INSPIRE, a publicly available research dataset for perioperative medicine.

We present the INSPIRE dataset, a publicly available research dataset in perioperative medicine, which includes approximately 130,000 surgical operations at an academic institution in South Korea over a ten-year period between 2011 and 2020. This comprehensive dataset includes patient characteristics such as age, sex, American Society of Anesthesiologists physical status classification, diagnosis, surgical procedure code, department, and type of anaesthesia. The dataset also includes vital signs in the operating theatre, general wards, and intensive care units (ICUs), laboratory results from six months before admission to six months after discharge, and medication during hospitalisation. Complications include total hospital and ICU length of stay and in-hospital death. We hope this dataset will inspire collaborative research and development in perioperative medicine and serve as a reproducible external validation dataset to improve surgical outcomes.

CON: The hypotension prediction index is not a validated predictor of hypotension.

The Hypotension Prediction Index (HPI) algorithm is a commercial prediction algorithm developed to predict hypotension, a mean arterial pressure (MAP) below 65 mmHg. Although HPI has been investigated in several studies, recent concerns of have been raised regarding HPI's predictive abilities, which may have been overstated. A selection bias may have forced the HPI algorithm to learn almost exclusively from MAP. This CON position paper describes the selection bias further and summarises the scientific status of HPI's predictive abilities, including the meaning of a recent erratum retracting the primary conclusion of a published HPI validation study. We argue that the HPI algorithm needs re-validation or complete re-development to achieve a clinically relevant 'added value' in comparison with the predictive performance of a simple and costless MAP alarm threshold in the range of 70 to 75 mmHg.

The effects of respiratory rate and tidal volume on pulse pressure variation in healthy lungs-a generalized additive model approach may help overcome limitations.

Pulse pressure variation (PPV) is a well-established method for predicting fluid responsiveness in mechanically ventilated patients. The predictive accuracy is, however, disputed for ventilation with low tidal volume (VT) or low heart-rate-to-respiratory-rate ratio (HR/RR). We investigated the effects of VT and RR on PPV and on PPV's ability to predict fluid responsiveness. We included patients scheduled for open abdominal surgery. Prior to a 250 ml fluid bolus, we ventilated patients with combinations of VT from 4 to 10 ml kg-1 and RR from 10 to 31 min-1. For each of 10 RR-VT combinations, PPV was derived using both a classic approach and a generalized additive model (GAM) approach. The stroke volume (SV) response to fluid was evaluated using uncalibrated pulse contour analysis. An SV increase > 10% defined fluid responsiveness. Fifty of 52 included patients received a fluid bolus. Ten were fluid responders. For all ventilator settings, fluid responsiveness prediction with PPV was inconclusive with point estimates for the area under the receiver operating characteristics curve between 0.62 and 0.82. Both PPV measures were nearly proportional to VT. Higher RR was associated with lower PPV. Classically derived PPV was affected more by RR than GAM-derived PPV. Correcting PPV for VT could improve PPV's predictive utility. Low HR/RR has limited effect on GAM-derived PPV, indicating that the low HR/RR limitation is related to how PPV is calculated. We did not demonstrate any benefit of GAM-derived PPV in predicting fluid responsiveness.Trial registration: ClinicalTrials.gov, reg. March 6, 2020, NCT04298931.

Combined effects of methadone and quetiapine on respiratory rate, haemodynamic variables, and temperature in conscious rats.

Fatal poisonings where both methadone and quetiapine are detected post-mortem occurs frequently in legal autopsy cases. It is unclear whether quetiapine increases the risk of fatal methadone poisoning or if it is merely detected due to widespread use. We hypothesized that methadone and quetiapine would have additive toxic effects on respiratory rate, blood pressure, and the QTc-interval. To investigate this hypothesis, we used telemetry implants for measurements of respiratory rate, haemodynamic variables, the velocity of blood pressure changes, temperature, and movement in conscious, freely moving male Wistar rats aged 12-13 weeks. The combined effects of three accumulative i.p. doses of methadone (2.5, 10, 15 mg/kg) and quetiapine (3, 10, 30 mg/kg) were compared to rats treated with the same doses of each drug alone, and a vehicle-treated group in a randomized investigator blinded study. No additive effects of quetiapine and methadone on respiratory rate, haemodynamic variables, or movement were observed. However, body temperature was significantly lower by approximately 1.5°C on average in the group treated with both methadone and quetiapine (15 + 30 mg/kg) compared to the other groups. This indicates a synergistic effect of quetiapine and methadone on thermoregulation, which may increase the risk of fatal poisoning. We suggest studying this finding further in human settings.

