Mary Cooter

Platelet Counts, Acute Kidney Injury, and Mortality after Coronary Artery Bypass Grafting Surgery

Background:Cardiac surgery requiring cardiopulmonary bypass is associated with platelet activation. Because platelets are increasingly recognized as important effectors of ischemia and end-organ inflammatory injury, the authors explored whether postoperative nadir platelet counts are associated with acute kidney injury (AKI) and mortality after coronary artery bypass grafting (CABG) surgery. Methods:The authors evaluated 4,217 adult patients who underwent CABG surgery. Postoperative nadir platelet counts were defined as the lowest in-hospital values and were used as a continuous predictor of postoperative AKI and mortality. Nadir values in the lowest 10th percentile were also used as a categorical predictor. Multivariable logistic regression and Cox proportional hazard models examined the association between postoperative platelet counts, postoperative AKI, and mortality. Results:The median postoperative nadir platelet count was 121 × 109/l. The incidence of postoperative AKI was 54%, including 9.5% (215 patients) and 3.4% (76 patients) who experienced stages II and III AKI, respectively. For every 30 × 109/l decrease in platelet counts, the risk for postoperative AKI increased by 14% (adjusted odds ratio, 1.14; 95% CI, 1.09 to 1.20; P < 0.0001). Patients with platelet counts in the lowest 10th percentile were three times more likely to progress to a higher severity of postoperative AKI (adjusted proportional odds ratio, 3.04; 95% CI, 2.26 to 4.07; P < 0.0001) and had associated increased risk for mortality immediately after surgery (adjusted hazard ratio, 5.46; 95% CI, 3.79 to 7.89; P < 0.0001). Conclusion:The authors found a significant association between postoperative nadir platelet counts and AKI and short-term mortality after CABG surgery.

The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial

BACKGROUND Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimers disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). OBJECTIVE We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. METHODS Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. RESULTS The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aβ levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations). CONCLUSION Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

Retrospective comparison of ephedrine and phenylephrine for the treatment of spinal anesthesia induced hypotension in pre-eclamptic patients.

Abstract Objective: To compare neonatal acid base status in parturients who underwent cesarean delivery and received either ephedrine or phenylephrine boluses for the treatment of spinal anesthesia induced hypotension. Research design and methods: After institutional review board approval, the perioperative database of the University of Iowa Hospitals and Clinics was used to identify all women diagnosed with pre-eclampsia and had cesarean delivery under spinal anesthesia for the period 1 January 2005 to 31 July 2014. Data retrieved included patient demographics, indication for cesarean delivery, severity of pre-eclampsia, dose of vasopressor, neonatal umbilical artery pH and Apgar scores. Main outcome measures: Primary outcome was umbilical artery pH. Results: Data for 146 patients was included in the analysis. Ephedrine was used in 57 patients (group E) and phenylephrine in 89 (group PE) patients. The median umbilical artery pH was 7.30 (IQR 7.20–7.30) and 7.30 (IQR 7.20–7.30) in the ephedrine and phenylephrine groups respectively (P = 0.41). Non-reassuring fetal heart trace was the only factor significantly associated with lower umbilical artery pH on multivariable regression analysis (β = −0.09, P = 0.002). Conclusions: We found no difference in neonatal umbilical artery pH between ephedrine and phenylephrine when used to treat spinal anesthesia induced hypotension during cesarean delivery in pre-eclamptic patients. Limitations of the study include its retrospective single center design and the fact that the choice of vasopressor was not randomized.

Platelet Counts and Postoperative Stroke after Coronary Artery Bypass Grafting Surgery

BACKGROUND: Declining platelet counts may reveal platelet activation and aggregation in a postoperative prothrombotic state. Therefore, we hypothesized that nadir platelet counts after on-pump coronary artery bypass grafting (CABG) surgery are associated with stroke. METHODS: We evaluated 6130 adult CABG surgery patients. Postoperative platelet counts were evaluated as continuous and categorical (mild versus moderate to severe) predictors of stroke. Extended Cox proportional hazard regression analysis with a time-varying covariate for daily minimum postoperative platelet count assessed the association of day-to-day variations in postoperative platelet count with time to stroke. Competing risks proportional hazard regression models examined associations between day-to-day variations in postoperative platelet counts with timing of stroke (early: 0–1 days; delayed: ≥2 days). RESULTS: Median (interquartile range) postoperative nadir platelet counts were 123.0 (98.0–155.0) × 109/L. The incidences of postoperative stroke were 1.09%, 1.50%, and 3.02% for platelet counts >150 × 109/L, 100 to 150 × 109/L, and <100 × 109/L, respectively. The risk for stroke increased by 12% on a given postoperative day for every 30 × 109/L decrease in platelet counts (adjusted hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01–1.24; P= .0255). On a given day, patients with moderate to severe thrombocytopenia were almost twice as likely to develop stroke (adjusted HR, 1.89; 95% CI, 1.13–3.16; P= .0155) as patients with nadir platelet counts >150 × 109/L. Importantly, such thrombocytopenia, defined as a time-varying covariate, was significantly associated with delayed (≥2 days after surgery; adjusted HR, 2.83; 95% CI, 1.48–5.41; P= .0017) but not early postoperative stroke. CONCLUSIONS: Our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and postoperative stroke, and timing of stroke after CABG surgery.

