Tanja A. Treschan

The vasopressin system : Physiology and clinical strategies

Vasopressin, synthesized in the hypothalamus, is released by increased plasma osmolality, decreased arterial pressure, and reductions in cardiac volume. Three subtypes of vasopressin receptors, V1, V2, and V3, have been identified, mediating vasoconstriction, water reabsorption, and central nervous system effects, respectively. Vasopressin and its analogs have been studied intensively for the treatment of states of “relative vasopressin deficiency,” such as sepsis, vasodilatory shock, intraoperative hypotension, and cardiopulmonary resuscitation. Infusion of vasopressin (0.01–0.04 U/min) decreases catecholamine requirements in patients with sepsis and other types of vasodilatory shock. Bolus application of 1 mg terlipressin, the V1 agonist, reverses refractory hypotension in anesthetized patients and has been studied in patients with septic shock and chronic liver failure. During cardiopulmonary resuscitation, a 40-U bolus dose of vasopressin may be considered to replace the first or second bolus of epinephrine regardless of the initial rhythm. The side effects of vasopressin and its analogs must be further characterized.

Protective versus Conventional Ventilation for Surgery: A Systematic Review and Individual Patient Data Meta-analysis.

Background:Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can prevent postoperative pulmonary complications (PPCs). The aim of this individual patient data meta-analysis is to evaluate the individual associations between VT size and positive end–expiratory pressure (PEEP) level and occurrence of PPC. Methods:Randomized controlled trials comparing protective ventilation (low VT with or without high levels of PEEP) and conventional ventilation (high VT with low PEEP) in patients undergoing general surgery. The primary outcome was development of PPC. Predefined prognostic factors were tested using multivariate logistic regression. Results:Fifteen randomized controlled trials were included (2,127 patients). There were 97 cases of PPC in 1,118 patients (8.7%) assigned to protective ventilation and 148 cases in 1,009 patients (14.7%) assigned to conventional ventilation (adjusted relative risk, 0.64; 95% CI, 0.46 to 0.88; P < 0.01). There were 85 cases of PPC in 957 patients (8.9%) assigned to ventilation with low VT and high PEEP levels and 63 cases in 525 patients (12%) assigned to ventilation with low VT and low PEEP levels (adjusted relative risk, 0.93; 95% CI, 0.64 to 1.37; P = 0.72). A dose–response relationship was found between the appearance of PPC and VT size (R2 = 0.39) but not between the appearance of PPC and PEEP level (R2 = 0.08). Conclusions:These data support the beneficial effects of ventilation with use of low VT in patients undergoing surgery. Further trials are necessary to define the role of intraoperative higher PEEP to prevent PPC during nonopen abdominal surgery.

Argatroban Anticoagulation in Critically Ill Patients

Background: Despite long-term use of argatroban in clinical practice, no dosing recommendations exist for critically ill patients with multiple organ dysfunction (MODS) and suspected or proven heparin-induced thrombocytopenia (HIT). Objective: To determine the suitability of argatroban use in critically ill patients with MODS and HIT. Methods: We conducted prospective observation of 24 consecutive patients with suspected HIT who were being anticoagulated with argatroban (target activated partial thromboplastin time [aPTT] 1.5–2 times normal or 50–60 sec) using 2 μg/kg/min in the first 5 patients and 0.2 μg/kg/min in the subsequent 19 patients. Results: Infusion of argatroban 2 μg/kg/min over 4 hours caused bleeding complications in 3 patients as aPTT increased from 51 ± 18 to 86 ± 34 seconds (p = 0.02), prothrombin time (PT) decreased from 76 ± 27% to 33 ± 12% of normal reference values, and international normalized ratio (INR) increased from 1.4 ± 0.4 to 2.5 ± 0.9 (p = 0.007). Infusion of argatroban 0.2 μg/kg/min over 4 hours provided sufficient anticoagulation without bleeding complications. The aPTT in this population increased from 44 ± 9 to 59 ± 13 seconds (p < 0.001), and PT and INR remained unchanged (76 ± 22% and 69 ± 23% of normal reference values, 1.3 ± 0.3 and after 1.3 ± 0.3, respectively [p = 0.4]). Coagulation variables (aPTT, PT, INR) were significantly different between both dosing regimens after 4 hours of infusion (p = 0.042 and p = 0.003, respectively). The maintenance dose for target aPTT averaged 0.22 ± 0.15 μg/kg/min in both groups. Conclusions: In critically ill patients with MODS, argatroban 2 μg/kg/min, as recommended by the manufacturer, resulted in extensive anticoagulation. A tenfold lower starting dose is sufficient and safe for effective anticoagulation in this specific patient population.

