79%. For these four arterial pressure-derived parameters, large gray zones were found, and more than 60% of the patients lay within this inconclusive zone. A VE-induced decrease in pulse pressure variation of 3% or more allowed detecting a fluid-induced increase in CO of more than 15% with a sensitivity of 90% and a specificity of 77% and a gray zone between 2.2 and 4.7% decrease in pulse pressure variation including 14% of the patients., Conclusion: Only changes in pulse pressure variation accurately detect VE-induced changes in CO and have a potential clinical applicability.

Background: Lactate has been shown to be a prognostic biomarker in trauma. Although lactate clearance has already been proposed as an intermediate endpoint in randomized trials, its precise role in trauma patients remains to be determined., Methods: Blood lactate levels and lactate clearance (LC) were calculated at admission and 2 and 4 h later in trauma patients. The association of initial blood lactate level and lactate clearance with mortality was tested using receiver-operating characteristics curve, logistic regression using triage scores, Trauma Related Injury Severity Score as a reference standard, and reclassification method., Results: The authors evaluated 586 trauma patients (mean age 38±16 yr, 84% blunt and 16% penetrating, mortality 13%). Blood lactate levels at admission were elevated in 327 (56%) patients. The lactate clearance should be calculated within the first 2 h after admission as LC0-2 h was correlated with LC0-4 h (R=0.55, P<0.001) but not with LC2-4 h (R=0.04, not significant). The lactate clearance provides additional predictive information to initial blood lactate levels and triage scores and the reference score. This additional information may be summarized using a categorical approach (i.e., less than or equal to -20 %/h) in contrast to initial blood lactate. The results were comparable in patients with high (5 mM/l or more) initial blood lactate., Conclusions: Early (0-2 h) lactate clearance is an important and independent prognostic variable that should probably be incorporated in future decision schemes for the resuscitation of trauma patients.

Background: It has been suggested that predicting difficult tracheal intubation is useless because of the poor predictive capacity of individual signs and scores. The authors tested the hypothesis that an accurate prediction of difficult tracheal intubation using simple clinical signs is possible using a computer-assist model., Methods: In a cohort of 1,655 patients, the authors analyzed the predictive properties of each of the main signs (Mallampati score, mouth opening, thyromental distance, and body mass index) to predict difficult tracheal intubation. They built the best score possible using a simple logistic model (SCOREClinic) and compared it with the more recently described score in the literature (SCORENaguib). Then they used a boosted tree analysis to build the best score possible using computer-assisted calculation (SCOREComputer)., Results: Difficult tracheal intubation occurred in 101 patients (6.1%). The predictive properties of each sign remain low (maximum area under the receiver operating characteristic curve 0.70). Using receiver operating characteristic curve, the global prediction of the SCOREClinic (0.74, 95% CI: 0.72-0.76) was greater than that of the SCORENaguib (0.66, 95% CI: 0.60-0.72, P<0.001) but significantly lower than that of the SCOREComputer (0.86, 95% CI: 0.84-0.91, P<0.001). The proportion of patients in the inconclusive zone was 71% using SCORENaguib, 56% using SCOREClinic, and only 32 % using SCOREComputer (all P<0.001)., Conclusion: Computer-assisted models using complex interaction between variables enable an accurate prediction of difficult tracheal intubation with a low proportion of patients in the inconclusive zone. An external validation of the model is now required.

Background: The use of β-blockers during the perioperative period remains controversial. Although some studies have demonstrated their protective effects regarding postoperative cardiac complications, others have demonstrated increased mortality when β-blockers were introduced before surgery., Methods: In this observational study involving 1,801 patients undergoing aortic reconstruction, we prospectively assessed β-blocker therapy compared with no β-blocker therapy, with regard to cardiac and noncardiac postoperative outcomes using a propensity score approach. The impact of β-blockers was analyzed according to the intraoperative bleeding estimated by transfusion requirements., Results: In-hospital mortality was 2.5% (n=45), β-blocker use was associated with a reduced frequency of postoperative myocardial infarction (OR=0.46, 95% CI [0.26; 0.80]) and myocardial necrosis (OR=0.62, 95% CI [0.43; 0.88]) in all patients, but also with an increased frequency of multiple organ dysfunction syndromes (OR=2.78, 95% CI [1.71; 4.61]). In patients with severe bleeding (n=163; 9.1%), the frequency of in-hospital death (OR=6.65, 95% CI [1.09; 129]) and/or multiple organ dysfunction syndromes (OR=4.18, 95% CI [1.81; 10.38]) were markedly increased. Furthermore, no more than 28% of the patients who died presented with postoperative myocardial infarction, whereas 69% of the patient with a postoperative myocardial infarction also presented an excessive bleeding., Conclusions: Perioperative β-blocker therapy was associated with an overall reduction in postoperative cardiac events. In the vast majority of patients with low perioperative bleeding, the global effect of β-blockers was protective; in contrast, patients given β-blockers who experienced severe bleeding had higher mortality and an increased frequency of multiorgan dysfunction syndrome.