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre‐clinical models. To date, proteomic level validation of widely used patient‐derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre‐clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR.

Primary graft dysfunction after heart transplantation: Incidence, trends, and associated risk factors

Changes in heart transplantation (HT) donor and recipient demographics may influence the incidence of primary graft dysfunction (PGD). We conducted a retrospective study to evaluate PGD incidence, trends, and associated risk factors by analyzing consecutive adult patients who underwent HT between January 2009 and December 2014 at our institution. Patients were categorized as having PGD using the International Society for Heart & Lung Transplantation (ISHLT)–defined criteria. Variables, including clinical and demographic characteristics of donors and recipients, were selected to assess their independent association with PGD. A time‐trend analysis was performed over the study period. Three‐hundred seventeen patients met inclusion criteria. Left ventricular PGD, right ventricular PGD, or both, were observed in 99 patients (31%). Risk factors independently associated with PGD included ischemic time, recipient African American race, and recipient amiodarone treatment. Over the study period, there was no change in the PGD incidence; however, there was an increase in the recipient pretransplantation use of amiodarone. The rate of 30‐day mortality was significantly elevated in those with PGD versus those without PGD (6.06% vs 0.92%, P = .01). Despite recent advancements, incidence of PGD remains high. Understanding associated risk factors may allow for implementation of targeted therapeutic interventions.

Intraoperative Frontal Alpha-Band Power Correlates with Preoperative Neurocognitive Function in Older Adults

Each year over 16 million older Americans undergo general anesthesia for surgery, and up to 40% develop postoperative delirium and/or cognitive dysfunction (POCD). Delirium and POCD are each associated with decreased quality of life, early retirement, increased 1-year mortality, and long-term cognitive decline. Multiple investigators have thus suggested that anesthesia and surgery place severe stress on the aging brain, and that patients with less ability to withstand this stress will be at increased risk for developing postoperative delirium and POCD. Delirium and POCD risk are increased in patients with lower preoperative cognitive function, yet preoperative cognitive function is not routinely assessed, and no intraoperative physiological predictors have been found that correlate with lower preoperative cognitive function. Since general anesthesia causes alpha-band (8–12 Hz) electroencephalogram (EEG) power to decrease occipitally and increase frontally (known as “anteriorization”), and anesthetic-induced frontal alpha power is reduced in older adults, we hypothesized that lower intraoperative frontal alpha power might correlate with lower preoperative cognitive function. Here, we provide evidence that such a correlation exists, suggesting that lower intraoperative frontal alpha power could be used as a physiological marker to identify older adults with lower preoperative cognitive function. Lower intraoperative frontal alpha power could thus be used to target these at-risk patients for possible therapeutic interventions to help prevent postoperative delirium and POCD, or for increased postoperative monitoring and follow-up. More generally, these results suggest that understanding interindividual differences in how the brain responds to anesthetic drugs can be used as a probe of neurocognitive function (and dysfunction), and might be a useful measure of neurocognitive function in older adults.

Temporal Trends in Difficult and Failed Tracheal Intubation in a Regional Community Anesthetic Practice