Individualised perioperative blood pressure and fluid therapy in oesophagectomy ­ study protocol for a randomised clinical trial

INTRODUCTION: Oesophagectomy is the mainstay of curative treatment for oesophageal cancer, but it is associated with a high risk of major complications. Goal-directed fluid therapy and individualised blood pressure management may prevent complications after surgery. Extending goal-directed fluid therapy after surgery and applying an individual blood pressure target may have substantial benefit in oesophagectomy. This is a protocol for a clinical trial implementing a novel haemodynamic protocol from the start of anaesthesia to the next day with the patient's own night-time blood pressure as the lower threshold. METHODS: This is a single-centre, single-blind, randomised, clinical trial. Oesophagectomy patients are randomised 1:1 for either perioperative haemodynamic management according to a goal-directed fluid therapy protocol with an individual target blood pressure or for standard care. The primary endpoint is the total burden of morbidity and mortality assessed by the Comprehensive Complication Index 30 days after surgery. Secondary endpoints are complications, reoperations, fluid and vasopressor dosage and quality of life at 90 days after surgery. CONCLUSIONS: The results from this trial provide an objective and easy-to-follow algorithm for fluid administration, which may improve patient-centred outcomes in oesophagectomy patients. FUNDING: The trial is supported by Aarhus University (1,293,400 DKK) and the Novo Nordisk Foundation (625,200 DKK). TRIAL REGISTRATION: EudraCT number: 2021-002816-30.

Using generalized additive models to decompose time series and waveforms, and dissect heart-lung interaction physiology.

Common physiological time series and waveforms are composed of repeating cardiac and respiratory cycles. Often, the cardiac effect is the primary interest, but for, e.g., fluid responsiveness prediction, the respiratory effect on arterial blood pressure also convey important information. In either case, it is relevant to disentangle the two effects. Generalized additive models (GAMs) allow estimating the effect of predictors as nonlinear, smooth functions. These smooth functions can represent the cardiac and respiratory cycles' effects on a physiological signal. We demonstrate how GAMs allow a decomposition of physiological signals from mechanically ventilated subjects into separate effects of the cardiac and respiratory cycles. Two examples are presented. The first is a model of the respiratory variation in pulse pressure. The second demonstrates how a central venous pressure waveform can be decomposed into a cardiac effect, a respiratory effect and the interaction between the two cycles. Generalized additive models provide an intuitive and flexible approach to modelling the repeating, smooth, patterns common in medical monitoring data.

Performance of the Hypotension Prediction Index May Be Overestimated Due to Selection Bias.

The Hypotension Prediction Index is a proprietary prediction model incorporated into a commercially available intraoperative hemodynamic monitoring system. The Hypotension Prediction Index uses multiple features of the arterial blood pressure waveform to predict hypotension. The index publication introducing the Hypotension Prediction Index describes the selection of training and validation data. Although precise details of the Hypotension Prediction Index algorithm are proprietary, the authors describe a selection process whereby a mean arterial pressure (MAP) less than 75 mmHg will always predict hypotension. We hypothesize that the data selection process introduced a systematic bias that resulted in an overestimation of the current MAP value's ability to predict future hypotension. Since current MAP is a predictive variable contributing to Hypotension Prediction Index, this exaggerated predictive performance likely also applies to the corresponding Hypotension Prediction Index value. Other existing validation studies appear similarly problematic, suggesting that additional validation work and, potentially, updates to the Hypotension Prediction Index model may be necessary.

Kinetics of 2 different high-sensitive troponins during targeted temperature management in out-of-hospital cardiac arrest patients with acute myocardial infarction: a post hoc sub-study of a randomised clinical trial.

