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.

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.

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.

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.

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.

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.

Ability of an Arterial Waveform Analysis-Derived Hypotension Prediction Index to Predict Future Hypotensive Events in Surgical Patients.

BACKGROUND: Intraoperative hypotension is associated with worse perioperative outcomes for patients undergoing major noncardiac surgery. The Hypotension Prediction Index is a unitless number that is derived from an arterial pressure waveform trace, and as the number increases, the risk of hypotension occurring in the near future increases. We investigated the diagnostic ability of the Hypotension Prediction Index in predicting impending intraoperative hypotension in comparison to other commonly collected perioperative hemodynamic variables. METHODS: This is a 2-center retrospective analysis of patients undergoing major surgery. Data were downloaded and analyzed from the Edwards Lifesciences EV1000 platform. Receiver operating characteristic curves were constructed for the Hypotension Prediction Index and other hemodynamic variables as well as event rates and time to event. RESULTS: Two hundred fifty-five patients undergoing major surgery were included in the analysis yielding 292,025 data points. The Hypotension Prediction Index predicted hypotension with a sensitivity and specificity of 85.8% (95% CI, 85.8%-85.9%) and 85.8% (95% CI, 85.8%-85.9%) 5 minutes before a hypotensive event (area under the curve, 0.926 [95% CI, 0.925-0.926]); 81.7% (95% CI, 81.6%-81.8%) and 81.7% (95% CI, 81.6%-81.8%) 10 minutes before a hypotensive event (area under the curve, 0.895 [95% CI, 0.894-0.895]); and 80.6% (95% CI, 80.5%-80.7%) and 80.6% (95% CI, 80.5%-80.7%) 15 minutes before a hypotensive event (area under the curve, 0.879 [95% CI, 0.879-0.880]). The Hypotension Prediction Index performed superior to all other measured hemodynamic variables including mean arterial pressure and change in mean arterial pressure over a 3-minute window. CONCLUSIONS: The Hypotension Prediction Index provides an accurate real time and continuous prediction of impending intraoperative hypotension before its occurrence and has superior predictive ability than the commonly measured perioperative hemodynamic variables.

Post-extrasystolic characteristics in the arterial blood pressure waveform are associated with right ventricular dysfunction in intensive care patients.

Right ventricular dysfunction (RVD) is associated with end-organ dysfunction and mortality, but has been an overlooked condition in the ICU. We hypothesized that analysis of the arterial waveform in the presence of ventricular extrasystoles could differentiate patients with RVD from patients with a normally functioning right ventricle, because the 2nd and 3rd post-ectopic beat could reflect right ventricular state (pulmonary transit time) during the preceding ectopy. We retrospectively identified patients with echocardiographic evidence of moderate-to-severe RVD and patients with a normal functioning right ventricle (control) from the MIMIC database. We identified waveform records where ECG and arterial pressure were available in combination, simultaneously with echocardiographic evaluation. Ventricular extrasystoles were visually confirmed and the median systolic blood pressure (SBP) of the 2nd and 3rd post-ectopic beats compared with the median SBP of the ten sinus beats preceding the extrasystole. We identified 34 patients in the control group and 24 patients in the RVD group with ventricular extrasystoles. The mean SBP reduction at the 2nd and 3rd beat was lower in the RVD group compared with the control group [- 1.7 (SD: 1.9) % vs. - 3.6 (SD: 1.9) %, p < 0.001], and this characteristic differentiated RVD subjects from control subjects with an AUC of 0.76 (CI [0.64; 0.89]), with a specificity of 91% and sensitivity of 50%. In this proof-of-concept study, we found that post-extrasystolic ABP characteristics were associated with RVD.

Extrasystoles for fluid responsiveness prediction in critically ill patients.

BACKGROUND: Fluid responsiveness prediction with continuously available monitoring is an unsettled matter for the vast majority of critically ill patients, and development of new and reliable methods is desired. We hypothesized that the post-ectopic beat, which is associated with increased preload, could be analyzed in relation to preceding sinus beats and that the change in cardiac performance (e.g., systolic blood pressure) at the post-ectopic beat could predict fluid responsiveness. METHODS: Critically ill patients were observed when scheduled for a 500-ml volume expansion. The 30-min ECG prior to volume expansion was analyzed for the occurrence of extrasystoles. Classification variables were defined as the change in a variable (e.g., systolic blood pressure or pre-ejection period) from the median of ten preceding sinus beats to extrasystolic post-ectopic beat. A stroke volume increase > 10% following volume expansion defined fluid responsiveness. RESULTS: Twenty-six patients were included. The change in systolic blood pressure predicted fluid responsiveness with receiver operating characteristic (ROC) area 0.79 (CI [0.52:1.00]), specificity 100%, sensitivity 67%, positive predictive value 100%, and negative predictive value 91% (threshold: 5%). The change in pre-ejection period predicted fluid responsiveness with ROC area 0.74 (CI [0.53:0.94]), specificity 78%, sensitivity 67%, positive predictive value 50%, and negative predictive value 88% (threshold 7.5 ms). CONCLUSIONS: Based on standard critical care monitoring, analysis of the extrasystolic post-ectopic beat predicts fluid responsiveness in critical care patients with good accuracy. The presented results are considered preliminary proof-of-concept results, and further validation is needed to confirm these preliminary findings.