Background: When tracheal intubation is difficult or unachievable before surgery or during an emergent resuscitation, this is a critical safety event. Consensus algorithms and airway devices have been introduced in hopes of reducing such occurrences. However, evidence of improved safety in clinical practice related to their introduction is lacking. Therefore, we selected a large perioperative database spanning 2002 to 2015 to look for changes in annual rates of difficult and failed tracheal intubation. Methods: Difficult (more than three attempts) and failed (unsuccessful, requiring awakening or surgical tracheostomy) intubation rates in patients 18 yr and older were compared between the early and late periods (pre- vs. post-January 2009) and by annual rate join-point analysis. Primary findings from a large, urban hospital were compared with combined observations from 15 smaller facilities. Results: Analysis of 421,581 procedures identified fourfold reductions in both event rates between the early and late periods (difficult: 6.6 of 1,000 vs. 1.6 of 1,000, P < 0.0001; failed: 0.2 of 1,000 vs. 0.06 of 1,000, P < 0.0001), with join-point analysis identifying two significant change points (2006, P = 0.02; 2010, P = 0.03) including a pre-2006 stable period, a steep drop between 2006 and 2010, and gradual decline after 2010. Data from 15 affiliated practices (442,428 procedures) demonstrated similar reductions. Conclusions: In this retrospective assessment spanning 14 yr (2002 to 2015), difficult and failed intubation rates by skilled providers declined significantly at both an urban hospital and a network of smaller affiliated practices. Further investigations are required to validate these findings in other data sets and more clearly identify factors associated with their occurrence as clues to future airway management advancements. Visual Abstract: An online visual overview is available for this article at http://links.lww.com/ALN/B635.

The impact of gestational age and fetal weight on the risk of failure of spinal anesthesia for cesarean delivery

BACKGROUND There are limited data about spinal dosing for cesarean delivery in preterm parturients. We investigated the hypothesis that preterm gestation is associated with an increased incidence of inadequate spinal anesthesia for cesarean delivery compared with term gestation. METHODS We searched our perioperative database for women who underwent cesarean delivery under spinal or combined spinal-epidural anesthesia with hyperbaric bupivacaine ⩾10.5mg. The primary outcome was the incidence of inadequate surgical anesthesia needing conversion to general anesthesia or repetition or supplementation of the block. We divided patients into four categories: <28, 28 to <32, 32 to <37 and ⩾37weeks of gestation. The chi-square test was used to compare failure rates and a multivariable regression analysis was performed to investigate potential confounders of the relationship between gestational age and failure. RESULTS A total of 5015 patients (3387 term and 1628 preterm) were included. There were 278 failures (5.5%). The incidence of failure was higher in preterm versus term patients (6.4% vs. 5.1%, P=0.02). Failure rates were 10.8%, 7.7%, 5.3% and 5% for <28, 28 to <32, 32 to <37 and ⩾37weeks of gestation, respectively. In the multivariable model, low birth weight (P<0.0001), gestational age (P=0.03), ethnicity (P=0.02) and use of combined spinal-epidural anesthesia (P<0.0001) were significantly associated with failure. CONCLUSIONS At standard spinal doses of hyperbaric bupivacaine used in our practice (⩾10.5mg), there were higher odds of inadequate surgical anesthesia in preterm parturients. When adjusting for potential confounders, low birth weight was the main factor associated with failure.

The Effect of Propofol vs. Isoflurane Anesthesia on Postoperative Changes in Cerebrospinal Fluid Cytokine Levels: Results from a Randomized Trial

Introduction Aside from direct effects on neurotransmission, inhaled and intravenous anesthetics have immunomodulatory properties. In vitro and mouse model studies suggest that propofol inhibits, while isoflurane increases, neuroinflammation. If these findings translate to humans, they could be clinically important since neuroinflammation has detrimental effects on neurocognitive function in numerous disease states. Materials and methods To examine whether propofol and isoflurane differentially modulate neuroinflammation in humans, cytokines were measured in a secondary analysis of cerebrospinal fluid (CSF) samples from patients prospectively randomized to receive anesthetic maintenance with propofol vs. isoflurane (registered with http://www.clinicaltrials.gov, identifier NCT01640275). We measured CSF levels of EGF, eotaxin, G-CSF, GM-CSF, IFN-α2, IL-1RA, IL-6, IL-7, IL-8, IL-10, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α before and 24 h after intracranial surgery in these study patients. Results After Bonferroni correction for multiple comparisons, we found significant increases from before to 24 h after surgery in G-CSF, IL-10, IL-1RA, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α. However, we found no difference in cytokine levels at baseline or 24 h after surgery between propofol- (n = 19) and isoflurane-treated (n = 21) patients (p > 0.05 for all comparisons). Increases in CSF IL-6, IL-8, IP-10, and MCP-1 levels directly correlated with each other and with postoperative CSF elevations in tau, a neural injury biomarker. We observed CSF cytokine increases up to 10-fold higher after intracranial surgery than previously reported after other types of surgery. Discussion These data clarify the magnitude of neuroinflammation after intracranial surgery, and raise the possibility that a coordinated neuroinflammatory response may play a role in neural injury after surgery.