Background: Respiratory arterial pulse pressure variations (PPV) are the best predictors of fluid responsiveness in mechanically ventilated patients during general anesthesia. However, previous studies were performed in a small number of patients and determined a single cutoff point to make clinical discrimination. The authors sought to test the predictive value of PPV in a large, multicenter study and to express it using a gray zone approach., Methods: The authors studied 413 patients during general anesthesia and mechanical ventilation in four centers. PPV, central venous pressure, and cardiac output were recorded before and after volume expansion (VE). Response to VE was defined as more than 15% increase in cardiac output after VE. The following approaches were used to determine the gray zones: resampled and two-graph receiver operator characteristic curves. The impact of changes in the benefit-risk balance of VE on the gray zone was also evaluated., Results: The authors observed 209 responders (51%) and 204 nonresponders (49%) to VE. The area under receiver operating characteristic curve was 0.89 (95% CI: 0.86-0.92) for PPV, compared with 0.57 (95% CI: 0.54-0.59) for central venous pressure (P < 10). The gray zone approach identified a range of PPV values (between 9% and 13%) for which fluid responsiveness could not be predicted reliably. These PPV values were seen in 98 (24%) patients. Changes in the cost ratio of VE moderately affected the gray zone limits., Conclusion: Despite a strong predictive value, PPV may be inconclusive (between 9% and 13%) in approximately 25% of patients during general anesthesia.

Background: Reclassification tables have never been used to compare concentrations of cardiac troponin I (cTnI) with predictive models of risk in the perioperative setting. The current study aimed to evaluate the prognostic value of pre- and/or postoperative serum cTnI when combined with The European System for Cardiac Operative Risk Evaluation (EuroSCORE) in predicting adverse outcome after cardiac surgery., Methods: Nine hundred five consecutive patients were included. Standard EuroSCORE as well as preoperative and 24-h postoperative cTnI were measured in all patients. Major adverse cardiac events and in-hospital mortality were chosen as study endpoints. The performance of EuroSCORE with and without pre- and/or postoperative cTnI were assessed by means of receiver operating characteristic curves, net reclassification index, and integrated discrimination improvement analyses. Data are expressed as ±SD., Results: Death occurred in 28 of 905 (3%) patients and major adverse cardiac events in 202/905 (22%) patients. Models including EuroSCORE alone were characterized by a low discriminative power (c-index = 0.60 ± 0.05) in predicting major adverse cardiac events. The c-index increased to 0.61 ± 0.05 (P = 0.46), 0.70 ± 0.04 (P < 0.001), and 0.71 ± 0.04 (P < 0.001) when preoperative, postoperative, and pre/postoperative cTnI were included, respectively. The better predictive ability was confirmed by net reclassification index (0.41 ± 0.08, P < 0.001; 0.67 ± 0.08, P < 0.001; and 0.68 ± 0.08, P < 0.001, respectively) and integrated discrimination improvement (0.003 ± 0.002, P = 0.12; 0.099 ± 0.015, P < 0.001; and 0.094 ± 0.016, P < 0.001, respectively). Similar results were observed for in-hospital mortality., Conclusions: The combination of EuroSCORE and postoperative cTnI provides the best discriminative power and performance in predicting adverse outcome after cardiac surgery and is suggested as being an effective model that improves early identification of high-risk patients.