Thoracic epidural anesthesia increases tissue oxygenation during major abdominal surgery.

Intraoperative surgical stress may markedly increase adrenergic nerve activity and plasma catecholamine concentrations, which causes peripheral vasoconstriction and decreased tissue oxygen partial pressure possibly leading to tissue hypoxia. Tissue hypoxia is associated with an increased incidence of surgical wound infections. Thoracic epidural anesthesia blocks afferent neural stimuli and inhibits efferent sympathetic outflow in response to painful stimuli. Consequently, we tested the hypothesis that supplemental thoracic epidural anesthesia during major abdominal surgery improves tissue perfusion and subcutaneous oxygen tension. Thirty patients were randomly assigned to two groups: general (n = 15) or combined general and epidural anesthesia (n = 15). Anesthesia technique and fluid management were standardized. Subcutaneous tissue oxygen tension was measured continuously in the upper arm with a Clark type electrode. Data were compared with unpaired, two-tailed t-tests, Wilcoxon’s ranked sum test, or repeated-measures analysis of variance and Scheffé F tests as appropriate; P < 0.05 was considered statistically significant. After 60 min, intraoperative tissue oxygen tension was significantly larger during combined anesthesia than during general anesthesia (54.3 ± 7.4 mm Hg versus 42.1 ± 8.6 mm Hg; P = 0.0002). Subcutaneous tissue oxygen tension remained significantly higher in the combined general/epidural anesthesia group throughout the observation period. Hemodynamic responses and global oxygen variables were similar in the groups. Thoracic epidural anesthesia improved intraoperative tissue oxygen tension outside the area of the epidural block. Thus, our results give evidence that supplemental neural nociceptive block blunts generalized vasoconstriction caused by surgical stress and adrenergic responses.

Ventilation with low tidal volumes during upper abdominal surgery does not improve postoperative lung function

BACKGROUND Prolonged postoperative decrease in lung function is common after major upper abdominal surgery. Evidence suggests that ventilation with low tidal volumes may limit the damage during mechanical ventilation. We compared postoperative lung function of patients undergoing upper abdominal surgery, mechanically ventilated with high or low tidal volumes. METHODS This was a double-blind, prospective, randomized controlled clinical trial. One hundred and one patients (age ≥ 50 yr, ASA ≥ II, duration of surgery ≥ 3 h) were ventilated with: (i) high [12 ml kg(-1) predicted body weight (PBW)] or (ii) low (6 ml kg(-1) PBW) tidal volumes intraoperatively. The positive end-expiratory pressure was 5 cm H(2)O in both groups and breathing frequency adjusted to normocapnia. Time-weighted averages (TWAs) of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) until 120 h after operation were compared (P<0.025 considered statistically significant). Secondary outcomes were oxygenation, respiratory and non-respiratory complications, length of stay and mortality. RESULTS The mean (sd) values of TWAs of FVC and FEV(1) were similar in both groups: FVC: 6 ml group 1.8 (0.7) litre vs 12 ml group 1.6 (0.5) litre (P=0.12); FEV(1): 6 ml group 1.4 (0.5) litre vs 12 ml group 1.2 (0.4) litre (P=0.15). FVC and FEV(1) at any single time point and secondary outcomes did not differ significantly between groups. CONCLUSIONS Prolonged impaired lung function after major abdominal surgery is not ameliorated by low tidal volume ventilation.

Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a meta-analysis of individual patient data.

BACKGROUND Protective mechanical ventilation strategies using low tidal volume or high levels of positive end-expiratory pressure (PEEP) improve outcomes for patients who have had surgery. The role of the driving pressure, which is the difference between the plateau pressure and the level of positive end-expiratory pressure is not known. We investigated the association of tidal volume, the level of PEEP, and driving pressure during intraoperative ventilation with the development of postoperative pulmonary complications. METHODS We did a meta-analysis of individual patient data from randomised controlled trials of protective ventilation during general anesthaesia for surgery published up to July 30, 2015. The main outcome was development of postoperative pulmonary complications (postoperative lung injury, pulmonary infection, or barotrauma). FINDINGS We included data from 17 randomised controlled trials, including 2250 patients. Multivariate analysis suggested that driving pressure was associated with the development of postoperative pulmonary complications (odds ratio [OR] for one unit increase of driving pressure 1·16, 95% CI 1·13-1·19; p<0·0001), whereas we detected no association for tidal volume (1·05, 0·98-1·13; p=0·179). PEEP did not have a large enough effect in univariate analysis to warrant inclusion in the multivariate analysis. In a mediator analysis, driving pressure was the only significant mediator of the effects of protective ventilation on development of pulmonary complications (p=0·027). In two studies that compared low with high PEEP during low tidal volume ventilation, an increase in the level of PEEP that resulted in an increase in driving pressure was associated with more postoperative pulmonary complications (OR 3·11, 95% CI 1·39-6·96; p=0·006). INTERPRETATION In patients having surgery, intraoperative high driving pressure and changes in the level of PEEP that result in an increase of driving pressure are associated with more postoperative pulmonary complications. However, a randomised controlled trial comparing ventilation based on driving pressure with usual care is needed to confirm these findings. FUNDING None.

Inspired Oxygen Fraction of 0.8 Does Not Attenuate Postoperative Nausea and Vomiting after Strabismus Surgery

Background:Postoperative nausea and vomiting (PONV) is a distressing problem after strabismus surgery. An inspired oxygen fraction has been reported to decrease PONV in patients after colon resection and to be more effective than ondansetron after gynecologic laparoscopy. Therefore, in a randomized, prospective, placebo-controlled study, the authors tested whether an inspired oxygen fraction of 0.8 decreases PONV in patients undergoing strabismus surgery and whether oxygen is more effective than ondansetron. Methods:With approval of the authors’ institutional review board, 210 patients were randomly assigned to receive one of three treatments: (1) 30% inspired oxygen in air plus intravenous administration of saline, (2) 80% inspired oxygen in air plus intravenous administration of saline, or (3) 30% inspired oxygen in air plus 75 &mgr;g/kg ondansetron intravenously during induction. General anesthesia was standardized and included etomidate, alfentanil, and mivacurium for induction and sevoflurane for maintenance. PONV was evaluated 6 and 24 h postoperatively by an investigator unaware of treatment assignment. Results:Overall postoperative incidence of nausea and vomiting was 41% for inspired oxygen fraction of 0.3 plus placebo, 38% for inspired oxygen fraction of 0.8 plus placebo, and 28% for inspired oxygen fraction of 0.3 plus ondansetron, respectively (P = 0.279). Therefore, there was no statistically significant difference of PONV incidence among groups. Conclusions:An inspired oxygen fraction of 0.8 during general anesthesia with sevoflurane does not decrease PONV in patients undergoing strabismus repair. Ondansetron also did not significantly decrease PONV in our study setting.

Nitrous oxide increases the incidence of bowel distension in patients undergoing elective colon resection

Background:  Nitrous oxide rapidly inflates gas‐filled spaces such as the intestines; but whether the resulting bowel distension is clinically important remains unclear. We therefore tested the hypothesis that nitrous oxide produces clinically important bowel distension.

Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial

IntroductionCritically ill patients often require renal replacement therapy accompanied by thrombocytopenia. Thrombocytopenia during heparin anticoagulation may be due to heparin-induced thrombocytopenia with need for alternative anticoagulation. Therefore, we compared argatroban and lepirudin in critically ill surgical patients.MethodsFollowing institutional review board approval and written informed consent, critically ill surgical patients more than or equal to 18 years with suspected heparin-induced thrombocytopenia, were randomly assigned to receive double-blind argatroban or lepirudin anticoagulation targeting an activated Partial Thromboplastin Time (aPTT) of 1.5 to 2 times baseline. In patients requiring continuous renal replacement therapy we compared the life-time of hemodialysis filters. We evaluated in all patients the incidence of bleeding and thrombembolic events.ResultsWe identified 66 patients with suspected heparin-induced thrombocytopenia, including 28 requiring renal replacement therapy. Mean filter lifetimes did not differ between groups (argatroban 32 ± 25 hours (n = 12) versus lepirudin 27 ± 21 hours (n = 16), mean difference 5 hours, 95% CI −13 to 23, P = 0.227). Among all 66 patients, relevant bleeding occurred in four argatroban- versus eleven lepirudin-patients (OR 3.9, 95% CI 1.1 to 14.0, P = 0.040). In the argatroban-group, three thromboembolic events occurred compared to two in the lepirudin group (OR 0.7, 95% CI 0.1 to 4.4, P = 0.639). The incidence of confirmed heparin-induced thrombocytopenia was 23% (n = 15) in our study population.ConclusionsThis first randomized controlled double-blind trial comparing two direct thrombin inhibitors showed comparable effectiveness for renal replacement therapy, but suggests fewer bleeds in surgical patients with argatroban anticoagulation.Trial registrationClinical Trials.gov NCT00798525. Registered 25 November 2008

Electrical impedance tomography during major open upper abdominal surgery: a pilot-study.

BackgroundElectrical impedance tomography (EIT) of the lungs facilitates visualization of ventilation distribution during mechanical ventilation. Its intraoperative use could provide the basis for individual optimization of ventilator settings, especially in patients at risk for ventilation-perfusion mismatch and impaired gas exchange, such as patients undergoing major open upper abdominal surgery. EIT throughout major open upper abdominal surgery could encounter difficulties in belt positioning and signal quality. Thus, we conducted a pilot-study and tested whether EIT is feasible in patients undergoing major open upper abdominal surgery.MethodsFollowing institutional review board’s approval and written informed consent, we included patients scheduled for major open upper abdominal surgery of at least 3 hours duration. EIT measurements were conducted prior to intubation, at the time of skin incision, then hourly during surgery until shortly prior to extubation and after extubation. Number of successful intraoperative EIT measurements and reasons for failures were documented. From the valid measurements, a functional EIT image of changes in tidal impedance was generated for every time point. Regions of interest were defined as horizontal halves of the picture. Monitoring of ventilation distribution was assessed using the center of ventilation index, and also using the total and dorsal ventilated lung area. All parameter values prior to and post intubation as well as extubation were compared. A p < 0.05 was considered statistically significant.ResultsA total of 120 intraoperative EIT measurements during major abdominal surgery lasting 4-13 hours were planned in 14 patients. The electrode belt was attached between the 2nd and 4th intercostal space. Consecutive valid measurements could be acquired in 13 patients (93%). 111 intraoperative measurements could be retrieved as planned (93%). Main obstacle was the contact of skin electrodes. Despite the high belt position, distribution of tidal volume showed a significant shift of ventilation towards ventral lung regions after intubation. This was reversed after weaning from mechanical ventilation.ConclusionsDespite a high belt position, monitoring of ventilation distribution is feasible in patients undergoing major open upper abdominal surgery lasting from 4 to 13 hours. Therefore, further interventional trials in order to optimize ventilatory management should be initiated.