How to Dose Vancomycin in Overweight and Obese Patients with Varying Renal (Dys)function in the Novel Era of AUC 400-600 mg·h/L-Targeted Dosing.

BACKGROUND AND OBJECTIVE: The latest vancomycin guideline recommends area under the curve (AUC)-targeted dosing and monitoring for efficacy and safety. However, guidelines for AUC-targeted starting dosing in patients with obesity and/or renal insufficiency are currently lacking. This study quantifies the pharmacokinetics (PK) of vancomycin in this population and provides AUC-targeted dosing recommendations. METHODS: Vancomycin concentrations (n = 1188) from therapeutic drug monitoring of 210 overweight and obese patients with varying degrees of renal (dys)function from the ward (74.8%) and intensive care unit (ICU, 25.2%) were pooled with published rich concentration-time data (n = 207) from 20 (morbidly) obese subjects undergoing bariatric surgery. A population model was developed using NONMEM 7.4. Stochastic simulations were performed to design dosing guidelines targeting an AUC24 between 400-600 mg·h/L. RESULTS: Vancomycin clearance (CL) was found to increase linearly with total bodyweight and with renal function (CKD-EPI) in a power relation. Additionally, CL proved 15.5% lower in ICU patients. Our model shows that, to reach the target AUC between 400 and 600 mg·h/L in the first 48 h, two loading doses are required for both continuous infusion and intermittent dosing regimens. Maintenance doses were found to require adjustment for total bodyweight, renal function, and ICU admission status. With this guideline, the median AUC24 is well within the target from the start of the treatment onwards. CONCLUSIONS: To achieve safe and effective vancomycin exposure for maintenance doses in overweight and obese patients, renal function, total bodyweight, and ICU admission status should be taken into account. TRIAL REGISTRATION: The AMIGO trial was registered in the Dutch Trial Registry [NTR6058].

The association between preoperative multidisciplinary team care and patient outcome in frail patients undergoing cardiac surgery.

OBJECTIVE: To evaluate the influence of preoperative multidisciplinary team (MDT) care on perioperative management and outcomes of frail patients undergoing cardiac surgery. BACKGROUND: Frail patients are at increased risk for complications and poor functional outcome after cardiac surgery. In these patients, preoperative MDT care may improve outcomes. METHODS: Between 2018 and 2021, 1168 patients aged 70 years or older were scheduled for cardiac surgery, of whom 98 (8.4%) frail patients were referred for MDT care. The MDT discussed surgical risk, prehabilitation, and alternative treatment. Outcomes of MDT patients were compared with 183 frail patients (non-MDT group) from a historical study cohort (2015-2017). Inverse probability of treatment weighting was used to minimize bias from nonrandom allocation of MDT versus non-MDT care. Outcomes were severe postoperative complications, total days in hospital after 120 days, disability, and health-related quality of life after 120 days. RESULTS: This study included 281 patients (98 MDT and 183 non-MDT patients). Of the MDT patients, 67 (68%) had open surgery, 21 (21%) underwent minimally invasive procedures, and 10 (10%) received conservative treatment. In the non-MDT group, all patients had open surgery. Fourteen (14%) MDT patients experienced a severe complication versus 42 (23%) non-MDT patients (adjusted relative risk, 0.76; 95% CI, 0.51-0.99). Adjusted total days in hospital after 120 days was 8 days (interquartile range, 3-12 days) versus 11 days (interquartile range, 7-16 days) for MDT and non-MDT patients, respectively (P = .01). There was no difference in disability or health-related quality of life. CONCLUSIONS: Preoperative MDT care for frail patients undergoing cardiac surgery is associated with alterations in surgical management and with a lower risk for severe complications.

Advanced glycation end products for preoperative frailty screening in older cardiac surgery patients.