Background: Chronic statin therapy is associated with reduced postoperative mortality. Renal and cardiovascular benefits have been described, but the effect of chronic statin therapy on postoperative adverse events has not yet been explored., Methods: In this observational study involving 1,674 patients undergoing aortic reconstruction, we prospectively assessed chronic statin therapy compared with no statin therapy, with regard to serious outcomes, by propensity score and multivariable methods., Results: In propensity-adjusted multivariable logistic regression (c-index: 0.83), statins were associated with an almost threefold reduction in the risk of death in patients undergoing major vascular surgery (odds ratio: 0.40; 95% CI: 0.28-0.59) and an almost twofold reduction in the risk of postoperative myocardial infarction (odds ratio: 0.52; 95% CI: 0.38-0.71). Likewise, the use of chronic statin therapy was associated with a reduced risk of postoperative stroke and renal failure. Statins did not significantly reduce the risk of pneumonia, multiple organ dysfunction syndrome, and surgical complications; however, in the case of postoperative multiple organ dysfunction syndrome (odds ratio: 0.34; 95% CI: 0.12-0.94) and surgical complications (odds ratio: 0.39; 95% CI: 0.17-0.86), reduced mortality was observed., Conclusions: Chronic statin therapy was associated with a reduction in all cardiac and vascular outcomes after major vascular surgery. Furthermore, in major adverse events, such as multiple organ dysfunction syndrome and surgical complications, statins were also associated with decreased mortality.

A biomarker may provide a diagnosis, assess disease severity or risk, or guide other clinical interventions such as the use of drugs. Although considerable progress has been made in standardizing the methodology and reporting of randomized trials, less has been accomplished concerning the assessment of biomarkers. Biomarker studies are often presented with poor biostatistics and methodologic flaws that precludes them from providing a reliable and reproducible scientific message. A host of issues are discussed that can improve the statistical evaluation and reporting of biomarker studies. Investigators should be aware of these issues when designing their studies, editors and reviewers when analyzing a manuscript, and readers when interpreting results.

Background: Simultaneous assessment of cardiac troponin I, B-type natriuretic peptide, and C-reactive protein has been found to provide unique prognostic information in acute coronary syndromes. The current study addressed the prognostic implication of a multiple-marker approach in cardiac surgery., Methods: Two hundred twenty-four patients undergoing cardiac surgery were included and followed up within 12 months after surgery. Serial blood samples were drawn in all patients the day before surgery, at the end of surgery, and 6, 24, and 120 h after surgery. Major adverse cardiac events within 12 months after surgery were chosen as study endpoints and were defined as malignant ventricular arrhythmia, myocardial infarction, congestive heart failure, the need for myocardial revascularization, and/or death from cardiac cause. Predictive ability of each cardiac biomarker was assessed using logistic regression., Results: Accuracies of C-reactive protein, cardiac troponin I, and B-type natriuretic peptide, considered as continuous variables, to predict the occurrence of major adverse cardiac events were limited (area under receiver operating characteristic curve: 0.54 [0.47-0.60], P = 0.42; 0.62 [0.55-0.68], P = 0.01; and 0.68 [0.61-0.74], P < 0.001, respectively). When biomarkers were considered as 75% specificity dichotomized variables, elevated C-reactive protein (> 180 mg/l), cardiac troponin I (> 3.5 ng/ml), and B-type natriuretic peptide (> 880 pg/ml) were independent predictors of major adverse cardiac events (odds ratio: 2.14 [1.03-4.49], P = 0.043; 2.37 [1.25-5.64], P = 0.011; and 2.65 [1.16-4.85], P = 0.018, respectively) in a multivariate model including the European System for Cardiac Operative Risk Evaluation score., Conclusions: Simultaneous measurement of cardiac troponin I, B-type natriuretic peptide, and C-reactive protein improves the risk assessment of long-term adverse cardiac outcome after cardiac surgery.

Background: Tight perioperative control of blood glucose improves the outcome of diabetic patients undergoing cardiac surgery. Because stress response and cardiopulmonary bypass can induce profound hyperglycemia, intraoperative glycemic control may become difficult. The authors undertook a prospective cohort study to determine whether poor intraoperative glycemic control is associated with increased intrahospital morbidity., Methods: Two hundred consecutive diabetic patients undergoing on-pump heart surgery were enrolled. A standard insulin protocol based on subcutaneous intermediary insulin was given the morning of the surgery. Intravenous insulin therapy was initiated intraoperatively from blood glucose concentrations of 180 mg/dl or greater and titrated according to a predefined protocol. Poor intraoperative glycemic control was defined as four consecutive blood glucose concentrations greater than 200 mg/dl without any decrease in despite insulin therapy. Postoperative blood glucose concentrations were maintained below 140 mg/dl by using aggressive insulin therapy. The main endpoints were severe cardiovascular, respiratory, infectious, neurologic, and renal in-hospital morbidity., Results: Insulin therapy was required intraoperatively in 36% of patients, and poor intraoperative glycemic control was observed in 18% of patients. Poor intraoperative glycemic control was significantly more frequent in patients with severe postoperative morbidity (37% vs. 10%; P < 0.001). The adjusted odds ratio for severe postoperative morbidity among patients with a poor intraoperative glycemic control as compared with patients without was 7.2 (95% confidence interval, 2.7-19.0)., Conclusion: Poor intraoperative control of blood glucose concentrations in diabetic patients undergoing cardiac surgery is associated with a worsened hospital outcome after surgery.

Background: Although postoperative myocardial infarction (PMI) after vascular surgery has been described to be associated with prolonged ischemia, its exact pathophysiology remains unclear., Methods: The authors used intense cardiac troponin I (cTnI) surveillance after abdominal aortic surgery in 1,136 consecutive patients to better evaluate the incidence and timing of PMI (cTnI > or = 1.5 ng/ml) or myocardial damage (abnormal cTnI < 1.5 ng/ml)., Results: Abnormal cTnI concentrations was noted in 163 patients (14%), of which 106 (9%) had myocardial damage and 57 (5%) had PMI. In 34 patients (3%), PMI was preceded by a prolonged (> 24 h) period of increased cTnI (delayed PMI), and in 21 patients (2%), the increase in cTnI lasted less than 24 h (early PMI). The mean times from end of surgery to PMI were 37 +/- 22 and 74 +/- 39 h in the early PMI and delayed PMI groups, respectively (P < 0.001). The mean time between the first abnormal cTnI and PMI in the delayed PMI group was 54 +/- 35 h, during which the cTnI profiles of the myocardial damage and delayed PMI groups were identical. In-hospital mortality rates were 24, 21, 7, and 3% for the early PMI, delayed PMI, myocardial damage, and normal groups, respectively., Conclusions: Intense postoperative cTnI surveillance revealed two types of PMI according to time of appearance and rate of increase in cTnI. The identification of early and delayed PMI may be suggestive of different pathophysiologic mechanisms. Abnormal but low postoperative cTnI is associated with increased mortality and may lead to delayed PMI.

Background: Terlipressin, a synthetic analog of arginine-vasopressin (AVP), has been proposed as an effective vasopressive therapy in catecholamine-resistant vasodilatory shock. Although beneficial effects of terlipressin on systemic arterial pressure have been clearly demonstrated, its intrinsic effects on coronary circulation and myocardial performances remain unknown., Methods: The authors compared the coronary and myocardial effects of terlipressin (1-100 nM, n = 10), AVP (10-1000 pM, n = 10), and norepinephrine (1-100 nM, n = 10) on an erythrocyte-perfused isolated rabbit heart. The cardiac effects of terlipressin were also assessed in erythrocyte-perfused hearts in which the myocardial oxygen delivery was maintained constant and buffer-perfused hearts. Finally, the cardiac effects of terlipressin and AVP were studied in hearts pretreated by [d(CH2)5Tyr(Me)]AVP (0.1 microM), a selective V1a receptor antagonist., Results: Norepinephrine induced a biphasic coronary effect associated with a concentration-dependent increase in myocardial performances. AVP and terlipressin significantly decreased coronary blood flow and impaired myocardial performances from 30 pM and 30 nM, respectively (P < 0.05). The cardiac side-effects of terlipressin were confirmed in buffer-perfused hearts but the maintenance of a constant myocardial oxygen delivery constant abolished its effects on myocardial performances. The cardiac effects induced by terlipressin and AVP were nearly completely abolished on hearts pretreated by [d(CH2)5Tyr(Me)]AVP., Conclusions: On isolated rabbit heart, terlipressin induced a coronary vasopressor effect and in turn myocardial depression only at supratherapeutic concentrations (> or =30 nM). Its effects are mainly mediated via V1a receptors. However, these potential negative side effects on the heart were less pronounced than were those of AVP.