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1.
Anesth Analg ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32175948

RESUMO

BACKGROUND: Two-thirds of the US population is considered obese and about 8% morbidly obese. Obese patients may present a unique challenge to anesthesia clinicians in airway management. Videolaryngoscopes may provide better airway visualization, which theoretically improves intubation success. However, previous work in morbidly obese patients was limited. We therefore tested the primary hypothesis that the use of McGrath video laryngoscope improves visualization of the vocal cords versus Macintosh direct laryngoscopy (Teleflex, Morrisville, NC) in morbidly obese patients. METHODS: We enrolled 130 surgical patients, aged 18-99 years, with a body mass index ≥40 kg/m and American Society of Anaesthesiologists (ASA) physical status I-III. Patients were randomly allocated 1:1-stratified for patient's body mass index ≥50 kg/m-to McGrath video laryngoscope versus direct laryngoscopy with a Macintosh blade. The study groups were compared on glottis visualization, defined as improved Cormack and Lehane classification, with proportional odds logistic regression model. RESULTS: McGrath video laryngoscope provided significantly better glottis visualization than Macintosh direct laryngoscopy with an estimated odds ratio of 4.6 (95% confidence interval [CI], 2.2-9.8; P < .01). We did not observe any evidence that number of intubation attempts and failed intubations increased or decreased. CONCLUSIONS: McGrath video laryngoscope improves glottis visualization versus Macintosh direct laryngoscopy in morbidly obese patients. Large clinical trials are needed to determine whether improved airway visualization with videolaryngoscopy reduces intubation attempts and failures.

2.
Elife ; 92020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32043966

RESUMO

In embryonic stem cells (ESCs), a core transcription factor (TF) network establishes the gene expression program necessary for pluripotency. To address how interactions between four key TFs contribute to cis-regulation in mouse ESCs, we assayed two massively parallel reporter assay (MPRA) libraries composed of binding sites for SOX2, POU5F1 (OCT4), KLF4, and ESRRB. Comparisons between synthetic cis-regulatory elements and genomic sequences with comparable binding site configurations revealed some aspects of a regulatory grammar. The expression of synthetic elements is influenced by both the number and arrangement of binding sites. This grammar plays only a small role for genomic sequences, as the relative activities of genomic sequences are best explained by the predicted occupancy of binding sites, regardless of binding site identity and positioning. Our results suggest that the effects of transcription factor binding sites (TFBS) are influenced by the order and orientation of sites, but that in the genome the overall occupancy of TFs is the primary determinant of activity.

3.
J Clin Anesth ; 62: 109729, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32006800

RESUMO

BACKGROUND: Childhood and adolescent obesity increased in recent decades, and caregivers face an increasing number of obese pediatric surgical patients. Some clinical and pharmacogenetic data suggest that obese patients have altered pain sensitivity and analgesic requirements. OBJECTIVE: To test the primary hypothesis that increased BMI in pediatric patients is associated with increased pain during the initial 48 postoperative hours. Secondarily, we tested whether BMI is associated with increased opioid consumption during the same period. DESIGN: Retrospective single-center cohort study. SETTING: Pediatric surgical wards in a tertiary medical center. PATIENTS: A total of 808 opioid naïve patients aged 8 to 18 years having elective non-cardiac surgery with hospital stay of at least 48 h in the Cleveland Clinic between 2010 and 2015. INTERVENTIONS: None. MEASUREMENTS: Using U.S. Centers for Disease Control definitions for childhood weight classifications, we retrospectively evaluated the association between body mass index (BMI) percentile and time-weighted average pain scores and opioid consumption. We used multivariable linear regression to test for an association with postoperative pain scores, and multivariable gamma regression to test for an association with postoperative opioid consumption (in mg morphine equivalents Kg-1). RESULTS: BMI was not associated with postoperative pain after general, orthopedic, or neuro-spinal surgeries. Pain increased by 0.07 [98.75% CI: (0.01, 0.13), Padj < 0.05] points per 5 percentile increase in BMI after neuro-cranial surgery. Higher BMI was associated with a decrease in postoperative opioid consumption (mean change [95% CI] -2.12% [-3.12%, -1.10%] in morphine equivalents Kg-1 per 5 percentile increase in BMI, P < 0.001). CONCLUSION: We found no clinically important increase in pain scores or opioid consumption in association with higher BMI in patients 8 to 18 years of age recovering from elective non-cardiac surgery.