BACKGROUND: Advanced glycation end products (AGEs) are potential biomarkers of biological age. Skin Auto Fluorescence (SAF) can assess AGEs non-invasively. We evaluated the association of SAF levels with frailty and its predictive ability for adverse outcomes in older cardiac surgery patients. METHODS: This was a retrospective analysis of prospectively acquired data from a two-center observational cohort study. We measured SAF level in cardiac surgery patients aged ≥70. Primary outcome was preoperative frailty. A comprehensive frailty assessment was performed before surgery based on 11 individual tests assessing the physical, mental, and social domain. Frailty was defined as at least 1 positive test in each domain. Secondary outcome measures were severe postoperative complications and a composite endpoint of 1-year disability (defined by WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) questionnaire) or mortality. RESULTS: Among 555 enrolled patients, 122 (22%) were frail. SAF level was most strongly associated with dependent living status (aRR 2.45 (95% CI 1.28-4.66)) and impaired cognition (aRR 1.61 (95% CI 1.10-2.34)). A decision algorithm to identify frail patients including SAF level, sex, prescription drugs, preoperative hemoglobin, and EuroSCORE II resulted in a C-statistic of 0.72 (95% CI 0.67-0.77). SAF level was also associated with disability or death after 1 year (aRR 1.38 (95% CI 1.06-1.80)). The aRR for severe complications was 1.28 (95% CI 0.87-1.88). CONCLUSIONS: Higher SAF level is associated with frailty in older cardiac surgery patients, as well as an increased risk of death or disability. This biomarker could potentially optimize preoperative risk stratification for cardiac surgery.

Preoperative frailty and one-year functional recovery in elderly cardiac surgery patients.

OBJECTIVE: Frailty increases risk for morbidity and mortality after cardiac surgery. Its influence on functional outcome is largely unknown. We studied the association of frailty with health-related quality of life and disability after cardiac surgery. METHODS: A prospective 2-center observational cohort of 555 patients aged 70 years or more undergoing cardiac surgery. A comprehensive frailty assessment was performed before surgery based on 11 individual assessments in physical, mental, and social domains. Frailty was defined as at least 1 positive test in each domain. The primary outcome was health-related quality of life over 1 year, and the secondary outcomes were severe in-hospital complications and disability over 1 year. Adverse functional outcome was defined as the composite of a decreased health-related quality of life and disability. RESULTS: Physical frailty was most common (91%) compared with mental (39%) or social frailty (42%). Adverse functional outcome occurred in 257 patients (46%) and consisted of decreased physical health-related quality of life in 134 (24%), decreased mental health-related quality of life in 141 (25%), and disability in 120 (22%). Frailty was more common in patients with adverse functional outcome (29%) compared with patients without adverse functional outcome (16%, P < .001). Poor mobility, malnutrition, and polypharmacy were associated with a decreased health-related quality of life over time, whereas impaired physical functioning and higher self-rated health were related to increased health-related quality of life. Disability after cardiac surgery was associated with poor mobility, polypharmacy, dependent living, living alone, and lower self-rated mental health before surgery. CONCLUSIONS: Mobility, nutrition, medication use, physical functioning, and self-rated health before surgery are associated with health-related quality of life in elderly patients 1 year after cardiac surgery.

Does Intraoperative Fibrinogen Affect Blood Loss or Transfusion Practice After Aortic Arch Surgery: A Prematurely Ended Randomized Trial.

Cardiovascular surgery is often complicated by significant bleeding due to perioperative coagulopathy. The effectiveness of treatment with fibrinogen concentrate to reduce the perioperative blood transfusion rate after thoracic aortic replacement surgery in prior studies has shown conflicting results. Therefore, we conducted a double-blind randomized controlled trial to investigate if a single dose of intraoperative fibrinogen administration reduced blood loss and allogeneic transfusion rate after elective surgery for thoracic arch aneurysm with deep hypothermic circulatory arrest. Twenty patients were randomized to fibrinogen concentrate (N = 10) or placebo (N = 10). The recruitment of study patients was prematurely ended due to a low inclusion rate. Perioperative transfusion, 5-minute bleeding mass after study medication and postoperative blood loss were not different between the groups with fibrinogen concentrate or placebo. Due to small volumes of postoperative blood loss and premature study termination, a beneficial effect of fibrinogen concentrate on the number of blood transfusions could not be established. However, treatment with fibrinogen efficiently restored fibrinogen levels and clot strength to preoperative values with a more effective preserved postoperative thrombin generation capacity. This result might serve as a pilot for further multicenter studies to assess the prospective significance of automated and standardized thrombin generation as a routine assay for monitoring perioperative coagulopathy and its impact on short- and long-term operative results.

Preoperative frailty and chronic pain after cardiac surgery: a prospective observational study.