INTRODUCTION: Short term hypothermia has been suggested to have cardio protective properties in acute myocardial infarction (AMI) by reducing infarct size as assessed by troponins. There are limited data on the kinetics of these biomarkers in comatose out-of-hospital cardiac arrest (OHCA) patients, with and without AMI, undergoing targeted temperature management (TTM) in the ICU. PURPOSE: The aim of this post hoc analyses was to evaluate and compare the kinetics of two high-sensitivity cardiac troponins in OHCA survivors, with and without acute myocardial infarction (AMI), during TTM of different durations [24 h (standard) vs. 48 h (prolonged)]. METHODS: In a sub-cohort (n = 114) of the international, multicentre, randomized controlled study "TTH48" we measured high-sensitive troponin T (hs-cTnT), high-sensitive troponin I (hs-cTnI) and CK-MB at the following time points: Arrival, 24 h, 48 h and 72 h from reaching the target temperature range of 33 ± 1 °C. All patients diagnosed with an AMI at the immediate coronary angiogram (CAG)-18 in the 24-h group and 25 in the 48-h group-underwent PCI with stent implantation. There were no stent thromboses. RESULTS: Both the hs-cTnT and hs-cTnI changes over time were highly influenced by the cause of OHCA (AMI vs. non-AMI). In contrast to non-AMI patients, both troponins remained elevated at 72 h in AMI patients. There was no difference between the two time-differentiated TTM groups in the kinetics for the two troponins. CONCLUSION: In comatose OHCA survivors with an aetiology of AMI levels of both hs-cTnI and hs-cTnT remained elevated for 72 h, which is in contrast to the well-described kinetic profile of troponins in normotherm AMI patients. There was no difference in kinetic profile between the two high sensitive assays. Different duration of TTM did not influence the kinetics of the troponins. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01689077, 20/09/2012.

Changes in arterial blood pressure characteristics following an extrasystolic beat or a fast 50 ml fluid challenge do not predict fluid responsiveness during cardiac surgery.

Prediction of fluid responsiveness is essential in perioperative goal directed therapy, but dynamic tests of fluid responsiveness are not applicable during open-chest surgery. We hypothesised that two methods could predict fluid responsiveness during cardiac surgery based on their ability to alter preload and thereby induce changes in arterial blood pressure characteristics: (1) the change caused by extrasystolic beats and (2) the change caused by a fast infusion of 50 ml crystalloid (micro-fluid challenge). Arterial blood pressure and electrocardiogram waveforms were collected during surgical preparation of the left internal mammary artery in patients undergoing coronary artery bypass surgery. Patients received a fluid challenge (5 ml/kg ideal body weight). The first 50 ml were infused in 10 s and comprised the micro-fluid challenge. Predictor variables were defined as post-ectopic beat changes (compared with sinus beats preceding ectopy) in arterial blood pressure characteristics, such as pulse pressure and systolic pressure, or micro-fluid challenge induced changes in the same blood pressure characteristics. Patients were considered fluid responsive if stroke volume index increased by 15% or more after the full fluid challenge. Diagnostic accuracy was calculated by the area under the receiver operating characteristics curve (AUC). Fifty-six patients were included for statistical analysis. Thirty-one had extrasystoles. The maximal AUC was found for the extrasystolic change in pulse pressure and was 0.70 (CI [0.35 to 1.00]). The micro-fluid challenge method generally produced lower AUC point estimates. Extrasystoles did not predict fluid responsiveness with convincing accuracy in patients undergoing cardiac surgery and changes in arterial waveform indices following a micro-fluid challenge could not predict fluid responsiveness. Given a low number of fluid responders and inherently reduced statistical power, our data does not support firm conclusions about the utility of the extrasystolic method. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT02903316. https://clinicaltrials.gov/ct2/show/NCT02903316?cond=NCT02903316&rank=1 .

Existing fluid responsiveness studies using the mini-fluid challenge may be misleading: Methodological considerations and simulations.