4.
J Clin Monit Comput ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31989416

RESUMO

An algorithm derived from machine learning uses the arterial waveform to predict intraoperative hypotension some minutes before episodes, possibly giving clinician's time to intervene and prevent hypotension. Whether the Hypotension Prediction Index works well with noninvasive arterial pressure waveforms remains unknown. We therefore evaluated sensitivity, specificity, and positive predictive value of the Index based on non-invasive arterial waveform estimates. We used continuous hemodynamic data measured from ClearSight (formerly Nexfin) noninvasive finger blood pressure monitors in surgical patients. We re-evaluated data from a trial that included 320 adults ≥ 45 years old designated ASA physical status 3 or 4 who had moderate-to-high-risk non-cardiac surgery with general anesthesia. We calculated sensitivity and specificity for predicting hypotension, defined as mean arterial pressure ≤ 65 mmHg for at least 1 min, and characterized the relationship with receiver operating characteristics curves. We also evaluated the number of hypotensive events at various ranges of the Hypotension Prediction Index. And finally, we calculated the positive predictive value for hypotension episodes when the Prediction Index threshold was 85. The algorithm predicted hypotension 5 min in advance, with a sensitivity of 0.86 [95% confidence interval 0.82, 0.89] and specificity 0.86 [0.82, 0.89]. At 10 min, the sensitivity was 0.83 [0.79, 0.86] and the specificity was 0.83 [0.79, 0.86]. And at 15 min, the sensitivity was 0.75 [0.71, 0.80] and the specificity was 0.75 [0.71, 0.80]. The positive predictive value of the algorithm prediction at an Index threshold of 85 was 0.83 [0.79, 0.87]. A Hypotension Prediction Index of 80-89 provided a median of 6.0 [95% confidence interval 5.3, 6.7] minutes warning before mean arterial pressure decreased to < 65 mmHg. The Hypotension Prediction Index, which was developed and validated with invasive arterial waveforms, predicts intraoperative hypotension reasonably well from non-invasive estimates of the arterial waveform. Hypotension prediction, along with appropriate management, can potentially reduce intraoperative hypotension. Being able to use the non-invasive pressure waveform will widen the range of patients who might benefit.Clinical Trial Number: ClinicalTrials.gov NCT02872896.

5.
Br J Anaesth ; 124(3): e171-e177, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31980158

RESUMO

BACKGROUND: Previous studies have confirmed gender imbalance in anaesthesia leadership. Whether women anaesthesiologists aspire to career advancement has not been reported. This European Society of Anaesthesiology (ESA) survey explored anaesthesiologists' motivation to advance their careers into leadership positions, and to identify reported barriers to advancement. METHODS: ESA members (n=10 033, 5245 men, 3759 women, 1029 undefined) were invited to complete a 25-item, Internet-based survey, and responses were analysed thematically. RESULTS: In total, 3048 ESA members (1706 women, 1342 men, 30% of all members) responded to the survey. The majority were specialists, married or with a partner, and have children; 47% of women and 48% of men wish to pursue a leadership career. Barriers to career promotion noted by women were primarily attributed to work-private time considerations (extra workload and less personal time [84%], responsibility for care of family [65%], lack of part-time work opportunities [67%]), and the shift away from clinical work [59%]). Men respondents indicated the same barriers although the proportions were significantly lower. Considerations related to the partner (lack of support, career development of partner) were last on the list of variables reported by women as barriers. Importantly, many women noted deficiencies in leadership (68%) and research education (55%), and women role models (41%) and self-confidence (44%). CONCLUSIONS: This is the largest survey to date of women anaesthesiologists' view on career advancement. Despite the many barriers noted by women, they are as eager as men to assume leadership positions. The survey results help in identifying possible areas for intervention to assist in career development.