BACKGROUND: Chronic pain after cardiac surgery, whether or not related to the operation, is common and has negative impact on health related quality of life (HRQL). Frailty is a risk factor for adverse surgical outcomes, but its relationship with chronic pain after cardiac surgery is unknown. This study aimed to address the association between frailty and chronic pain following cardiac surgery. METHODS: This sub-study of the Anesthesia Geriatric Evaluation study included 518 patients ≥ 70 years undergoing elective cardiac surgery. Pain was evaluated with the Short-Form 36 questionnaire prior to and one year after surgery. Associations between chronic postoperative pain and frailty domains, including medication use, nutritional status, mobility, physical functioning, cognition, HRQL, living situation and educational level, were investigated with multivariable regression analysis. RESULTS: Chronic pain one year after cardiac surgery was reported in 182 patients (35%). Medication use, living situation, mobility, gait speed, Nagi's physical functioning and preoperative HRQL were frailty domains associated with chronic pain after surgery. For patients with chronic pain physical HRQL after one year was worse compared to patients without chronic pain (ß -10.37, 99% CI -12.57 - -8.17). CONCLUSIONS: Preoperative polypharmacy, living alone, physical frailty and lower mental HRQL are associated with chronic pain following cardiac surgery. Chronic postoperative pain is related to worse physical HRQL one year after cardiac surgery. These findings may guide future preoperative interventions to reduce chronic pain and poor HRQL after cardiac surgery in older patients. TRIAL REGISTRATION: This trial has been registered before initiation under number NCT02535728 at clinicaltrials.gov.

Ciprofloxacin Pharmacokinetics After Oral and Intravenous Administration in (Morbidly) Obese and Non-obese Individuals: A Prospective Clinical Study.

BACKGROUND AND OBJECTIVE: Ciprofloxacin is a fluoroquinolone used for empirical and targeted therapy of a wide range of infections. Despite the increase in obesity prevalence, only very limited guidance is available on whether the ciprofloxacin dose needs to be adjusted when administered orally or intravenously in (morbidly) obese individuals. Our aim was to evaluate the influence of (morbid) obesity on ciprofloxacin pharmacokinetics after both oral and intravenous administration, to ultimately guide dosing in this population. METHODS: (Morbidly) obese individuals undergoing bariatric surgery received ciprofloxacin either orally (500 mg; n = 10) or intravenously (400 mg; n = 10), while non-obese participants received semi-simultaneous oral dosing of 500 mg followed by intravenous dosing of 400 mg 3 h later (n = 8). All participants underwent rich sampling (11-17 samples) for 12 h after administration. Non-linear mixed-effects modelling and simulations were performed to evaluate ciprofloxacin exposure in plasma. Prior data from the literature were subsequently included in the model to explore exposure in soft tissue in obese and non-obese patients. RESULTS: Overall, 28 participants with body weights ranging from 57 to 212 kg were recruited. No significant influence of body weight on bioavailability, clearance or volume of distribution was identified (all p > 0.01). Soft tissue concentrations were predicted to be lower in obese individuals despite similar plasma concentrations compared with non-obese individuals. CONCLUSION: Based on plasma pharmacokinetics, we found no evidence of the influence of obesity on ciprofloxacin pharmacokinetic parameters; therefore, ciprofloxacin dosages do not need to be increased routinely in obese individuals. In the treatment of infections in tissue where impaired ciprofloxacin penetration is anticipated, higher dosages may be required. TRIAL REGISTRATION: Registered in the Dutch Trial Registry (NTR6058).

Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults.

BACKGROUND: Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the pharmacokinetics and therapeutic efficacy of a drug. In this study, we aim to assess the impact of obesity on fluconazole pharmacokinetics given orally or IV to guide dose adjustments for the obese population. METHODS: We performed a prospective pharmacokinetic study with intensive sampling in obese subjects undergoing bariatric surgery (n = 17, BMI ≥ 35 kg/m2) and non-obese healthy controls (n = 8, 18.5 ≤ BMI < 30.0 kg/m2). Participants received a semi-simultaneous oral dose of 400 mg fluconazole capsules, followed after 2 h by 400 mg IV. Population pharmacokinetic modelling and simulation were performed using NONMEM 7.3. RESULTS: A total of 421 fluconazole concentrations in 25 participants (total bodyweight 61.0-174 kg) until 48 h after dosing were obtained. An estimated bioavailability of 87.5% was found for both obese and non-obese subjects, with a 95% distribution interval of 43.9%-98.4%. With increasing total bodyweight, both higher CL and Vd were found. Sex also significantly impacted Vd, being 27% larger in male compared with female participants. CONCLUSIONS: In our population of obese but otherwise healthy individuals, obesity clearly alters the pharmacokinetics of fluconazole, which puts severely obese adults, particularly if male, at risk of suboptimal exposure, for which adjusted doses are proposed.