BACKGROUND: The mini-fluid challenge (MFC) is a clinical concept of predicting fluid responsiveness by rapidly infusing a small amount of intravenous fluids, typically 100 ml, and systematically assessing its haemodynamic effect. The MFC method is meant to predict if a patient will respond to a subsequent, larger fluid challenge, typically another 400 ml, with a significant increase in stroke volume. METHODS: We critically evaluated the general methodology of MFC studies, with statistical considerations, secondary analysis of an existing study and simulations. RESULTS: Secondary analysis of an existing study showed that the MFC could predict the total fluid response (MFC + 400 ml) with an area under the receiver operator characteristic curve (AUROC) of 0.92, but that the prediction was worse than random for the response to the remaining 400 ml (AUROC = 0.33). In a null simulation with no response to both the MFC and the subsequent fluid challenge, the commonly used analysis could predict fluid responsiveness with an AUROC of 0.73. CONCLUSION: Many existing MFC studies are likely overestimating the classification accuracy of the MFC. This should be considered before adopting the MFC into clinical practice. A better study design includes a second, independent measurement of stroke volume after the MFC. This measurement serves as reference for the response to the subsequent fluid challenge.

Persistent Opioid Use After Spine Surgery: A Prospective Cohort Study.

STUDY DESIGN: Single-center, investigator-initiated, prospective cohort study. OBJECTIVE: This study aimed to determine patient-reported reasons for persistent opioid use following elective spine surgery, assess the frequency of withdrawal symptoms, and characterize pain-related care sought after discharge. SUMMARY OF BACKGROUND DATA: Patients are often prescribed opioids at discharge from hospital following surgery. Several studies have shown that a large number of patients fail to discontinue opioid treatment and use opioids even months to years after surgery. Spine surgery has proven to be a high-risk procedure in regard to persistent opioid use. There is, however, limited evidence on why patients continue to take opioids. METHODS: Three hundred patients, scheduled to undergo spine surgery at Aarhus University Hospital, Denmark, were included. Baseline characteristics and discharge data on opioid consumption were collected. Data on opioid consumption, patient-reported reasons for opioid use, withdrawal symptoms, and pain-related care sought were collected at 3- and 6-month follow-up via a REDCap survey. RESULTS: Before surgery, opioid use was reported in 53% of patients. Three months after surgery, opioid use was reported in 60% of preoperative opioid-users and in 9% of preoperative opioid non-users. Patients reported the following reasons for postoperative opioid use: treatment of surgery-related pain (53%), treatment of surgery-related pain combined with other reasons (37%), and reasons not related to spine surgery (10%). Withdrawal symptoms were experienced by 33% of patients during the first 3 months after surgery and were associated with failure to discontinue opioid treatment (P < 0.001). Half of patients (52%) contacted health care after discharge with pain-related topics the first 3 months. CONCLUSION: Patients use opioids after spine surgery for reasons other than surgery-related pain. Withdrawal symptoms are frequent even though patients are given tapering plans at discharge. Further studies should address how to facilitate successful and safe opioid tapering in patients undergoing spine surgery.Level of Evidence: 3.

Current use of inotropes in circulatory shock.

BACKGROUND: Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treatment of patients with circulatory shock. METHODS: From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 14 questions focused on the profile of respondents, the triggering factors, first-line choice, dosing, timing, targets, additional treatment strategy, and suggested effect of inotropes. In addition, a group of 42 international ESICM experts was asked to formulate recommendations for the use of inotropes based on 11 questions. RESULTS: A total of 839 physicians from 82 countries responded. Dobutamine was the first-line inotrope in critically ill patients with acute heart failure for 84% of respondents. Two-thirds of respondents (66%) stated to use inotropes when there were persistent clinical signs of hypoperfusion or persistent hyperlactatemia despite a supposed adequate use of fluids and vasopressors, with (44%) or without (22%) the context of low left ventricular ejection fraction. Nearly half (44%) of respondents stated an adequate cardiac output as target for inotropic treatment. The experts agreed on 11 strong recommendations, all of which were based on excellent (> 90%) or good (81-90%) agreement. Recommendations include the indications for inotropes (septic and cardiogenic shock), the choice of drugs (dobutamine, not dopamine), the triggers (low cardiac output and clinical signs of hypoperfusion) and targets (adequate cardiac output) and stopping criteria (adverse effects and clinical improvement). CONCLUSION: Inotrope use in critically ill patients is quite heterogeneous as self-reported by individual caregivers. Eleven strong recommendations on the indications, choice, triggers and targets for the use of inotropes are given by international experts. Future studies should focus on consistent indications for inotrope use and implementation into a guideline for circulatory shock that encompasses individualized targets and outcomes.