Assuntos
Anestesiologistas , Atitude do Pessoal de Saúde , Liderança , Médicas , Adulto , Mobilidade Ocupacional , Feminino , Identidade de Gênero , Humanos , Masculino , Mentores , Pessoa de Meia-Idade , Motivação , Sexismo
6.
Anesthesiology ; 132(2): 291-306, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31939844

RESUMO

BACKGROUND: Arterial pressure is a complex signal that can be characterized by systolic, mean, and diastolic components, along with pulse pressure (difference between systolic and diastolic pressures). The authors separately evaluated the strength of associations among intraoperative pressure components with myocardial and kidney injury after noncardiac surgery. METHODS: The authors included 23,140 noncardiac surgery patients at Cleveland Clinic who had blood pressure recorded at 1-min intervals from radial arterial catheters. The authors used univariable smoothing and multivariable logistic regression to estimate probabilities of each outcome as function of patients' lowest pressure for a cumulative 5 min for each component, comparing discriminative ability using C-statistics. The authors further assessed the association between outcomes and both area and minutes under derived thresholds corresponding to the beginning of increased risk for the average patient. RESULTS: Out of 23,140 patients analyzed, myocardial injury occurred in 6.1% and acute kidney injury in 8.2%. Based on the lowest patient blood pressure experienced for greater than or equal to 5 min, estimated thresholds below which the odds of myocardial or kidney injury progressively increased (slope P < 0.001) were 90 mmHg for systolic, 65 mmHg for mean, 50 mmHg for diastolic, and 35 mmHg for pulse pressure. Weak discriminative ability was noted between the pressure components, with univariable C-statistics ranging from 0.55 to 0.59. Area under the curve in the highest (deepest) quartile of exposure below the respective thresholds had significantly higher odds of myocardial injury after noncardiac surgery and acute kidney injury compared to no exposure for systolic, mean, and pulse pressure (all P < 0.001), but not diastolic, after adjusting for confounding. CONCLUSIONS: Systolic, mean, and pulse pressure hypotension were comparable in their strength of association with myocardial and renal injury. In contrast, the relationship with diastolic pressure was poor. Baseline factors were much more strongly associated with myocardial and renal injury than intraoperative blood pressure, but pressure differs in being modifiable.

7.
Anesthesiology ; 132(4): 614-624, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31977517

RESUMO

BACKGROUND: Both saline and lactated Ringer's solutions are commonly given to surgical patients. However, hyperchloremic acidosis consequent to saline administration may provoke complications. The authors therefore tested the primary hypothesis that a composite of in-hospital mortality and major postoperative complications is less common in patients given lactated Ringer's solution than normal saline. METHODS: The authors conducted an alternating cohort controlled trial in which adults having colorectal and orthopedic surgery were given either lactated Ringer's solution or normal saline in 2-week blocks between September 2015 and August 2018. The primary outcome was a composite of in-hospital mortality and major postoperative renal, respiratory, infectious, and hemorrhagic complications. The secondary outcome was postoperative acute kidney injury. RESULTS: Among 8,616 qualifying patients, 4,187 (49%) were assigned to lactated Ringer's solution, and 4,429 (51%) were assigned to saline. Each group received a median 1.9 l of fluid. The primary composite of major complications was observed in 5.8% of lactated Ringer's versus 6.1% of normal saline patients, with estimated average relative risk across the components of the composite of 1.16 (95% CI, 0.89 to 1.52; P = 0.261). The secondary outcome, postoperative acute kidney injury, Acute Kidney Injury Network stage I-III versus 0, occurred in 6.6% of lactated Ringer's patients versus 6.2% of normal saline patients, with an estimated relative risk of 1.18 (99.3% CI, 0.99 to 1.41; P = 0.009, significance criterion of 0.007). Absolute differences between the treatment groups for each outcome were less than 0.5%, an amount that is not clinically meaningful. CONCLUSIONS: In elective orthopedic and colorectal surgery patients, there was no clinically meaningful difference in postoperative complications with lactated Ringer's or saline volume replacement. Clinicians can reasonably use either solution intraoperatively.