Fluid loading and norepinephrine infusion mask the left ventricular preload decrease induced by pleural effusion.

BACKGROUND: Pleural effusion (PLE) may lead to low blood pressure and reduced cardiac output. Low blood pressure and reduced cardiac output are often treated with fluid loading and vasopressors. This study aimed to determine the impact of fluid loading and norepinephrine infusion on physiologic determinants of cardiac function obtained by ultrasonography during PLE. METHODS: In this randomised, blinded, controlled laboratory study, 30 piglets (21.9 ± 1.3 kg) had bilateral PLE (75 mL/kg) induced. Subsequently, the piglets were randomised to intervention as follows: fluid loading (80 mL/kg/h for 1.5 h, n = 12), norepinephrine infusion (0.01, 0.03, 0.05, 0.1, 0.2 and 0.3 µg/kg/min (15 min each, n = 12)) or control (n = 6). Main outcome was left ventricular preload measured as left ventricular end-diastolic area. Secondary endpoints included contractility and afterload as well as global measures of circulation. All endpoints were assessed with echocardiography and invasive pressure-flow measurements. RESULTS: PLE decreased left ventricular end-diastolic area, mean arterial pressure and cardiac output (p values < 0.001), but fluid loading (20 mL/kg) and norepinephrine infusion (0.05 µg/kg/min) restored these values (p values > 0.05) to baseline. Left ventricular contractility increased with norepinephrine infusion (p = 0.002), but was not affected by fluid loading (p = 0.903). Afterload increased in both active groups (p values > 0.001). Overall, inferior vena cava distensibility remained unchanged during intervention (p values ≥ 0.085). Evacuation of PLE caused numerical increases in left ventricular end-diastolic area, but only significantly so in controls (p = 0.006). CONCLUSIONS: PLE significantly reduced left ventricular preload. Both fluid and norepinephrine treatment reverted this effect and normalised global haemodynamic parameters. Inferior vena cava distensibility remained unchanged. The haemodynamic significance of PLE may be underestimated during fluid or norepinephrine administration, potentially masking the presence of PLE.

Using extra systoles to predict fluid responsiveness in cardiothoracic critical care patients.

Fluid responsiveness prediction is an unsettled matter for most critical care patients and new methods relying only on the continuous basic monitoring are desired. It was hypothesized that the post-ectopic beat, which is associated with increased preload, could be analyzed in relation to preceding sinus beats and that the change in cardiac performance (e.g. systolic blood pressure) at the post-ectopic beat could predict fluid responsiveness. Cardiothoracic critical care patients scheduled for a 500 ml volume expansion were observed. In the 30 min prior to volume expansion, the ECG was analyzed for occurrence of extra systoles preceded by at least 10 sinus beats. Classification variables, were defined as the change in a variable (e.g. systolic blood pressure or pre-ejection period) from the median of 10 preceding sinus beats to extra systolic post-ectopic beat. A stroke volume increase >15 % following volume expansion defined fluid responsiveness. Thirty patients were included. The change in systolic blood pressure predicted fluid responsiveness in 24 patients correctly with 83 % specificity and 75 % sensitivity (optimal threshold: 5 % systolic blood pressure increase), receiver operating characteristic (ROC) area: 0.81 (CI [0.64;0.98]). The change in pre-ejection period predicted fluid responsiveness in 22 patients correctly with 67 % specificity and 83 % sensitivity (optimal threshold: 19 ms pre-ejection period decrease), ROC area: 0.81 (CI [0.66;0.96]). Pulse pressure variation had ROC area of 0.57 (CI [0.39;0.75]). Based on standard critical care monitoring, analysis of the extra systolic post-ectopic beat predicts fluid responsiveness in cardiothoracic critical care patients with good accuracy.

Association between the sensory-motor nervous system and the autonomic nervous system in neurorehabilitation patients with severe acquired brain injury.

UNLABELLED: Abstract Introduction: The relation between motor and cognitive function and autonomic nervous system (ANS) function during neurorehabilitation following acquired brain injury (ABI) has only been investigated sporadically. In the present study, it was hypothesized that clinical measures in severely injured patients would relate to heart rate variability (HRV), a measure of autonomic function. METHODS: HRV measurements were initially performed on 49 patients (enrolled in a previous study) and follow-up (> 28 days) HRV measurements were performed. Standard deviation of normal-to-normal intervals (SDNN) and low frequency (LF) were extracted and these HRV variables were related to the clinical measures, Early Functional Ability (EFA) and Functional Independence Measure (FIM). Associations between HRV and clinical measures were analysed on admission data (only EFA), at follow-up and for the longitudinal change in measures. RESULTS: Follow-up HRV was extracted from 19 patients. SDNN and LF were significantly correlated (p < 0.05) to the EFA and FIM at follow-up, but not at admission. SDNN and LF changes were significantly correlated to EFA changes, but not FIM changes. Admission SDNN and LF were unable to provide prognostic information for the EFA and FIM at follow-up. CONCLUSION: HRV and its change during neurorehabilitation were associated to EFA and EFA changes over time. Further studies are required to clarify a number of limitations arising from this observational study.

Heart rate variability in neurorehabilitation patients with severe acquired brain injury.

INTRODUCTION: Acquired brain injury (ABI) cause neural deficits. In addition to motor and cognitive deficits, the autonomic nervous system may be affected. This has been shown for neurorehabilitation patients with traumatic brain injury (TBI) by means of reduced heart rate variability (HRV). It was hypothesized that patient groups with other ABI aetiology (mainly stroke, subarachnoid haemorrhage and anoxia) would also present reduced HRV. METHODS: Patients consecutively admitted and severely ABI injured were considered for HRV measurements. HRV was extracted as a mean of four 5-minute ECG recordings at 6 pm, 10 pm, 2 am and 6 am the following day (scheduled resting periods). One 5-minute HRV recording from a sex- and age-matched group of healthy volunteers constituted control data. Standard deviation of normal-to-normal intervals (SDNN) and low frequency (LF) were primary HRV variables. RESULTS: Of 71 admitted patients, HRV was extracted from 49 patients. Patient SDNN and LF were reduced compared to controls (SDNN: 13 ms (CI = [10.8; 15.3]) vs 40.3 ms (CI = [36.6; 44.2]), p < 0.0001; LF: 29.4 ms² (CI = [19.8; 43.7]) vs 518 ms² (CI = [419; 639]), p < 0.0001). HRV appeared identical across ABI aetiology. CONCLUSION: It was found that HRV was considerably reduced in an heterogenic ABI patient group admitted for neurorehabilitation.

Variations in the pre-ejection period induced by deep breathing do not predict the hemodynamic response to early haemorrhage in healthy volunteers.

Monitoring that can predict fluid responsiveness is an unsettled matter for spontaneously breathing patients. Mechanical ventilation induces cyclic variations in blood pressure, e.g. pulse pressure variation, whose magnitude predicts fluid responsiveness in mechanically ventilated patients. In this study, we hypothesised that a deep breathing manoeuvre with its effect on heart rate variability (HRV) could induce similar cyclic variations in blood pressure in spontaneously breathing healthy subjects and that the magnitude of these variations could predict the hemodynamic response to controlled haemorrhage. 37 blood donors were instructed to perform two simple deep breathing manoeuvres prior to blood donation; one manoeuvre with a respiratory cycle every 10 s (0.1 Hz) and one every 6 s (0.167 Hz). The variation in the pre-ejection period (∆PEP) was captured with the electrocardiographic and plethysmographic curves, while the hemodynamic response to haemorrhage was estimated with the cardiac output change assessed with ultrasonography. Respiratory HRV was estimated with root mean square of successive differences (RMSSD). Deep breathing induced cyclic changes in ∆PEP magnitude was significantly correlated to RMSSD (p < 0.005). ∆PEP indexed to RMSSD increased significantly following haemorrhage at the 0.167 Hz respiratory frequency (p = 0.01). At none of the respiratory manoeuvres was ∆PEP nor ∆PEP/RMSSD prior to haemorrhage correlated to changes in cardiac output following haemorrhage. Deep breathing induces cyclic changes in blood pressure that are strongly dependent on HRV. These blood pressure variations do, however, not predict the cardiac output response to controlled haemorrhage.