External Validation of the ACTA-PORT Transfusion Risk Score in Older Cardiac Surgery Patients at Risk of Frailty.

OBJECTIVES: Accurate preoperative transfusion risk stratification may serve to better manage older patients undergoing cardiac surgery. Therefore, the aim of the present study was to externally validate the existing Association of Cardiothoracic Anesthetists perioperative risk of blood transfusion (ACTA-PORT) score in a population ≥70 years of age scheduled for cardiac surgery. Furthermore, the study authors investigated the additional prognostic value of individual frailty variables to this transfusion risk score. DESIGN: A retrospective analysis. SETTING: At a tertiary-care hospital. PARTICIPANTS: Five hundred seven patients aged ≥70 years undergoing elective cardiac surgery from July 2015 to August 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the administration of a perioperative blood transfusion. Frailty domains were assessed in a preanesthesia geriatric assessment, and a priori selection of biomarkers derived from blood was determined. The original ACTA-PORT score resulted in a c-statistic of 0.78 (95% confidence interval 0.74-0.82), with moderate calibration in predicting perioperative allogeneic transfusion in older patients undergoing cardiac surgery. Model updating, using the closed testing procedure, resulted in model revision with a higher discriminatory performance (c-statistic of 0.83, 95% confidence interval 0.79-0.86) and corrected calibration slope. Iron deficiency, impaired nutritional status, and physical impairment were associated with perioperative transfusions. The addition of individual frailty variables to the updated ACTA-PORT model did not result in improved predictive performance. CONCLUSIONS: External validation of the original ACTA-PORT score showed good discrimination and moderate calibration in older patients at risk of frailty undergoing cardiac surgery. Updating the original ACTA-PORT improved the predictive performance. Careful evaluation of additional frailty domains did not add prognostic value to the ACTA-PORT score.

Critical oxygen delivery threshold during cardiopulmonary bypass in older cardiac surgery patients with increased frailty risk.

OBJECTIVES: Older patients have a higher cardiac surgery-associated acute kidney injury (CSA-AKI) related mortality. Low oxygen delivery (DO2) during cardiopulmonary bypass (CPB) is a risk factor for CSA-AKI, but critical DO2 thresholds for older patients are unknown. This study investigated critical DO2 thresholds for CSA-AKI in patients ≥70 years undergoing on-pump cardiac surgery. METHODS: Patients were enrolled from July 2015 until August 2017. CPB data from 432 patients were collected, and DO2 values were calculated per minute. The primary outcome was CSA-AKI. The association between DO2 and CSA-AKI was analysed with multivariable regression analysis. Multiple DO2 thresholds were analysed. The association between CSA-AKI and the area below the DO2 thresholds (DO2 deficit) was evaluated, as was the association between frailty and CSA-AKI. RESULTS: CSA-AKI occurred in 63 (14.6%) patients. Mean and nadir (lowest) DO2 values were lower in patients with CSA-AKI (283 vs 312 ml/min/m2; P-value <0.001 and 238 vs 270 ml/min/m2; P-value <0.001, respectively). The adjusted relative risk for CSA-AKI was 1.006 [99% confidence interval (CI) 1.001-1.012] per ml/min/m2 nadir DO2 decrease. The critical DO2 threshold was 270 ml/min/m2 [adjusted relative risk 2.06 (99% CI 1.33-2.80)]. The DO2 deficit below 270 ml/min/m2 was associated with CSA-AKI [adjusted relative risk 2.84 (99% CI 1.87-3.81)]. No association between frailty and CSA-AKI was found (P = 0.82). CONCLUSIONS: Low DO2 increased the risk for CSA-AKI in older patients who had cardiac surgery. A critical DO2 threshold of 270 ml/min/m2 was applicable for frail and non-frail patients. The efficacy of a DO2 >270 ml/min/m2 to reduce CSA-AKI in older patients needs further evaluation.