8.
Anesthesiology ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31929326

RESUMO

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Perioperative acute kidney injury is commonIt is unclear whether this merely represents a transient increase in creatinine or has prognostic value WHAT THIS ARTICLE TELLS US THAT IS NEW: Patients with mild postoperative kidney injury (stage I) after noncardiac surgery had an estimated 2.4 times higher odds of having long-term renal dysfunction compared with patients without postoperative kidney injuryA quarter of patients who had stage I acute kidney injury postoperatively still had stage I kidney injury 1 to 2 yr later, and an additional 11% had even worse renal function BACKGROUND:: Perioperative acute kidney injury is common. However, it is unclear whether this merely represents a transient increase in creatinine or has prognostic value. Therefore, the long-term clinical importance of mild postoperative acute kidney injury remains unclear. This study assessed whether adults who do and do not experience mild kidney injury after noncardiac surgery are at similar risk for long-term renal injury. METHODS: This study is a retrospective cohort analysis of adults having noncardiac surgery at the Cleveland Clinic who had preoperative, postoperative, and long-term (1 to 2 yr after surgery) plasma creatinine measurements. The exposure (postoperative kidney injury) and outcome (long-term renal injury) were defined and staged according to the Kidney Disease: Improving Global Outcomes (KDIGO) initiative criteria. The primary analysis was for lack of association between postoperative kidney injury (stage I vs. no injury) and long-term renal injury. RESULTS: Among 15,621 patients analyzed, 3% had postoperative stage I kidney injury. Long-term renal outcomes were not similar in patients with and without postoperative stage I injury. Specifically, about 26% of patients with stage I postoperative kidney injury still had mild injury 1 to 2 yr later, and 11% had even more severe injury. A full third (37%) of patients with stage I kidney injury therefore had renal injury 1 to 2 yr after surgery. Patients with postoperative stage I injury had an estimated 2.4 times higher odds of having long-term renal dysfunction (KDIGO stage I, II, or III) compared with patients without postoperative kidney injury (odds ratio [95% CI] of 2.4 [2.0 to 3.0]) after adjustment for potential confounding factors. CONCLUSIONS: In adults recovering from noncardiac surgery, even small postoperative increases in plasma creatinine, corresponding to stage I kidney injury, are associated with renal dysfunction 1 to 2 yr after surgery. Even mild postoperative renal injury should therefore be considered a clinically important perioperative outcome.

9.
J Invest Dermatol ; 140(3): 556-567.e9, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31465738

RESUMO

An effective epidermal barrier requires structural and functional integration of adherens junctions, tight junctions, gap junctions (GJ), and desmosomes. Desmosomes govern epidermal integrity while GJs facilitate small molecule transfer across cell membranes. Some patients with severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, caused by biallelic desmoglein 1 (DSG1) mutations, exhibit skin lesions reminiscent of erythrokeratodermia variabilis, caused by mutations in connexin (Cx) genes. We, therefore, examined whether SAM syndrome-causing DSG1 mutations interfere with Cx expression and GJ function. Lesional skin biopsies from SAM syndrome patients (n = 7) revealed decreased Dsg1 and Cx43 plasma membrane localization compared with control and nonlesional skin. Cultured keratinocytes and organotypic skin equivalents depleted of Dsg1 exhibited reduced Cx43 expression, rescued upon re-introduction of wild-type Dsg1, but not Dsg1 constructs modeling SAM syndrome-causing mutations. Ectopic Dsg1 expression increased cell-cell dye transfer, which Cx43 silencing inhibited, suggesting that Dsg1 promotes GJ function through Cx43. As GJA1 gene expression was not decreased upon Dsg1 loss, we hypothesized that Cx43 reduction was due to enhanced protein degradation. Supporting this, PKC-dependent Cx43 S368 phosphorylation, which signals Cx43 turnover, increased after Dsg1 depletion, while lysosomal inhibition restored Cx43 levels. These data reveal a role for Dsg1 in regulating epidermal Cx43 turnover.

