Jaap Jan Vos

Melatonin (MEL) is an endogenous hormone that regulates circadian rhythm, immune function and oxidative stress responses. Norepinephrine (NE), an endogenous catecholamine, increases blood pressure through the sympathetic nervous system and is commonly administered intraoperatively or in the clinically ill patient for hemodynamic support. Although endogenous NE is known to stimulate MEL synthesis, the effects of exogenous intravenous NE on plasma MEL concentration, particularly under general anaesthesia (GA), remain poorly characterised. This study examined the influence of intravenous NE on plasma MEL concentrations in healthy volunteers, both awake and under general anaesthesia. A secondary analysis was conducted using data from a prospective, single‐centre, cross‐over study involving volunteers who received stepwise NE infusions while awake and under total intravenous general anaesthesia. Arterial blood samples were collected to determine plasma MEL and NE concentrations. Linear mixed‐effects modelling was used to assess the relationship between NE and MEL concentrations. A total of 36 healthy volunteers were enroled, yielding 417 MEL‐NE samples. Intravenous NE administration was significantly associated with higher plasma MEL concentration, corresponding to an estimated 26% increase in MEL per 1 standard‐deviation increase in NE concentration (Estimate = 0.230, p < 0.001). MEL concentrations were approximately 43% higher in the awake phase compared to GA (Estimate = 0.356, p < 0.001). GA did not significantly modify the NE‐MEL association (Estimate = −0.02877, p = 0.528). Substantial positive correlation was observed between baseline MEL concentrations and the magnitude of the response to NE administration ( r = 0.74). In conclusion, intravenous NE increases plasma MEL concentrations in both awake and anaesthetised individuals. Substantial interindividual variation in MEL response suggests underlying physiological differences. Future studies should explore the long‐term effects of NE administration on MEL concentrations. Trial Registration: The study is registered in the Dutch Trial Register (NL9312).

BACKGROUND: Norepinephrine is commonly used to optimise arterial blood pressure during anaesthesia, yet data on its dose–response relationship are limited. Furthermore, the influence of general anaesthesia on this relationship is not well understood. OBJECTIVES: To examine the dose–response relationship between norepinephrine dose and mean arterial pressure (MAP) in healthy volunteers with and without general anaesthesia. DESIGN: Observational healthy volunteer study. SETTING: Tertiary university medical centre. PARTICIPANTS: Thirty-six healthy volunteers aged 18 to 70 years. INTERVENTION(S): Norepinephrine infusion was initiated at 0.04 μg kg ⁻¹ min ⁻¹ and increased in four equal increments to 0.20 μg kg ⁻¹ min ⁻¹ , each lasting 15 min. After a washout period, anaesthesia was induced and maintained with propofol/remifentanil, and the norepinephrine infusion protocol was repeated. Surgical stimuli were simulated using intermittent 30-s tetanic electrical stimulus. MAIN OUTCOME MEASURES: The primary endpoint was the dose–response relationship between norepinephrine dose or plasma concentration and MAP. Secondary outcomes included other haemodynamic variables such as heart rate and cardiac index. RESULTS: Norepinephrine dose–response models outperformed concentration-response models. The slope of the dose–MAP relationship was 103 (95% confidence interval (CI): 81 to 124) mmHg μg ⁻¹ kg min during the awake phase. After induction, MAP decreased by 34 mmHg (95% CI: −37 to −31) from 88 mmHg (95% CI: 85 to 91) and slope increased by 119 (95% CI: 119 to 120) mmHg μg ⁻¹ kg min during anaesthesia ( P < 0.001 difference in slopes and intercepts; cumulative slope equals approximately 222 mmHg μg ⁻¹ kg min). Norepinephrine requirement under anaesthesia can be calculated as ((target MAP − 54)/222) μg kg ⁻¹ min ⁻¹ . CONCLUSIONS: Linear models accurately described norepinephrine dose–response relationships in healthy volunteers in a simulated surgical environment, with a steeper slope observed during general anaesthesia. This relationship allows for a simple equation to estimate the required norepinephrine dose for a target blood pressure, although clinical observation and titration remain essential.