Frailty and health related quality of life three months after non-metastatic colorectal cancer diagnosis in older patients: A multi-centre prospective observational study.

BACKGROUND: Health related quality of life (HRQL) is an important outcome measure in geriatric oncology. Surgery is the main treatment for colorectal cancer (CRC) but has been associated with a loss of HRQL in older patients. This study aimed to identify determinants for a decreased HRQL at three months after CRC diagnosis. METHOD: This multi-centre observational cohort study (NCT04443816) included 273 patients aged ≥70 years diagnosed with non-metastatic CRC. A multi-domain frailty screening was performed in each patient. A decreased HRQL was defined as a mean difference ≥ 10 on the EORTC QLQ-C30 questionnaire between baseline and three months after CRC diagnosis. Determinants of a decreased HRQL were analysed using multivariable logistic regression. RESULTS: A decrease in HRQL occurred in 63 patients (23.1%). Non-surgical patients had the highest risk of decreased HRQL three months after diagnosis (adjusted odds ratio (OR) 6.4 (95% confidence interval (CI) 2.0-19.8)). The Charlson Comorbidity Index (CCI) (aOR 2.3 (95% (CI) 1.2-4.2)), the American Association of Anesthesiologists class (aOR 2.6 (95%CI 1.4-4.9)), impaired daily functioning (aOR 2.7 (95%CI 1.3-5.6)) and dependent living (aOR 1.9 (95%CI 1.1-4.5)) were associated with a decreased HRQL, mainly caused by non-surgical patients. In surgical patients, a major postoperative complication was a strong determinant of decreased HRQL and was associated with preoperative comorbidity and cognitive impairment (aOR 4.0 (95%CI 1.9-8.8)). CONCLUSION: Frailty characteristics are highly prevalent in older patients at time of CRC diagnosis but not strongly associated with a decreased HRQL after three months. Non-surgical patients and patients with major postoperative complications had the highest risk of decreased HRQL. Registered at clinicaltrials.gov trial number: NCT04443816.

The association of polypharmacy with functional decline in elderly patients undergoing cardiac surgery.

AIMS: Identifying preoperative risk factors in older patients becomes more important to reduce adverse functional outcome. This study investigated the association between preoperative medication use and functional decline in elderly cardiac surgery patients and compared polypharmacy as a preoperative screening tool to a clinical frailty assessment. METHODS: This sub-study of the Anaesthesia Geriatric Evaluation study included 518 patients aged ≥70 years undergoing elective cardiac surgery. The primary outcome was functional decline, defined as a worse health-related quality of life or disability 1 year after surgery. The association between polypharmacy (i.e. ≥5 prescriptions and <10 prescriptions) or excessive polypharmacy (i.e. ≥10 prescriptions) and functional decline was investigated using multivariable Poisson regression. Discrimination, calibration and reclassification indices were used to compare preoperative screening tools for patient selection. RESULTS: Functional decline was reported in 284 patients (55%) and preoperative polypharmacy and excessive polypharmacy showed higher risks (adjusted relative risk 1.57, 95% confidence interval [CI] 1.23-1.98 and 1.93, 95% CI 1.48-2.50, respectively). Besides cardiovascular medication, proton-pump inhibitors and central nervous system medication were significantly associated with functional decline. Discrimination between models with polypharmacy or frailty was similar (area under the curve 0.67, 95% CI 0.61-0.72). The net reclassification index improved when including polypharmacy to the basic model (17%, 95% CI 0.06-0.27). CONCLUSION: Polypharmacy is associated with functional decline in elderly cardiac surgery patients. A preoperative medication review is easily performed and could be used as screening tool to identify patients at risk for adverse outcome after cardiac surgery.

Associations Between Preoperative Biomarkers and Cardiac Surgery-Associated Acute Kidney Injury in Elderly Patients: A Cohort Study.

