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Open Access
Association between Initial Fluid Choice and Subsequent In-hospital Mortality during the Resuscitation of Adults with Septic Shock.
(Anesthesiology, 2015-12) Raghunathan, Karthik; Bonavia, Anthony; Nathanson, Brian H; Beadles, Christopher A; Shaw, Andrew D; Brookhart, M Alan; Miller, Timothy E; Lindenauer, Peter K
BACKGROUND: Currently, guidelines recommend initial resuscitation with intravenous (IV) crystalloids during severe sepsis/septic shock. Albumin is suggested as an alternative. However, fluid mixtures are often used in practice, and it is unclear whether the specific mixture of IV fluids used impacts outcomes. The objective of this study is to test the hypothesis that the specific mixture of IV fluids used during initial resuscitation, in severe sepsis, is associated with important in-hospital outcomes. METHODS: Retrospective cohort study includes patients with severe sepsis who were resuscitated with at least 2 l of crystalloids and vasopressors by hospital day 2, patients who had not undergone any major surgical procedures, and patients who had a hospital length of stay (LOS) of at least 2 days. Inverse probability weighting, propensity score matching, and hierarchical regression methods were used for risk adjustment. Patients were grouped into four exposure categories: recipients of isotonic saline alone ("Sal" exclusively), saline in combination with balanced crystalloids ("Sal + Bal"), saline in combination with colloids ("Sal + Col"), or saline in combination with balanced crystalloids and colloids ("Sal + Bal + Col"). In-hospital mortality was the primary outcome, and hospital LOS and costs per day (among survivors) were secondary outcomes. RESULTS: In risk-adjusted Inverse Probability Weighting analyses including 60,734 adults admitted to 360 intensive care units across the United States between January 2006 and December 2010, in-hospital mortality was intermediate in the Sal group (20.2%), lower in the Sal + Bal group (17.7%, P < 0.001), higher in the Sal + Col group (24.2%, P < 0.001), and similar in the Sal + Bal + Col group (19.2%, P = 0.401). In pairwise propensity score-matched comparisons, the administration of balanced crystalloids by hospital day 2 was consistently associated with lower mortality, whether colloids were used (relative risk, 0.84; 95% CI, 0.76 to 0.92) or not (relative risk, 0.79; 95% CI, 0.70 to 0.89). The association between colloid use and in-hospital mortality was inconsistent, and survival was not uniformly affected, whereas LOS and costs per day were uniformly increased. Results were robust in sensitivity analyses. CONCLUSIONS: During the initial resuscitation of adults with severe sepsis/septic shock, the types of IV fluids used may impact in-hospital mortality. When compared with the administration of isotonic saline exclusively during resuscitation, the coadministration of balanced crystalloids is associated with lower in-hospital mortality and no difference in LOS or costs per day. When colloids are coadministered, LOS and costs per day are increased without improved survival. A large randomized controlled trial evaluating crystalloid choice is warranted. Meanwhile, the use of balanced crystalloids seems reasonable. (Anesthesiology 2015; 123:1385-93).
Open Access
Association of Early Beta-Blocker Exposure and Functional Outcomes in Critically Ill Patients With Moderate to Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.
(Critical care explorations, 2023-09) Kelly-Hedrick, Margot; Liu, Sunny Yang; Temkin, Nancy; Barber, Jason; Komisarow, Jordan; Manley, Geoffrey; Ohnuma, Tetsu; Colton, Katharine; Treggiari, Miriam M; Monson, Eric E; Vavilala, Monica S; Grandhi, Ramesh; Laskowitz, Daniel T; Mathew, Joseph P; Hernandez, Adrian; James, Michael L; Raghunathan, Karthik; Goldstein, Ben; Markowitz, Amy J; Krishnamoorthy, Vijay
Objectives
We aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate-severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury.
Design
Retrospective cohort study.
Setting
ICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study.
Patients
Greater than or equal to 17 years enrolled in the TRACK-TBI study with moderate-severe TBI (Glasgow Coma Scale of <13) were admitted to the ICU after a blunt TBI.
Interventions
None.