Purpose: Pediatric patients undergoing cardiac surgery are at risk of developing postoperative acute kidney injury (AKI). We hypothesized that a reduction in intraoperative renal (SrO ₂ ) or cerebral (ScO ₂ ) tissue oxygen saturation is associated with postoperative AKI. Methods: We conducted a prospective observational study including fifty pediatric patients with non-cyanotic heart disease undergoing elective surgical repair with cardiopulmonary bypass. Intraoperative SrO ₂ and ScO ₂ were monitored using near-infrared spectroscopy (O3 ^® Regional Oximetry). Relative decreases of 10% and 20% from baseline SrO ₂ and ScO ₂ were analysed, calculating the total time below the threshold, area under the threshold, and time-weighted average. The primary outcome was the association between intraoperative SrO ₂ and ScO ₂ decreases, and the occurrence of postoperative AKI defined with the ‘Kidney Disease: Improving Global Outcomes’ criteria. Secondary outcomes included the association between other known or potential risk factors for AKI and postoperative AKI. Results: The incidence of postoperative AKI was 18.4%. There was no association between the duration and extent of intraoperative reductions of SrO ₂ and ScO ₂ below 10% and 20% from baseline, and postoperative AKI (e.g., area under the threshold for ScO ₂ decreases below 10%: 36.8 [11.8 to 419.9] % min in patients with AKI vs. 9.6 [0.6 to 92.8] % min in patients without AKI, P = 0.117). Preoperative serum creatinine, body mass index, intraoperative hypotension, and blood lactate were associated with postoperative AKI. Conclusion: A decrease in intraoperative renal or cerebral tissue oxygen saturation was not associated with postoperative AKI in pediatric patients undergoing surgery for non-cyanotic congenital heart disease.

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Post-induction hypotension (MAP < 65 mmHg) occurs frequently and is usually caused by the cardiovascular adverse effects of the anaesthetic induction drugs used. We hypothesize that a clinically significant difference in the incidence and severity of hypotension will be found when different doses of propofol and remifentanil are used for induction of anaesthesia. Methods: This is a secondary analysis of a randomised controlled trial wherein four groups (A-D) of patients received one out of four different combinations of propofol and remifentanil, titrated to a predicted equipotency in probability of tolerance to laryngoscopy (PTOL) according to the Bouillon interaction model. In group A, a high dose of propofol and a low dose of remifentanil was administered, and across the groups this ratio was gradually changed until it was reversed in group D. Mean and systolic arterial blood pressure (MAP, SAP) were compared at four time points (T_baseline, T_post−bolus, T_3min, T_nadir) within and between groups Heart rate, bispectral index (BIS) and the incidence of hypotension were compared. Results: Data from 76 patients was used. At T_post−bolus a statistically significant lower MAP and SAP was found in group A versus D (p = 0.011 and p = 0.002). A significant higher heart rate was found at T_3min and T_nadir between groups A and B when compared to groups C and D (p = < 0.001 and p = 0.002). A significant difference in BIS value was found over all groups at T_3min and T_nadir (both p < 0.001). All other outcomes did not differ significantly between groups. Conclusion: Induction of anaesthesia with different predicted equipotent combinations of propofol and remifentanil did result in statistically different but clinically irrelevant differences in haemodynamic endpoints during induction of anaesthesia. Our study could not identify preferable drug combinations that decrease the risk for hypotension after induction, although they all yield a similar predicted PTOL.

Background: The effects of selective pulmonary vascular tone alterations on cardiac preload have not been previously examined. Therefore, we evaluated whether changing pulmonary vascular tone either by hypoxia or the inhalation of aerosolized prostacyclin (PGI₂) altered intrathoracic or pulmonary blood volume (ITBV, PBV, respectively), both as surrogate for left ventricular preload. Additionally, the mean systemic filling pressure analogue (Pmsa) and pressure for venous return (Pvr) were calculated as surrogate of right ventricular preload. Methods: In a randomized controlled animal study in 6 spontaneously breathing dogs, pulmonary vascular tone was increased by controlled moderate hypoxia (FiO₂ about 0.10) and decreased by aerosolized PGI₂. Also, inhalation of PGI₂ was instituted to induce pulmonary vasodilation during normoxia and hypoxia. PBV, ITBV and circulating blood volume (Vd_circ) were measured using transpulmonary thermo-dye dilution. Pmsa and Pvr were calculated post hoc. Either the Wilcoxon-signed rank test or Friedman ANOVA test was performed. Results: During hypoxia, mean pulmonary artery pressure (PAP) increased from median [IQR] 12 [8–15] to 19 [17–25] mmHg (p < 0.05). ITBV, PBV and their ratio with Vd_circ remained unaltered, which was also true for Pmsa, Pvr and cardiac output. PGI₂ co-inhalation during hypoxia normalized mean PAP to 13 (12–16) mmHg (p < 0.05), but left cardiac preload surrogates unaltered. PGI₂ inhalation during normoxia further decreased mean PAP to 10 (9–13) mmHg (p < 0.05) without changing any of the other investigated hemodynamic variables. Conclusions: In spontaneously breathing dogs, changes in pulmonary vascular tone altered PAP but had no effect on cardiac output, central blood volumes or their relation to circulating blood volume, nor on Pmsa and Pvr. These observations suggest that cardiac preload is preserved despite substantial alterations in right ventricular afterload.