BACKGROUND: Acute kidney injury (AKI) is associated with mortality after cardiac surgery. Novel risk factors may improve identification of patients at risk for renal injury. The authors evaluated the association between preoperative biomarkers that reflect cardiac, inflammatory, renal, and metabolic disorders and cardiac surgery-associated AKI (CSA-AKI) in elderly patients. METHODS: This was a secondary analysis of the 2-center prospective cohort study "Anesthesia Geriatric Evaluation." Twelve biomarkers were determined preoperatively in 539 patients. Primary outcome was CSA-AKI. The association between biomarkers and CSA-AKI was investigated with multivariable logistic regression analysis. Secondary outcomes were 1-year mortality and patient-reported disability and were assessed with relative risks (RR) between patients with and without CSA-AKI. RESULTS: CSA-AKI occurred in 88 (16.3%) patients and was associated with increased risk of mortality (RR, 6.70 [95% confidence interval {CI}, 3.38-13.30]) and disability (RR, 2.13 [95% CI, 1.53-2.95]). Preoperative concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitive C-reactive protein (hs-CRP), hemoglobin, and magnesium had the strongest association with CSA-AKI. Identification of patients with CSA-AKI improved when a biomarker panel was used (area under the curve [AUC] 0.75 [95% CI, 0.69-0.80]) compared to when only clinical risk factors were used (European System for Cardiac Operative Risk Evaluation [EuroSCORE II] AUC 0.67 [95% CI, 0.62-0.73]). CONCLUSIONS: Preoperative cardiac, inflammatory, renal, and metabolic biomarkers are associated with CSA-AKI and may improve identification of patients at risk.

Increased Efficacy of Whole Lung Lavage Treatment in Alveolar Proteinosis Using a New Modified Lavage Technique.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis is an ultra-rare pulmonary disease. Whole lung lavage (WLL) is considered the gold standard therapy. We report a protocol for a new modified lavage technique (nMLT) in which controlled repetitive manual hyperinflation (MH) and intermittent chest percussion are used to enhance WLL efficacy. METHODS: We included all subjects with autoimmune pulmonary alveolar proteinosis treated with nMLT between 2013 and 2018. nMLT consisted of repetitive MH with intermittent chest percussion every third wash. We reported: instilled volume, protein concentration, and optical density using spectrophotometry. Pulmonary function (FVC %predicted and DLCO %predicted) at start of nMLT was recorded. Data are displayed as mean (±SD), median [interquartile range], or number (%). Comparisons within individuals were made using Students t test. RESULTS: We included 11 subjects (64% male) in whom a total of 67 nMLTs were performed. One nMLT consisted of 15 [12-18] washes. Protein removal was 9.80 [7.52-12.66] g per nMLT. After the first, second, and third cycle of 3 washes, 56% [49% to 61%], 81% [77% to 84%], and 91% [88% to 94%] of the final protein yield was removed, respectively. Optical density was measured 116 times and increased from 1.13 (±0.52) to 1.31 (±0.52) after MH (P<0.001). CONCLUSION: Efficacy of WLL seems to be enhanced by applying MH every 3 washes. Our technique of WLL with nMLT could be used to increase the amount of protein recruited while instilling the lung with the smallest volume of fluid as possible.

Association of Plasma Fibrinogen and Thromboelastography With Blood Loss in Complex Cardiac Surgery.

Postoperative coagulopathic bleeding is common in cardiac surgery and is associated with increased morbidity and mortality. Ideally, real-time information on in-vivo coagulation should be available. However, up to now it is unclear which perioperative coagulation parameters can be used best to accurately identify patients at increased risk of bleeding. The present study analyzed the associations of perioperative fibrinogen concentrations and whole blood viscoelastic tests with postoperative bleeding in 89 patients undergoing combined cardiac surgery procedures. Postoperative bleeding was recorded until 24 hours after surgery. Regression analyses were performed to establish associations between blood loss and coagulation parameters after cardiopulmonary bypass including a prediction model with known confounding factors for bleeding. Coagulation tests show large changes over the perioperative course with the strongest coagulopathic deviations from baseline after cardiopulmonary bypass. After adjustment for multiple confounders, viscoelastic clot strength instead of fibrinogen concentration showed a similar performance for 24 hour blood loss and a better performance for 6 hour blood loss. This makes intraoperative viscoelastic testing a useful tool to strengthen early clinical decision-making with the potential to reduce perioperative blood transfusions.

Predicting Unacceptable Pain in Cardiac Surgery Patients Receiving Morphine Maintenance and Rescue Doses: A Model-Based Pharmacokinetic-Pharmacodynamic Analysis.

BACKGROUND: Optimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery. METHODS: The rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4). RESULTS: Patients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL-1 (95% CI, 6.7-16). CONCLUSIONS: The pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed.