Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model.

Sepsis, defined as organ dysfunction caused by a dysregulated host-response to infection, is characterized by immunosuppression. The vasopressor norepinephrine is widely used to treat low blood pressure in sepsis but exacerbates immunosuppression. An alternative vasopressor is angiotensin-II, a peptide hormone of the renin-angiotensin system (RAS), which displays complex immunomodulatory properties that remain unexplored in severe infection. In a murine cecal ligation and puncture (CLP) model of sepsis, we found alterations in the surface levels of RAS proteins on innate leukocytes in peritoneum and spleen. Angiotensin-II treatment induced biphasic, angiotensin-II type 1 receptor (AT1R)-dependent modulation of the systemic inflammatory response and decreased bacterial counts in both the blood and peritoneal compartments, which did not occur with norepinephrine treatment. The effect of angiotensin-II was preserved when treatment was delivered remote from the primary site of infection. At an independent laboratory, angiotensin-II treatment was compared in LysM-Cre AT1aR-/- (Myeloid-AT1a-) mice, which selectively do not express AT1R on myeloid-derived leukocytes, and littermate controls (Myeloid-AT1a+). Angiotensin-II treatment significantly reduced post-CLP bacteremia in Myeloid-AT1a+ mice but not in Myeloid-AT1a- mice, indicating that the AT1R-dependent effect of angiotensin-II on bacterial clearance was mediated through myeloid-lineage cells. Ex vivo, angiotensin-II increased post-CLP monocyte phagocytosis and ROS production after lipopolysaccharide stimulation. These data identify a mechanism by which angiotensin-II enhances the myeloid innate immune response during severe systemic infection and highlight a potential role for angiotensin-II to augment immune responses in sepsis.

Hypotension During Vasopressor Infusion Occurs in Predictable Clusters: A Multicenter Analysis.

Background: Published evidence indicates that mean arterial pressure (MAP) below a goal range (hypotension) is associated with worse outcomes, though MAP management failures are common. We sought to characterize hypotension occurrences in ICUs and consider the implications for MAP management. Methods: Retrospective analysis of 3 hospitals' cohorts of adult ICU patients during continuous vasopressor infusion. Two cohorts were general, mixed ICU patients and one was exclusively acute spinal cord injury patients. "Hypotension-clusters" were defined where there were ≥10 min of cumulative hypotension over a 60-min period and "constant hypotension" was ≥10 continuous minutes. Trend analysis was performed (predicting future MAP using 14 min of preceding MAP data) to understand which hypotension-clusters could likely have been predicted by clinician awareness of MAP trends. Results: In cohorts of 155, 66, and 16 ICU stays, respectively, the majority of hypotension occurred within the hypotension-clusters. Failures to keep MAP above the hypotension threshold were notable in the bottom quartiles of each cohort, with hypotension durations of 436, 167, and 468 min, respectively, occurring within hypotension-clusters per day. Mean arterial pressure trend analysis identified most hypotension-clusters before any constant hypotension occurred (81.2%-93.6% sensitivity, range). The positive predictive value of hypotension predictions ranged from 51.4% to 72.9%. Conclusions: Across 3 cohorts, most hypotension occurred in temporal clusters of hypotension that were usually predictable from extrapolation of MAP trends.

Detection of cocaine 24 h after administration before nasotracheal intubation.

BACKGROUND: Cocaine may be applied to decongest the nasal mucosa before nasotracheal intubation, but patients risk a criminal offence if cocaine is detected when patients drive a car shortly after surgery. We aimed to evaluate whether benzoylecgonine levels in saliva exceeded the cut-off point 24 h after administration in patients undergoing nasotracheal intubation and whether cocaine would be detectable above the Danish legal fixed limit in blood samples 1 and 24 h after surgery. METHODS: We conducted a prospective study following approval from the local research ethics committee and the national medicine agency. Written informed consent was obtained from all patients. We included patients scheduled for surgery under general anaesthesia with nasotracheal intubation. They received 80 mg cocaine as a nasal spray 5 min before induction and nasotracheal intubation. The primary outcome was a dichotomous assessment of benzoylecgonine levels in saliva samples measured 24 h after administration of nasal cocaine with a cut-off limit of 200 ng/mL. Secondary outcomes were dichotomous assessments of cocaine in whole blood samples measured 1 and 24 h after administration of nasal cocaine with a cut-off limit of 0.01 mg/kg. RESULTS: Overall, 70 patients had valid saliva samples and 75 had valid blood samples 24 h after cocaine administration. Benzoylecgonine in saliva was traceable above the cut-off in 9/70 patients (13%; CI95%: 6% to 23%), and cocaine in blood was detected above the cut-off in 2/75 patients (3%; CI95%: 0.3% to 9%). CONCLUSION: We found benzoylecgonine traceable in saliva in 13% of patients and cocaine traceable in blood in 3% of patients 24 h after administration of 80 mg nasal cocaine. Patients should be informed when receiving cocaine and advised not to drive for at least 24 h.