11.
Anesthesiology ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31789639

RESUMO

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Arterial pressure is a complex signal that is characterized by three primary components - systolic, diastolic, and mean pressure, along with a derived component, pulse pressure (systolic minus diastolic pressure)Each blood pressure component reflects distinct hemodynamic variables, and therefore presumably differently influences perfusion of various organsPrevious work identifies associations between intraoperative systolic and mean hypotension with myocardial and kidney injury WHAT THIS ARTICLE TELLS US THAT IS NEW: For each blood pressure component, the authors report significant and clinically meaningful associations between the lowest pressure sustained for 5 min and myocardial and kidney injuryAbsolute population risk thresholds were similar for myocardial and kidney injury, being roughly 90 mmHg for systolic, 65 mmHg for mean, 50 mmHg for diastolic, and 35 mmHg for pulse pressuresThe odds for myocardial and kidney injury progressively increased with duration and severity of hypotension below each threshold, even after adjusting for potential baseline confounding factors BACKGROUND:: Arterial pressure is a complex signal that can be characterized by systolic, mean, and diastolic components, along with pulse pressure (difference between systolic and diastolic pressures). The authors separately evaluated the strength of associations among intraoperative pressure components with myocardial and kidney injury after noncardiac surgery. METHODS: The authors included 23,140 noncardiac surgery patients at Cleveland Clinic who had blood pressure recorded at 1-min intervals from radial arterial catheters. The authors used univariable smoothing and multivariable logistic regression to estimate probabilities of each outcome as function of patients' lowest pressure for a cumulative 5 min for each component, comparing discriminative ability using C-statistics. The authors further assessed the association between outcomes and both area and minutes under derived thresholds corresponding to the beginning of increased risk for the average patient. RESULTS: Out of 23,140 patients analyzed, myocardial injury occurred in 6.1% and acute kidney injury in 8.2%. Based on the lowest patient blood pressure experienced for greater than or equal to 5 min, estimated thresholds below which the odds of myocardial or kidney injury progressively increased (slope P < 0.001) were 90 mmHg for systolic, 65 mmHg for mean, 50 mmHg for diastolic, and 35 mmHg for pulse pressure. Weak discriminative ability was noted between the pressure components, with univariable C-statistics ranging from 0.55 to 0.59. Area under the curve in the highest (deepest) quartile of exposure below the respective thresholds had significantly higher odds of myocardial injury after noncardiac surgery and acute kidney injury compared to no exposure for systolic, mean, and pulse pressure (all P < 0.001), but not diastolic, after adjusting for confounding. CONCLUSIONS: Systolic, mean, and pulse pressure hypotension were comparable in their strength of association with myocardial and renal injury. In contrast, the relationship with diastolic pressure was poor. Baseline factors were much more strongly associated with myocardial and renal injury than intraoperative blood pressure, but pressure differs in being modifiable.

12.
Anesth Analg ; 129(6): 1468-1473, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31743165

RESUMO

BACKGROUND: Pain after cardiac surgery is largely treated with opioids, but their poor safety profile makes nonopioid medications attractive as part of multimodal pathways. Anti-inflammatory drugs reduce acute postoperative pain, but the role of steroids in reducing acute poststernotomy pain is unclear. We evaluated the association between the intraoperative administration of methylprednisolone and postoperative analgesia, defined as a composite of pain scores and opioid consumption, during the initial 24 hours after cardiac surgery. METHODS: We conducted a post hoc retrospective analysis of a large clinical trial in which adults having cardiac surgery were randomized 1:1 to receive 2 intraoperative doses of 250 mg IV methylprednisolone or placebo. Pain scores and opioid consumption were collected during the initial 24 hours after surgery. Methylprednisolone was considered to be associated with better pain control than placebo if proven noninferior (not worse) on both pain scores (defined a priori with delta of 1 point) and opioid consumption (delta of 20%) and superior to placebo in at least 1 of the 2 outcomes. This test was repeated in the opposite direction (testing whether placebo is better than methylprednisolone on postoperative pain management). RESULTS: Of 251 eligible patients, 127 received methylprednisolone and 124 received placebo. Methylprednisolone was noninferior to placebo on pain with difference in mean (CI) pain scores of -0.25 (-0.71 to 0.21); P < .001. However, methylprednisolone was not noninferior to placebo on opioid consumption (ratio of geometric means [CI]: 1.11 [0.64-1.91]; P = .37). Because methylprednisolone was not noninferior to placebo on both outcomes, we did not proceed to superiority testing based on the a priori stopping rules. Similar results were found when testing the opposite direction. CONCLUSIONS: In this post hoc analysis, we could not identify a beneficial analgesic effect after cardiac surgery associated with methylprednisolone administration. There are currently no data to suggest that methylprednisolone has significant analgesic benefit in adults having cardiac surgery.