Measurements
Primary exposure was a beta blocker during the first 7 days in the ICU, with a primary outcome of 6-month Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes included: length of hospital stay, in-hospital mortality, 6-month and 12-month mortality, 12-month GOSE score, and 6-month and 12-month measures of disability, well-being, quality of life, and life satisfaction.
Main results
Of the 450 eligible participants, 57 (13%) received early beta blockers (BB⁺ group). The BB⁺ group was on average older, more likely to be on a preinjury beta blocker, and more likely to have a history of hypertension. In the BB⁺ group, 34 participants (60%) received metoprolol only, 19 participants (33%) received propranolol only, 3 participants (5%) received both, and 1 participant (2%) received atenolol only. In multivariable regression, there was no difference in the odds of a higher GOSE score at 6 months between the BB⁺ group and BB^- group (odds ratio = 0.86; 95% CI, 0.48-1.53). There was no association between BB exposure and secondary outcomes.
Conclusions
About one-sixth of subjects in our study received early beta blockers, and within this group, dose, and timing of beta-blocker administration varied substantially. No significant differences in GOSE score at 6 months were demonstrated, although our ability to draw conclusions is limited by overall low total doses administered compared with prior studies.
Open Access
Association of Severe Acute Kidney Injury with Mortality and Healthcare Utilization Following Isolated Traumatic Brain Injury.
(Neurocritical care, 2021-01-13) Luu, David; Komisarow, Jordan; Mills, Brianna M; Vavilala, Monica S; Laskowitz, Daniel T; Mathew, Joseph; James, Michael L; Hernandez, Adrian; Sampson, John; Fuller, Matt; Ohnuma, Tetsu; Raghunathan, Karthik; Privratsky, Jamie; Bartz, Raquel; Krishnamoorthy, Vijay
Background/objective
Traumatic brain injury (TBI) is a leading cause of morbidity, mortality, and disability in the USA. While cardiopulmonary dysfunction can result in poor outcomes following severe TBI, the impact of acute kidney injury (AKI) is poorly understood. We examined the association of severe AKI with hospital mortality and healthcare utilization following isolate severe TBI.
Methods
We conducted a retrospective cohort study using the National Trauma Data Bank from 2007 to 2014. We identified a cohort of adult patients with isolated severe TBI and described the incidence of severe AKI, corresponding to Acute Kidney Injury Network stage 3 disease or greater. We examined the association of severe AKI with the primary outcome of hospital mortality using multivariable logistic regression models. In secondary analyses, we examined the association of severe AKI with dialysis catheter placement, tracheostomy and gastrostomy utilization, and hospital length of stay.
Results
There were 37,851 patients who experienced isolated severe TBI during the study period. Among these patients, 787 (2.1%) experienced severe (Stage 3 or greater) AKI. In multivariable models, the development of severe AKI in the hospital was associated with in-hospital mortality (OR 2.03, 95% CI 1.64-2.52), need for tracheostomy (OR 2.10, 95% CI 1.52-2.89), PEG tube placement (OR 1.88, 95% CI 1.45-2.45), and increased hospital length of stay (p < 0.001).
Conclusions
The overall incidence of severe AKI is relatively low (2.1%), but is associated with increased mortality and multiple markers of increased healthcare utilization following severe TBI.
Open Access
Atherosclerosis: Viewing the problem from a different perspective including possible treatment options
(Lipid Insights, 2011-12-01) Goldberg, JS
This paper proposes that atherosclerosis is initiated by a signaling event that deposits calcium hydroxyapatite (Ca-HAP). This event is preceded by a loss of mechanical structure in the arterial wall. After Ca-HAP has been deposited, it is unlikely that it will be reabsorbed because the solubility product constant (K sp) is very small, and the large stores of Ca +2 and PO 4-3 in the bones oppose any attempts to dissolve Ca-HAP by decreasing the common ions. The hydroxide ion (OH -) of Ca-HAP can be displaced in nature by fluoride (F -) and carbonate (CO 3-2) ions, and it is proposed that anions associated with cholesterol ester hydrolysis and, in very small quantities, the enolate of 7-ketocholesterol could also displace the OH -of Ca-HAP, forming an ionic bond. The free energy of hydration of Ca-HAP at 310 K is most likely negative, and the ionic radii of the anions associated with the hydrolysis of cholesterol ester are compatible with the substitution. Furthermore, examination of the pathology of atherosclerotic lesions by Raman and NMR spectroscopy and confocal microscopy supports deposition of Ca-HAP associated with cholesterol. Investigating the affinity of intermediates of cholesterol hydrolysis for Ca-HAP compared to lipoproteins such as HDL, LDL, and VLDL using isothermic titration calorimetry could add proof of this concept and may lead to the development of a new class of medications targeted at the deposition of cholesterol within Ca-HAP. Treatment of acute ischemic events as a consequence of atherosclerosis with denitrogenation and oxygenation is discussed. © the author(s), publisher and licensee Libertas Academica Ltd.
Open Access
Changes in analgesic strategies for lobectomy from 2009 to 2018
(JTCVS Open, 2021-06-01) Lo, Theresa; Schiller, Robin; Raghunathan, Karthik; Krishnamoorthy, Vijay; Jawitz, Oliver K; Pyati, Srinivas; Van De Ven, Thomas; Bartz, Raquel R; Thompson, Annemarie; Ohnuma, Tetsu
Objective: To evaluate trends in the use of epidural analgesia and nonopioid and opioid analgesics for patients undergoing lobectomy from 2009 to 2018. Methods: We queried the Premier database for adult patients undergoing open, video-assisted, and robotic-assisted lobectomy from 2009 to 2018. The outcome of interest was changes in the receipt of epidural analgesia and nonopioid and opioid analgesics as measured by charges on the day of surgery. We also evaluated postoperative daily opioid use. We used multivariable logistic and linear regression models to examine the association between the utilization of each analgesic modality and year. Results: We identified 86,308 patients undergoing lobectomy from 2009 to 2018 within the Premier database: 35,818 (41.5%) patients had open lobectomy, 35,951 (41.7%) patients had video-assisted lobectomy, and 14,539 (16.8%) patients had robotic-assisted lobectomy. For all 3 surgical cohorts, epidural analgesia use decreased, and nonopioid analgesics use increased over time, except for intravenous nonsteroidal anti-inflammatory drugs. Use of patient-controlled analgesia decreased, while opioid consumption on the day of surgery increased and postoperative opioid consumption did not decrease over time. Conclusions: In this large sample of patients undergoing lobectomy, utilization of epidural analgesia declined and use of nonopioid analgesics increased. Despite these changes, opioid consumption on day of surgery increased, and there was no significant reduction in postoperative opioid consumption. Further research is warranted to examine the association of these changes with patient outcomes.
Open Access
Chronic opioid therapy and opioid tolerance: a new hypothesis.
(Pain Res Treat, 2013) Goldberg, Joel S
Opioids are efficacious and cost-effective analgesics, but tolerance limits their effectiveness. This paper does not present any new clinical or experimental data but demonstrates that there exist ascending sensory pathways that contain few opioid receptors. These pathways are located by brain PET scans and spinal cord autoradiography. These nonopioid ascending pathways include portions of the ventral spinal thalamic tract originating in Rexed layers VI-VIII, thalamocortical fibers that project to the primary somatosensory cortex (S1), and possibly a midline dorsal column visceral pathway. One hypothesis is that opioid tolerance and opioid-induced hyperalgesia may be caused by homeostatic upregulation during opioid exposure of nonopioid-dependent ascending pain pathways. Upregulation of sensory pathways is not a new concept and has been demonstrated in individuals impaired with deafness or blindness. A second hypothesis is that adjuvant nonopioid therapies may inhibit ascending nonopioid-dependent pathways and support the clinical observations that monotherapy with opioids usually fails. The uniqueness of opioid tolerance compared to tolerance associated with other central nervous system medications and lack of tolerance from excess hormone production is discussed. Experimental work that could prove or disprove the concepts as well as flaws in the concepts is discussed.