Evolving Management Practices for Early Sepsis-induced Hypoperfusion: A Narrative Review.

Sepsis causes significant morbidity and mortality worldwide. Resuscitation is a cornerstone of management. This review covers five areas of evolving practice in the management of early sepsis-induced hypoperfusion: fluid resuscitation volume, timing of vasopressor initiation, resuscitation targets, route of vasopressor administration, and use of invasive blood pressure monitoring. For each topic, we review the seminal evidence, discuss the evolution of practice over time, and highlight questions for additional research. Intravenous fluids are a core component of early sepsis resuscitation. However, with growing concerns about the harms of fluid, practice is evolving toward smaller-volume resuscitation, which is often paired with earlier vasopressor initiation. Large trials of fluid-restrictive, vasopressor-early strategies are providing more information about the safety and potential benefit of these approaches. Lowering blood pressure targets is a means to prevent fluid overload and reduce exposure to vasopressors; mean arterial pressure targets of 60-65 mm Hg appear to be safe, at least in older patients. With the trend toward earlier vasopressor initiation, the need for central administration of vasopressors has been questioned, and peripheral vasopressor use is increasing, although it is not universally accepted. Similarly, although guidelines suggest the use of invasive blood pressure monitoring with arterial catheters in patients receiving vasopressors, blood pressure cuffs are less invasive and often sufficient. Overall, the management of early sepsis-induced hypoperfusion is evolving toward fluid-sparing and less-invasive strategies. However, many questions remain, and additional data are needed to further optimize our approach to resuscitation.

A retrospective study of the effects of a vasopressor bolus on systolic slope (dP/dt) and dynamic arterial elastance (Eadyn).

BACKGROUND: To enhance the utility of functional hemodynamic monitoring, the variables systolic slope (dP/dt) and dynamic arterial elastance (Eadyn) are calculated by the Hypotension Prediction Index (HPI) Acumen® Software. This study was designed to characterize the effects of phenylephrine and ephedrine on dP/dt and Eadyn. METHODS: This was a retrospective, non-randomized analysis of data collected during two clinical studies. All patients required intra-operative controlled mechanical ventilation and had an indwelling radial artery catheter connected to an Acumen IQ sensor. Raw arterial pressure waveform data was downloaded from the patient monitor and all hemodynamic measurements were calculated off-line. The anesthetic record was reviewed for bolus administrations of either phenylephrine or ephedrine. Cardiovascular variables prior to drug administration were compared to those following vasopressor administrations. The primary outcome was the difference for dP/dt and Eadyn at baseline compared with the average after the bolus administration. All data sets demonstrated non-normal distributions so statistical analysis of paired and unpaired data followed the Wilcoxon matched pairs signed-rank test or Mann-Whitney U test, respectively. RESULTS: 201 doses of phenylephrine and 100 doses of ephedrine were analyzed. All data sets are reported as median [95% CI]. Mean arterial pressure (MAP) increased from 62 [54,68] to 78 [76,80] mmHg following phenylephrine and from 59 [55,62] to 80 [77,83] mmHg following ephedrine. Stroke volume and cardiac output both increased. Stroke volume variation and pulse pressure variation decreased. Both drugs produced significant increases in dP/dt, from 571 [531, 645] to 767 [733, 811] mmHg/sec for phenylephrine and from 537 [509, 596] to 848 [779, 930] mmHg/sec for ephedrine. No significant changes in Eadyn were observed. CONCLUSION: Bolus administration of phenylephrine or ephedrine increases dP/dt but does not change Eadyn. dP/dt demonstrates potential for predicting the inotropic response to phenylephrine or ephedrine, providing guidance for the most efficacious vasopressor when treating hypotension. TRIAL REGISTRATION: Data was collected from two protocols. The first was deemed to not require written, informed consent by the Institutional Review Board (IRB). The second was IRB-approved (Effect of Diastolic Dysfunction on Dynamic Cardiac Monitors) and registered on ClinicalTrials.gov (NCT04177225).

Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials.

Vasodilatory hypotension is common in critically ill and perioperative patients, and is associated with adverse outcomes. As a nitric oxide production inhibitor, methylene blue (MB) exerts its vasoconstrictor property and is an adjuvant for catecholamine-refractory vasodilatory shock. However, the effects of MB on clinically relevant outcomes remain unclear. Therefore, the authors performed a meta-analysis of randomized trials on MB in critically ill and perioperative patients. The authors searched through databases for randomized trials on MB in critically ill and perioperative patients, which yielded 11 studies consisting of 556 patients. The primary outcome was mortality at the longest follow-up. Secondary outcomes included hemodynamic parameters and organ dysfunction (PROSPERO: CRD42023409243). Nine out of the 11 included randomized trials reported mortality, which was significantly lower in the MB group (risk ratio, 0.60 [95% CI 0.43-0.84] p = 0.003), with findings confirmed in septic shock and cardiac surgery subgroups. The authors found reduced lengths of stay in the intensive care unit (mean difference [MD], -0.9 days [95% CI -1.06 to -0.77] p < 0.001) and in the hospital (MD, -2.2 days [95% CI, -2.68 to -1.70] p < 0.001) in the MB group. MB was associated with increased mean arterial pressure (MD, 8.4 mmHg [95% CI 5.01-11.75] p < 0.001) and systemic vascular resistance (MD, 94.5 dyn/s/cm5 [95% CI 17.73-171.15] p = 0.02), with no difference in cardiac output (standardized MD, 0.16 [95% CI, -0.25 to 0.57] p = 0.45). This meta-analysis showed that MB reverses vasodilation in critically ill and perioperative patients and might improve survival. Further adequately powered randomized trials are needed to confirm these findings.

Angiotensin converting enzyme inhibitor and coenzyme Q10 as adjunctive treatment for patients with ventricular septal rupture following late onset myocardial infarction: a case report.

Ventricular Septal Rupture (VSR) is a rare complication of acute myocardial infarction and has a high mortality rate. Surgery is the definitive treatment. However, in hospitals with limited facilities, treating acute myocardial infarction patients with ventricular septal rupture, is challenging. A 74-year-old woman came to the emergency room of Dr. Koesma General Hospital, Tuban, East Java in December, 2019 with late-onset Acute Myocardial Infarction. On the following day, a new holosystolic murmur was heard in the left lower sternal border with palpable thrill. Transthoracic echocardiography showed VSR with severe pulmonary hypertension. This was followed by a drop in the blood pressure to 80/50 mmHg. The blood pressure was dependent on vasopressors until lisinopril and coenzyme Q10 were introduced. After 3 months, the haemodynamics of the patient were stable. This proved that the use of angiotensin-converting enzyme and coenzyme Q10 promotes more energy production, enables tissue healing and leads to balanced remodelling to increase the survival rate in cases of non-surgical treatment.

Incidence and outcomes of acute kidney injury including hepatorenal syndrome in hospitalized patients with cirrhosis in the US.