13.
Anesth Analg ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31490254

RESUMO

BACKGROUND: Perioperative hyperoxia has been recommended by the World Health Organization and the Centers for Disease Control and Prevention for the prevention of surgical site infections. Based on animal studies and physiological concerns, the kidneys and heart may be at risk from hyperoxia. We therefore conducted 2 unplanned subanalyses of a previous alternating cohort trial in which patients having colorectal surgery were assigned to either 30% or 80% inspired intraoperative oxygen. Specifically, we tested 2 coprimary hypotheses: (1) hyperoxia increases the incidence of acute kidney injury (AKI) within 7 postoperative days (PODs); and (2) hyperoxia worsens a composite of myocardial injury, in-hospital cardiac arrest, and 30-day mortality. METHODS: The underlying controlled trial included 5749 colorectal surgeries in 4481 patients, with the exposure alternating between 30% and 80% fraction of inspired oxygen (FIO2) during general anesthesia at 2-week intervals over a period of 39 months. AKI was defined as a 1.5-fold increase in creatinine from the preoperative level to the highest value measured during the initial 7 PODs. Myocardial injury was defined by fourth-generation troponin-T level >0.03 ng/mL. We assessed the effect of 80% vs 30% oxygen on the outcomes using generalized estimating equation (GEE) logistic models that adjusted for the possible within-patient correlation across multiple potential operations for a patient on different visits. RESULTS: For the AKI outcome, 2522 surgeries were allocated to 80% oxygen and 2552 to 30% oxygen. Hyperoxia had no effect on the primary outcome of postoperative AKI, with an incidence of 7.7% in the 80% oxygen group and 7.7% in the 30% oxygen group (relative risk = 0.99; 95% confidence interval [CI], 0.82-1.2; P = .95). One thousand six hundred forty-seven surgeries (all with scheduled troponin monitoring) were analyzed for the composite cardiovascular outcome. Hyperoxia had no effect on the collapsed composite of myocardial injury, cardiac arrest, and 30-day mortality, nor on any of its components (estimated relative risk = 0.71; 95% CI, 0.44-1.16; P = .17). CONCLUSIONS: We found no evidence that intraoperative hyperoxia causes AKI or cardiovascular complications in adults undergoing colorectal surgery. Consequently, we suggest that clinicians select intraoperative inspired oxygen fraction based on other considerations.

14.
Br J Clin Pharmacol ; 85(12): 2721-2733, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31418911

RESUMO

AIMS: Fremanezumab is a fully humanized IgG2 Δa/κ monoclonal antibody specific for calcitonin gene-related peptide developed and approved for the preventive treatment of migraine in adults. The population pharmacokinetics (PK) of fremanezumab were characterized in healthy subjects and patients with chronic migraine and episodic migraine, including the effects of intrinsic and extrinsic factors on PK variability. METHODS: Nonlinear mixed effects modelling was performed using NONMEM with data from 7 phase 1-3 clinical trials evaluating selected intravenous and subcutaneous dose regimens. The influence of covariates on fremanezumab PK was assessed and model evaluation was performed through visual predictive checks. RESULTS: A 2-compartment model with first-order absorption and elimination described the PK data well. Typical values for fremanezumab central clearance (0.0902 L/d) and central distribution volume (1.88 L) for a 71-kg subject were consistent with previously reported values for IgG antibodies. Higher body weight was associated with increased central clearance and distribution volume. Effects of other covariates (age, albumin, renal function, sex, race, injection site, and acute, analgesic and preventive medication use for migraine) were not found to statistically significantly influence fremanezumab PK. There was no indication of reduced exposure in participants with positive anti-drug antibody status or with mild to moderate hepatic impairment. Absolute bioavailability was estimated at 0.658. CONCLUSIONS: A comprehensive population PK model was developed for fremanezumab following intravenous and subcutaneous administration in healthy subjects and patients with chronic migraine or episodic migraine, which will be used to further evaluate exposure-response relationships for efficacy and safety endpoints.

15.
Anesth Analg ; 128(6): 1160-1166, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31094783

RESUMO

BACKGROUND: Postoperative pain is common and promotes opioid use. Surgical wounds are hypoxic because normal perfusion is impaired. Local wound ischemia and acidosis promote incisional pain. Some evidence suggests that improving oxygen supply to surgical wounds might reduce pain. We therefore tested the hypothesis that supplemental (80% inspired) intraoperative oxygen reduces postoperative pain and opioid consumption. METHODS: We conducted a post hoc analysis of a large, single-center alternating cohort trial allocating surgical patients having general anesthesia for colorectal surgery to either 30% or 80% intraoperative oxygen concentration in 2-week blocks for a total of 39 months. Irrespective of allocation, patients were given sufficient oxygen to maintain saturation ≥95%. Patients who had regional anesthesia or nerve blocks were excluded. The primary outcome was pain and opioid consumption during the initial 2 postoperative hours, analyzed jointly. The secondary outcome was pain and opioid consumption over the subsequent 24 postoperative hours. Subgroup analyses of the primary outcome were conducted for open versus laparoscopic procedures and for patients with versus without chronic pain. RESULTS: A total of 4702 cases were eligible for analysis: 2415 were assigned to 80% oxygen and 2287 to 30% oxygen. The groups were well balanced on potential confounding factors. Average pain scores and opioid consumption were similar between the groups (mean difference in pain scores, -0.01 [97.5% CI, -0.16 to 0.14; P = .45], median difference in opioid consumption, 0.0 [97.5% CI, 0 to 0] mg morphine equivalents; P = .82). There were also no significant differences in the secondary outcome or subgroup analyses. CONCLUSIONS: Supplemental intraoperative oxygen does not reduce acute postoperative pain or reduce opioid consumption.


Assuntos
Hiperóxia , Manejo da Dor/métodos , Dor Pós-Operatória/terapia , Acidose , Adulto , Idoso , Analgésicos Opioides/efeitos adversos , Anestesia/métodos , Estudos de Coortes , Cirurgia Colorretal/métodos , Interpretação Estatística de Dados , Feminino , Humanos , Hipóxia , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Oxigênio/uso terapêutico , Medição da Dor , Resultado do Tratamento
16.
Anesthesiology ; 130(4): 550-559, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30875354

RESUMO

BACKGROUND: Intraoperative and postoperative hypotension are associated with myocardial and kidney injury and 30-day mortality. Intraoperative blood pressure is measured frequently, but blood pressure on surgical wards is usually measured only every 4 to 6 h, leaving long intervals during which hypotension and hypertension may be undetected. This study evaluated the incidence and severity of postoperative hypotension and hypertension in adults recovering from abdominal surgery and the extent to which serious perturbations were missed by routine vital-sign assessments. METHODS: Blood pressure was recorded at 1-min intervals during the initial 48 h in adults recovering from abdominal surgery using a continuous noninvasive monitor. Caregivers were blinded to these measurements and depended on routine vital-sign assessments. Hypotension and hypertension were characterized as time under and above various mean arterial pressure thresholds. RESULTS: Of 502 available patients, 312 patients with high-quality records were analyzed, with a median measurement time of 48 [interquartile range: 41, 48] postoperative hours. Nearly a quarter experienced an episode of mean arterial pressure of less than 70 mm Hg lasting at least 30 min (24%; 95% CI, 20%, 29%), and 18% had an episode of mean arterial pressure of less than 65 mm Hg lasting at least 15 min. Nearly half the patients who had mean arterial pressure of less than 65 mm Hg for at least 15 min (47%; 95% CI, 34%, 61%) were undetected by routine vital-sign assessments. Episodes of mean arterial pressure greater than 110 mm Hg lasting at least 30 min were observed in 42% (95% CI, 37%, 48%) of patients; 7% had mean arterial pressure greater than 130 mm Hg for at least 30 min, 96% of which were missed by routine assessments. Episodes of mean arterial pressure less than 65 mm Hg and mean arterial pressure greater than 110 mm Hg captured by routine vital-sign assessments but not by continuous monitoring occurred in 34 and 8 patients, respectively. CONCLUSIONS: Postoperative hypotension and hypertension were common, prolonged, profound, and largely undetected by routine vital-sign assessments in a cohort of adults recovering from abdominal surgery. Frequent or continuous blood pressure monitoring may detect hemodynamic perturbations more effectively and potentially facilitate treatment.

17.
Eur J Anaesthesiol ; 36(5): 320-326, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30865003

RESUMO

BACKGROUND: The WHO recommends routine intra-operative and early postoperative use of high inspired oxygen concentrations (hyperoxia). However, a high intra-operative inspired oxygen fraction (FiO2) might result in an increased risk of postoperative respiratory complications. AIM: To test the hypothesis that intra-operative FiO2 of 80% compared with 30% inspired oxygen decreases the postoperative ratio of arterial saturation to fraction of inspired oxygen (SpO2/FiO2). Secondarily, to evaluate whether an intra-operative inspired FiO2 of 80% increases the incidence of pulmonary complications. DESIGN: Posthoc subanalysis of a large alternating cohort trial. SETTING: Cleveland Clinic, Cleveland, United States, from 2013 to 2016. PATIENTS: Adults having colorectal surgery. Cases lasting less than 2 h, re-operations on the same hospitalisation, and cases with missing intra-operative or postoperative data were excluded. INTERVENTION: Maintaining intra-operative FiO2 at 30 or 80% and alternating this management every 2 weeks for a study period of 39 months. MAIN OUTCOME: Minimal SpO2/FiO2 ratio value in the postanaesthesia care unit. Secondary outcome was a composite of postoperative pulmonary complications throughout hospitalisation. RESULTS: A total of 5056 patients were included. Groups were well balanced on all demographic, baseline and procedural variables. Median time-weighted averages of intra-operative FiO2 in the 30 and 80% groups were 43% (IQR 38 to 54%, N=2486) and 81% (IQR 78 to 82%, N=2570), respectively. No difference was found in the lowest SpO2/FiO2 ratio (estimated median difference 0 [95% confidence interval: 0, 0], P = 0.91). The incidence of postoperative pulmonary complications was 16.3 and 17.6% in the 30 and 80% FiO2 groups, respectively (relative risk 1.07 [95% confidence interval: 0.95, 1.21], P = 0.25). CONCLUSION: Intra-operative hyperoxia did not change the postoperative SpO2/FiO2 ratio or the risk for pulmonary complications. Clinicians should not refrain from using hyperoxia for fear of provoking respiratory complications. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01777568.

19.
Anesth Analg ; 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30801356

RESUMO

BACKGROUND: Pain after cardiac surgery is largely treated with opioids, but their poor safety profile makes nonopioid medications attractive as part of multimodal pathways. Anti-inflammatory drugs reduce acute postoperative pain, but the role of steroids in reducing acute poststernotomy pain is unclear. We evaluated the association between the intraoperative administration of methylprednisolone and postoperative analgesia, defined as a composite of pain scores and opioid consumption, during the initial 24 hours after cardiac surgery. METHODS: We conducted a post hoc retrospective analysis of a large clinical trial in which adults having cardiac surgery were randomized 1:1 to receive 2 intraoperative doses of 250 mg IV methylprednisolone or placebo. Pain scores and opioid consumption were collected during the initial 24 hours after surgery. Methylprednisolone was considered to be associated with better pain control than placebo if proven noninferior (not worse) on both pain scores (defined a priori with delta of 1 point) and opioid consumption (delta of 20%) and superior to placebo in at least 1 of the 2 outcomes. This test was repeated in the opposite direction (testing whether placebo is better than methylprednisolone on postoperative pain management). RESULTS: Of 251 eligible patients, 127 received methylprednisolone and 124 received placebo. Methylprednisolone was noninferior to placebo on pain with difference in mean (CI) pain scores of -0.25 (-0.71 to 0.21); P < .001. However, methylprednisolone was not noninferior to placebo on opioid consumption (ratio of geometric means [CI]: 1.11 [0.64-1.91]; P = .37). Because methylprednisolone was not noninferior to placebo on both outcomes, we did not proceed to superiority testing based on the a priori stopping rules. Similar results were found when testing the opposite direction. CONCLUSIONS: In this post hoc analysis, we could not identify a beneficial analgesic effect after cardiac surgery associated with methylprednisolone administration. There are currently no data to suggest that methylprednisolone has significant analgesic benefit in adults having cardiac surgery.

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