Patients undergoing coronary artery bypass grafting (CABG) are at risk of developing postoperative renal impairment, amongst others caused by renal ischemia and hypoxia. Intra-operative monitoring of renal region tissue oxygenation (SrtO₂) might be a useful tool to detect renal hypoxia and predict postoperative renal impairment. Therefore, the aim of this study was to assess the ability of intra-operative SrtO₂ to predict postoperative renal impairment, defined as an increase of serum creatinine concentrations of > 10% from individual baseline, and compare this with the predictive abilities of peripheral and cerebral tissue oxygenation (SptO₂ and SctO₂, respectively) and renal specific tissue deoxygenation. Forty-one patients undergoing elective CABG were included. Near-infrared spectroscopy (NIRS) was used to measure renal region, peripheral (thenar muscle) and cerebral tissue oxygenation during surgery. Renal region specific tissue deoxygenation was defined as a proportionally larger decrease in SrtO₂ than SptO₂. ROC analyses were used to compare predictive abilities. We did not observe an association between tissue oxygenation measured in the renal region and cerebral oxygenation and postoperative renal impairment in this small retrospective study. In contrast, SptO₂ decrease > 10% from baseline was a reasonable predictor with an AUROC of 0.767 (95%CI 0.619 to 0.14; p = 0.010). Tissue oxygenation of the renal region, although non-invasively and continuously available, cannot be used in adults to predict postoperative renal impairment after CABG. Instead, peripheral tissue deoxygenation was able to predict postoperative renal impairment, suggesting that SptO₂ provides a better indication of ‘general’ tissue oxygenation status.Registered at ClinicalTrials.gov: NCT01347827, first submitted April 27, 2011.

Perioperative goal-directed therapy is considered to improve patient outcomes after high-risk surgery. The association of compliance with perioperative goal-directed therapy protocols and postoperative outcomes is unclear. The purpose of this study is to determine the effect of protocol compliance on postoperative outcomes following high-risk surgery, after implementation of a perioperative goal-directed therapy protocol. Through a before-after study design, patients undergoing elective high-risk surgery before (before-group) and after implementation of a perioperative goal-directed therapy protocol (after-group) were included. Perioperative goal-directed therapy in the after-group consisted of optimized stroke volume variation or stroke volume index and optimized cardiac index. Additionally, the association of protocol compliance with postoperative complications when using perioperative goal-directed therapy was assessed. High protocol compliance was defined as ≥ 85% of the procedure time spent within the individual targets. The difference in complications during the first 30 postoperative days before and after implementation of the protocol was assessed. In the before-group, 214 patients were included and 193 patients in the after-group. The number of complications was higher in the before-group compared to the after-group (n = 414 vs. 282; p = 0.031). In the after-group, patients with high protocol compliance for stroke volume variation or stroke volume index had less complications compared to patients with low protocol compliance for stroke volume variation or stroke volume index (n = 187 vs. 90; p = 0.01). Protocol compliance by the attending clinicians is essential and should be monitored to facilitate an improvement in postoperative outcomes desired by the implementation of perioperative goal-directed therapy protocols.

The bed-side monitoring of patients with acute and complex perturbations in cardiocirculatory function focusses predominantly on the arterial, delivery side of the circulation. Yet, as cardiac output equals venous return under steady state conditions, an adequate cardiac output is highly dependent on the venous side of the circulation. The mean systemic filling pressure (Pmsf), which equals overall intravascular pressure under zero flow conditions, is the upstream pressure for venous return and is a quantitative index of intravascular blood volume and vascular tone. Nowadays, Pmsf can be estimated indirectly at the bed-side, allowing to track changes in Pmsf, for example during the administration of fluids and vasoactive agents. It has not been proven as of yet that guiding hemodynamic management by Pmsf directly benefits patient outcome. Nevertheless, Pmsf monitoring provides an excellent opportunity to “characterize” the physiological response to hemodynamic interventions other than solely looking at arterial blood pressure and cardiac output. Therefore, Pmsf monitoring might be an important tool for improving our knowledge on hemodynamic functioning in acutely ill patients, and its use in future (outcome-related) studies should be encouraged.