BACKGROUND & AIMS: Acute kidney injury (AKI) in cirrhosis is common and associated with high morbidity, but the incidence rates of different etiologies of AKI are not well described in the US. We compared incidence rates, practice patterns, and outcomes across etiologies of AKI in cirrhosis. METHODS: We performed a retrospective cohort study of 11 hospital networks, including consecutive adult patients admitted with AKI and cirrhosis in 2019. The etiology of AKI was adjudicated based on pre-specified clinical definitions (prerenal/hypovolemic AKI, hepatorenal syndrome [HRS-AKI], acute tubular necrosis [ATN], other). RESULTS: A total of 2,063 patients were included (median age 62 [IQR 54-69] years, 38.3% female, median MELD-Na score 26 [19-31]). The most common etiology was prerenal AKI (44.3%), followed by ATN (30.4%) and HRS-AKI (12.1%); 6.0% had other AKI, and 7.2% could not be classified. In our cohort, 8.1% of patients received a liver transplant and 36.5% died by 90 days. The lowest rate of death was observed in patients with prerenal AKI (22.2%; p <0.001), while death rates were higher but not significantly different from each other in those with HRS-AKI and ATN (49.0% vs. 52.7%; p = 0.42). Using prerenal AKI as a reference, the adjusted subdistribution hazard ratio (sHR) for 90-day mortality was higher for HRS-AKI (sHR 2.78; 95% CI 2.18-3.54; p <0.001) and ATN (sHR 2.83; 95% CI 2.36-3.41; p <0.001). In adjusted analysis, higher AKI stage and lack of complete response to treatment were associated with an increased risk of 90-day mortality (p <0.001 for all). CONCLUSION: AKI is a severe complication of cirrhosis. HRS-AKI is uncommon and is associated with similar outcomes to ATN. The etiology of AKI, AKI stage/severity, and non-response to treatment were associated with mortality. Further optimization of vasoconstrictors for HRS-AKI and supportive therapies for ATN are needed. IMPACT AND IMPLICATIONS: Acute kidney injury (AKI) in cirrhosis carries high morbidity, and management is determined by the etiology of injury. However, a large and well-adjudicated multicenter database from US centers that uses updated AKI definitions is lacking. Our findings demonstrate that acute tubular necrosis and hepatorenal syndrome have similar outcomes (∼50% mortality at 90 days), though hepatorenal syndrome is uncommon (12% of all AKI cases). These findings represent practice patterns at US transplant/tertiary centers and can be used as a baseline, presenting the situation prior to the adoption of terlipressin in the US.

MDCT-findings in patients with non-occlusive mesenteric ischemia (NOMI): influence of vasoconstrictor agents.

OBJECTIVES: To evaluate the influence of vasoconstrictor agents (VCAs) on signs of vasoconstriction and bowel ischemia on MDCT detected in patients with non-occlusive mesenteric ischemia (NOMI). METHODS: This 8-year single-center retrospective study consecutively included all patients with histopathologically proven NOMI who underwent MDCT ≤ 48 h prior to surgical bowel resection. Two blinded radiologists jointly reviewed each examination for signs of bowel ischemia, abdominal organ infarct, mesenteric vessel size and regularity, and ancillary vascular findings. VCA administration (length and dosage), clinical and biochemical data, risk factors, and outcomes were retrieved from patients' medical records. Subgroup comparisons were performed. RESULTS: Ninety patients were included (59 males, mean age 65 years); 40 (44.4%) had received VCAs before MDCT. Overall mortality was 32% (n = 29), with no significant difference between the two groups. In patients treated with VCAs, the calibre of the superior mesenteric artery (SMA) was smaller (p = 0.032), and vasoconstriction of its branches tended to be more important (p = 0.096) than in patients not treated with VCAs. The presence and extent of bowel ischemia did not significantly correlate with VCA administration, but abdominal organ infarcts tended to be more frequent (p = 0.005) and involved more organs (p = 0.088). The VCA group had lower mean arterial pressure (p = 0.006) and lower hemoglobin levels (p < 0.001). Several biomarkers of organ failure and inflammation, differed significantly with VCA use, proving worse clinical condition. CONCLUSIONS: MDCT demonstrates more severe SMA vasoconstriction and tends to show increased abdominal organ infarcts after VCA administration in NOMI patients compared to NOMI patients not treated with VCAs. KEY POINTS: • In critically ill patients with NOMI, MDCT demonstrates VCA support via increased vasoconstriction of the main SMA and its branches. • VCA administration in NOMI patients tends to contribute to the development of organ infarcts, as shown on MDCT. • An important degree of vasoconstriction in NOMI patients may indicate insufficient resuscitation and, thus, help clinicians in further patient management.

Vasopressin Response and Clinical Trajectory in Septic Shock Patients.

BACKGROUND: In septic shock, vasopressors aim to improve tissue perfusion and prevent persistent organ dysfunction, a characteristic of chronic critical illness (CCI). Adjunctive vasopressin is often used to decrease catecholamine dosage, but the association of vasopressin response with subsequent patient outcomes is unclear. We hypothesized vasopressin response is associated with favorable clinical trajectory. METHODS: We included patients with septic shock receiving vasopressin as a catecholamine adjunct in this retrospective cohort study. We defined vasopressin response as a lowering of the catecholamine dose required to maintain mean arterial pressure ≥65 mm Hg, 6 h after vasopressin initiation. Clinical trajectories were adjudicated as early death (ED; death before day 14), CCI (ICU stay ≥14 days with persistent organ dysfunction), or rapid recovery (RR; not meeting ED or CCI criteria). Trajectories were placed on an ordinal scale with ED the worst outcome, CCI next, and RR the best outcome. The association of vasopressin response with clinical trajectory was assessed with multivariable ordinal logistic regression. RESULTS: In total 938 patients were included; 426 (45.4%) were vasopressin responders. The most frequent trajectory was ED (49.8%), 29.7% developed CCI, and 20.5% had rapid recovery. In survivors to ICU day 14 (those without ED), 59.2% had CCI and 40.8% experienced RR. Compared with vasopressin non-responders, vasopressin responders less frequently experienced ED (42.5% vs. 55.9%) and more frequently experienced RR (24.6% vs. 17.0%; P < 0.01). After controlling for confounders, vasopressin response was independently associated with higher odds of developing a better clinical trajectory (OR 1.63; 95% CI 1.26-2.10). Medical patients most frequently developed ED and survivors more commonly developed CCI than RR; surgical patients developed the three trajectories with similar frequency (P < 0.01). CONCLUSIONS: Vasopressin responsive status was associated with improved clinical trajectory in septic shock patients. Early vasopressin response is a potential novel prognostic marker for short-term clinical trajectory.

Liberation from Invasive Mechanical Ventilation with Continued Receipt of Vasopressor Infusions.

Rationale: Weaning protocols for discontinuation of invasive mechanical ventilation often mandate resolution of shock. Whether extubation while receiving vasopressors is associated with harm is uncertain. Objectives: To examine whether extubation while still receiving vasopressors is associated with worse outcomes. Methods: We performed a retrospective cohort study of adults in Calgary ICUs who received vasopressors with invasive mechanical ventilation and an extubation attempt. The primary exposure was continued vasopressor use at extubation. The primary outcome was reintubation within 96 hours. Secondary outcomes included in-hospital mortality and ICU/hospital length of stay (LOS). We assessed associations of vasopressor use at extubation with outcomes using multivariable competing-risk (reintubation/LOS) and Cox proportional-hazards (mortality) models. Measurements and Main Results: Of 6,140 patients who received invasive mechanical ventilation while on vasopressors, 721 (11.7%) were extubated while receiving vasopressors, and 5,419 (88.3%) after discontinuation. Extubation on vasopressors was not, in aggregate, significantly associated with an increased hazard of reintubation (subhazard ratio [SHR], 1.81 [95% confidence interval, 0.91-3.61]; P = 0.09). Both mortality (hazard ratio, 1.22 [1.02-1.47]; P = 0.03) and time to hospital discharge (SHR for remaining hospitalized, 0.78 [0.68-0.91]; P < 0.01) were increased. Extubation on high-dose vasopressors (>0.1 µg/kg/min) was associated with a greater hazard of reintubation (SHR, 2.25 [1.01-4.98]; P = 0.046) compared with extubation after vasopressor discontinuation. Meanwhile, extubation on low-dose vasopressors (⩽0.1 µg/kg/min) was associated with a lower mortality (hazard ratio, 0.69 [0.51-0.91]; P = 0.01) and a shorter ICU LOS (SHR, 1.34 [1.09-1.65]; P = 0.01), but no difference in reintubation or hospital LOS as compared with those weaned off vasopressors. Conclusions: Extubation while receiving high-dose but not low-dose vasopressors was associated with an increased risk of reintubation.

Intraoperative Versus Postoperative Hydroxocobalamin for Vasoplegic Shock in Cardiothoracic Surgery.