SARS-CoV-2 infection and adverse outcomes in users of ACE inhibitors and angiotensin-receptor blockers: a nationwide case-control and cohort analysis.

OBJECTIVE: To examine the impact of ACE inhibitor (ACE-I)/angiotensin receptor blocker (ARB) use on rate of SARS-CoV-2 infection and adverse outcomes. METHODS: This nationwide case-control and cohort study included all individuals in Denmark tested for SARS-CoV-2 RNA with PCR from 27 February 2020 to 26 July 2020. We estimated confounder-adjusted ORs for a positive test among all SARS-CoV-2 tested, and inverse probability of treatment weighted 30-day risk and risk ratios (RRs) of hospitalisation, intensive care unit (ICU) admission and mortality comparing current ACE-I/ARB use with calcium channel blocker (CCB) use and with non-use. RESULTS: The study included 13 501 SARS-CoV-2 PCR-positive and 1 088 695 PCR-negative individuals. Users of ACE-I/ARB had a marginally increased rate of a positive PCR when compared with CCB users (aOR 1.17, 95% CI 1.00 to 1.37), but not when compared with non-users (aOR 1.00 95% CI 0.92 to 1.09).Among PCR-positive individuals, 1466 (11%) were ACE-I/ARB users. The weighted risk of hospitalisation was 36.5% in ACE-I/ARB users and 43.3% in CCB users (RR 0.84, 95% CI 0.70 to 1.02). The risk of ICU admission was 6.3% in ACE-I/ARB users and 5.4% in CCB users (RR 1.17, 95% CI 0.64 to 2.16), while the 30-day mortality was 12.3% in ACE-I/ARB users and 13.9% in CCB users (RR 0.89, 95% CI 0.61 to 1.30). The associations were similar when ACE-I/ARB users were compared with non-users. CONCLUSIONS: ACE-I/ARB use was associated neither with a consistently increased rate nor with adverse outcomes of SARS-CoV-2 infection. Our findings support the current recommendation of continuing use of ACE-Is/ARBs during the SARS-CoV-2 pandemic. TRIAL REGISTRATION NUMBER: EUPAS34887.

Renin-Angiotensin System Blockers and Adverse Outcomes of Influenza and Pneumonia: A Danish Cohort Study.

Background Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) may worsen the prognosis of coronavirus disease 2019, but any association could be confounded by the cardiometabolic conditions indicating ACE-I/ARB use. We therefore examined the impact of ACE-Is/ARBs on respiratory tract infection outcomes. Methods and Results This cohort study included all adult patients hospitalized with influenza or pneumonia from 2005 to 2018 in Denmark using population-based medical databases. Thirty-day mortality and risk of admission to the intensive care unit in ACE-Is/ARBs users was compared with nonusers and with users of calcium channel blockers. We used propensity scores to handle confounding and computed propensity score-weighted risks, risk differences (RDs), and risk ratios (RRs). Of 568 019 patients hospitalized with influenza or pneumonia, 100 278 were ACE-I/ARB users and 37 961 were users of calcium channel blockers. In propensity score-weighted analyses, ACE-I/ARB users had marginally lower 30-day mortality than users of calcium channel blockers (13.9% versus 14.5%; RD, -0.6%; 95% CI, -1.0 to -0.1; RR, 0.96; 95% CI, 0.93-0.99), and a lower risk of admission to the intensive care unit (8.0% versus 9.6%; RD, -1.6%; 95% CI, -2.0 to -1.2; RR, 0.83; 95% CI, 0.80-0.87). Compared with nonusers, current ACE-I/ARB users had lower mortality (RD, -2.4%; 95% CI, -2.8 to -2.0; RR, 0.85; 95% CI, 0.83-0.87), but similar risk of admission to the intensive care unit (RD, 0.4%; 95% CI, 0.0-0.7; RR, 1.04; 95% CI, 1.00-1.09). Conclusions Among patients with influenza or pneumonia, ACE-I/ARB users had no increased risk of admission to the intensive care unit and slightly reduced mortality after controlling for confounding.