OBJECTIVES: Hydroxocobalamin inhibits nitric oxide pathways contributing to vasoplegic shock in patients undergoing cardiopulmonary bypass (CPB). The objective of this study was to evaluate the effect of intraoperative versus postoperative application of hydroxocobalamin for vasoplegic shock in patients undergoing CPB. DESIGN: This was a historic cohort study. SETTING: The study was conducted at a quaternary academic cardiovascular surgery program. PARTICIPANTS: Adults undergoing cardiac surgery using CPB were participants in the study. INTERVENTIONS: Hydroxocobalamin (5 g) intravenously over 15 minutes. MEASUREMENTS AND MAIN RESULTS: The treatment groups were assigned based on the receipt location of hydroxocobalamin (ie, intensive care unit [ICU] versus operating room [OR]). The primary outcome was vasopressor-free days in the first 14 days after CPB. Of the 112 patients included, 37 patients received hydroxocobalamin in the OR and 75 in the ICU. Patients in the OR group were younger than those in the ICU group (57.5 v 63.9 years, p = 0.007), with statistically similar American Society of Anesthesiologists scores. The mean CPB duration was 3.4 hours in the OR group and 2.9 hours in the ICU group (p = 0.09). In both groups, the norepinephrine-equivalent dose of vasopressors at hydroxocobalamin was 0.27 µg/kg/min. Days alive and free of vasopressors were not different between the OR and ICU groups (estimated difference 0.48 [95% CI -1.76-2.72], p = 0.67). The odds of postoperative renal failure, mesenteric ischemia, ICU, hospital length of stay, and in-hospital mortality were also similar between groups. CONCLUSIONS: A difference in vasopressor-free days after CPB was not found between patients who received hydroxocobalamin intraoperatively versus postoperatively for vasoplegic shock.

Can a Therapeutic Strategy for Hypotension Improve Cerebral Perfusion and Oxygenation in an Experimental Model of Hemorrhagic Shock and Severe Traumatic Brain Injury?

BACKGROUND: Restoration of brain tissue perfusion is a determining factor in the neurological evolution of patients with traumatic brain injury (TBI) and hemorrhagic shock (HS). In a porcine model of HS without neurological damage, it was observed that the use of fluids or vasoactive drugs was effective in restoring brain perfusion; however, only terlipressin promoted restoration of cerebral oxygenation and lower expression of edema and apoptosis markers. It is unclear whether the use of vasopressor drugs is effective and beneficial during situations of TBI. The objective of this study is to compare the effects of resuscitation with saline solution and terlipressin on cerebral perfusion and oxygenation in a model of TBI and HS. METHODS: Thirty-two pigs weighing 20-30 kg were randomly allocated into four groups: control (no treatment), saline (60 ml/kg of 0.9% NaCl), terlipressin (2 mg of terlipressin), and saline plus terlipressin (20 ml/kg of 0.9% NaCl + 2 mg of terlipressin). Brain injury was induced by lateral fluid percussion, and HS was induced through pressure-controlled bleeding, aiming at a mean arterial pressure (MAP) of 40 mmHg. After 30 min of circulatory shock, resuscitation strategies were initiated according to the group. The systemic and cerebral hemodynamic and oxygenation parameters, lactate levels, and hemoglobin levels were evaluated. The data were subjected to analysis of variance for repeated measures. The significance level established for statistical analysis was p < 0.05. RESULTS: The terlipressin and saline plus terlipressin groups showed an increase in MAP that lasted until the end of the experiment (p < 0.05). There was a notable increase in intracranial pressure in all groups after starting treatment for shock. Cerebral perfusion pressure and cerebral oximetry showed no improvement after hemodynamic recovery in any group. The groups that received saline at resuscitation had the lowest hemoglobin concentrations after treatment. CONCLUSIONS: The treatment of hypotension in HS with saline and/or terlipressin cannot restore cerebral perfusion or oxygenation in experimental models of HS and severe TBI. Elevated MAP raises intracranial pressure owing to brain autoregulation dysfunction caused by TBI.

Assessment of cardiovascular alterations and catecholamines serum concentration after oral surgery in patients receiving local anesthetics with epinephrine: a randomized, blind, controlled clinical trial.

OBJECTIVES: A randomized controlled clinical trial was developed to evaluate the cardiovascular effects of local anesthetics with vasoconstrictors (LAVC) in healthy and hypertensive patients undergoing teeth extraction with lidocaine 2% with epinephrine 1:100,000. MATERIALS AND METHODS: Twenty patients were divided into control (CG - normotensive patients) and experimental groups (EG - hypertensive patients). The variables analyzed were heart rate (HR), oxygen saturation (SO2), systolic and diastolic blood pressure (SBP and DBP), serum catecholamine concentration (dopamine, epinephrine, and norepinephrine), ventricular and supraventricular extrasystoles (VES and SVES respectively), and ST segment depression. Data was obtained in three different moments (initial, trans, and final). Blood samples were taken to measure the catecholamines, and a Holter device was used to measure data from the electrocardiogram including a 24-h postoperative evaluation period. The Mann-Whitney test was used to identify differences between the two groups, and the Friedman test with the adjusted Wilcoxon posttest was used for intragroup evaluation for repeated measures. RESULTS: The EG presented a lower O2S in the initial period (p = 0,001) while the sysBP showed a statistical difference for the three evaluation periods with the EG presenting the highest values. The VES was higher for the EG during the 24-h postoperative evaluation period (p = 0,041). The SVES and the serum catecholamines showed were similar between the groups. The intragroup analysis revealed significant statistical difference for the sysBP in the EG with the trans period presenting the highest measurements. The extrasystole evaluation showed that the 24-h postoperative period presented most events with only the CG not presenting statistical difference for the variable VES during this period (p = 0,112). No ST segment depression was noticed for both groups. CONCLUSIONS: Teeth extraction with LAVC can be safely executed in hypertensive patients. Blood pressure should be monitored in these patients since the sysBP presented significant differences during the surgical procedures. Cardiac arrhythmia and the serum catecholamines concentration levels seem not to be altered by the surgical procedure. Also, serum catecholamines do not influence cardiovascular changes in this type of surgery. CLINICAL RELEVANCE: LAVC can be safely used in hypertensive patients and does not increase the risk of arrhythmias or cardiac ischemia.

Hepatorenal Syndrome-Novel Insights into Diagnostics and Treatment.

Hepatorenal syndrome (HRS) is a disorder associated with cirrhosis and renal impairment, with portal hypertension as its major underlying cause. Moreover, HRS is the third most common cause of acute kidney injury, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of HRS. We discuss pathogenesis associated with HRS. Mechanisms such as dysfunction of the circulatory system, bacterial infection, inflammation, impaired renal autoregulation, circulatory, and others, which have been identified as critical pathways for development of HRS, have become easier to diagnose in recent years. Additionally, relatively recently, renal dysfunction biomarkers have been found indicating renal injury, which are involved in the pathophysiology of HRS. This review also summarizes the available information on the management of HRS, focusing on vasoconstrictive drugs, renal replacement therapy, and liver transplant together with currently being investigated novel therapies. Analyzing new discoveries for the underlying causes of this condition assists the general research to improve understanding of the mechanism of pathophysiology and thus prevention of HRS.

Efficacy of fixed-dose phenylephrine bolus for treating post-spinal hypotension: Comparison between pre-eclamptics and normotensives.

Background and Aims: Pre-eclamptic parturients may have an exaggerated response to vasopressors. This study compares the efficacy of a 50 µg fixed bolus of phenylephrine for treatment of post-spinal hypotension in pre-eclamptic versus normotensive parturients. Material and Methods: After written informed consent and ethics committee approval, 30 normotensive and 30 pre-eclamptic parturients between 18 and 40 years with singleton term pregnancy about to undergo cesarean section (CS) under spinal anesthesia were included. Post-spinal hypotension was treated with a 50 µg fixed bolus of phenylephrine. The cumulative dose of phenylephrine, the number of boluses, and the median dose required to treat the first hypotensive episode, total number of hypotensive episodes, maternal side effects, neonatal appearance, pulse, grimace, activity, and respiration (APGAR) scores, and umbilical arterial cord blood pH were noted. Statistical analysis was done using Student's t-test, Mann-Whitney U-test, Chi-square test/Fisher's exact test as appropriate. A P <0.05 was considered significant. Results: The cumulative dose and number of boluses of phenylephrine required to treat post-spinal hypotension were comparable. The median dose required to treat the first episode of post-spinal hypotension was also similar (p = 0.792). The time to develop the first hypotensive episode was significantly earlier for group N (p = 0.002). The efficacy of a single fixed bolus of 50 µg phenylephrine was similar in both groups (p = 1.000). Neonatal median APGAR scores at 1 min after birth were significantly higher for group N (p = 0.016). Conclusion: A fixed-dose bolus of 50 µg phenylephrine is safe and effective in treating post-spinal hypotension in pre-eclampsia. The efficacy of phenylephrine is comparable in pre-eclamptic and normotensive parturients.

Terlipressin and the Treatment of Hepatorenal Syndrome: How the CONFIRM Trial Moves the Story Forward.

Hepatorenal syndrome (HRS) is a form of acute kidney injury (AKI) occurring in patients with advanced cirrhosis and is associated with significant morbidity and mortality. The pathophysiology underlying HRS begins with increasing portal pressures leading to the release of vasodilatory substances that result in pooling blood in the splanchnic system and a corresponding reduction in effective circulating volume. Compensatory activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and release of arginine vasopressin serve to defend mean arterial pressure but at the cost of severe constriction of the renal vasculature, leading to a progressive, often fulminant form of AKI. There are no approved treatments for HRS in the United States, but multiple countries, including much of Europe, use terlipressin, a synthetic vasopressin analogue, as a first-line therapy. CONFIRM (A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1), the third randomized trial based in North America evaluating terlipressin, met its primary end point of showing greater rates of HRS reversal in the terlipressin arm. However, due to concerns about the apparent increased rates of respiratory adverse events and a lack of evidence for mortality benefit, terlipressin was not approved by the Food and Drug Administration (FDA). We explore the history of regulatory approval for terlipressin in the United States, examine the results from CONFIRM and the concerns they raised, and consider the future role of terlipressin in this critical clinical area of continued unmet need.

Dental Management Considerations for Patients with Cardiovascular Disease-A Narrative Review.

Dental therapists encounter patients with various systemic diseases of which cardiovascular disease (CVD) patients form a significant segment. Relation between oral health and cardiac diseases has been well established. Common cardiac disorders encountered in a dental practice include arterial hypertension, heart failure, ischemic heart disease, cardiac arrhythmias, infective endocarditis, stroke, and cardiac pacemaker. Patients with CVDs pose a significant challenge to dental therapy. These patients need special considerations and an adequate understanding of the underlying cardiovascular condition to provide safe and effective dental treatment. Based on the cardiac condition, an appropriate modification in dental care is crucial. A multidisciplinary approach including the patient's cardiologist can potentially reduce complications and improve dental treatment results. This review aims at unfolding the risks associated with the dental management of a cardiac patient and outlines the measures to be undertaken for optimum dental treatment.

Fitting Pharmacodynamic Data to the Emax Model to Assess the Inherent Potency of Topical Corticosteroids.

The widespread use of topical corticosteroids (TCs) in dermatotherapy requires a consideration of their potency and benefit/risk ratios. Although there are a variety of topical corticosteroid products (TCPs) available on the market and their potencies are ranked using different classification systems, to our knowledge, no classification system to rank the inherent potencies of TC active pharmaceutical ingredients (APIs) currently exists. Most of the published classification systems for TCPs are based on randomized clinical comparative studies and/or vasoconstrictor assay (VCA) data. The objective was to apply the US FDA's VCA to classify the inherent potencies of several TCs using standardized doses to make appropriate comparisons of the relevant APIs in solutions of the same molar concentrations. Six TC APIs were assessed for their relative potencies using healthy human participants. The Emax model was used to fit skin blanching data following application of the respective TCs, and the parameters, Emax and ED50, were derived. Emax values were used as the metric to assess potency. Statistical analyses of the data revealed that the inherent potencies of fluticasone propionate, mometasone furoate, and hydrocortisone butyrate were similar. However, there was no significant difference between hydrocortisone butyrate and clobetasol propionate, while there was a significant difference between clobetasol propionate, fluticasone propionate, and mometasone furoate. Hence, the potency of hydrocortisone butyrate appears to overlap two potency classes. Furthermore, the potencies of betamethasone valerate and methylprednisolone aceponate were similar but lower than those of all of the other APIs. The application of the VCA to classify inherent potency provides a reliable method to establish a classification system for TCs. Inherent potency assessment of TCs provides information that will be useful when choosing an appropriate TC for the development of a TCP for a specific clinical indication.

Respiratory events with terlipressin and albumin in hepatorenal syndrome: A review and clinical guidance.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a serious complication of severe liver disease with a clinically poor prognosis. Supportive care using vasoconstrictors and intravenous albumin are the current mainstays of therapy. Terlipressin is an efficacious vasoconstrictor that has been used for 2 decades as the first-line treatment for HRS-AKI in Europe and has demonstrated greater efficacy in improving renal function compared to placebo and other vasoconstrictors. One of the challenges associated with terlipressin use is monitoring and mitigating serious adverse events, specifically adverse respiratory events, which were noted in a subset of patients in the recently published CONFIRM trial, the largest randomized trial examining terlipressin use for HRS-AKI. In this article, we review terlipressin's pharmacology, hypothesize how its mechanism contributes to the risk of respiratory compromise and propose strategies that will decrease the frequency of these events by rationally selecting patients at lower risk for these events.