Open Access
CITRATE DISSOLUTION OF BETA-2-MICROGLOBULIN AND AMYLOID BETA PEPTIDE (1-40) AGGREGATES
(2018-11-22) Goldberg, JS
Open Access
CITRATE RESORPTION OF BONE AS A TREATMENT FOR SPINAL STENOSIS
(2017-04-11) Goldberg, JS
Open Access
CITRATE RESORPTION OF BONE AS A TREATMENT FOR SPINAL STENOSIS
Goldberg, JS
Open Access
COHERENT ELECTROMAGNETIC WAVES AID RECONCILIATION
(2016-10-20) Goldberg, JS
Open Access
Confounders versus Mediators: An Important Distinction.
(Anesthesiology, 2015-07) Raghunathan, Karthik; Miller, Timothy E; Rashid, Ali M
Open Access
Correction to: American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) Joint Consensus Statement on Optimal Analgesia within an Enhanced Recovery Pathway for Colorectal Surgery: Part 2-From PACU to the Transition Home.
(Perioperative medicine (London, England), 2018-01) Scott, Michael J; McEvoy, Matthew D; Gordon, Debra B; Grant, Stuart A; Thacker, Julie KM; Wu, Christopher L; Gan, Tong J; Mythen, Monty G; Shaw, Andrew D; Miller, Timothy E; Perioperative Quality Initiative (POQI) I Workgroup
[This corrects the article DOI: 10.1186/s13741-017-0063-6.].
Open Access
Correction to: American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) joint consensus statement on perioperative fluid management within an enhanced recovery pathway for colorectal surgery.
(Perioperative medicine (London, England), 2018-01) Thiele, Robert H; Raghunathan, Karthik; Brudney, CS; Lobo, Dileep N; Martin, Daniel; Senagore, Anthony; Cannesson, Maxime; Gan, Tong Joo; Mythen, Michael Monty G; Shaw, Andrew D; Miller, Timothy E; Perioperative Quality Initiative (POQI) I Workgroup
[This corrects the article DOI: 10.1186/s13741-016-0049-9.].
Open Access
Corrigendum for "Stereocomplexes Formed From Select Oligomers of Polymer D-lactic Acid (PDLA) and L-lactate May Inhibit Growth of Cancer Cells and Help Diagnose Aggressive Cancers-Applications of the Warburg Effect"
(Perspect Medicin Chem, 2014) Goldberg, JS
[This corrects the article on p. 1 in vol. 5, PMID: 21487535.].
Open Access
DECALCIFICATION OF PASTURE GRASS FOR FOOD AND FUEL
(2016-09-22) Goldberg, JS
Open Access
Delaying Elective Surgery in Geriatric Patients: An Opportunity for Preoperative Optimization.
(Anesthesia and analgesia, 2019-07-17) Wong, Serena P; Zietlow, Kahli M; McDonald, Shelley R; Barbeito, Atilio; Colon-Emeric, Cathleen S; Lagoo-Deenadayalan, Sandhya A; Loyack, Nancy; Heflin, Mitchell T
Deciding whether to pursue elective surgery is a complex process for older adults. Comprehensive geriatric assessment (CGA) can help refine estimates of benefits and risks, at times leading to a delay of surgery to optimize surgical readiness. We describe a cohort of geriatric patients who were evaluated in anticipation of elective abdominal surgery and whose procedures were delayed for any reason. Themes behind the reasons for delay are described, and a holistic framework to guide preoperative discussion is suggested.
Open Access
Differential expression of systemic inflammatory mediators in amputees with chronic residual limb pain.
(Pain, 2017-01) Chamessian, Alexander; Van de Ven, Thomas; Buchheit, Thomas; Hsia, Hung-Lun; McDuffie, Mary; Gamazon, Eric R; Walsh, Colin; Bruehl, Stephen; Buckenmaier, Chester 'Trip'; Shaw, Andrew
Chronic postsurgical pain impacts most amputees, with more than half experiencing neuralgic residual limb pain. The transition from normal acute postamputation pain to chronic residual limb pain likely involves both peripheral and central inflammatory mechanisms. As part of the Veterans Integrated Pain Evaluation Research study, we investigated links between systemic inflammatory mediator levels and chronic residual limb pain. Subjects included 36 recent active duty military traumatic amputees with chronic residual limb pain and 40 without clinically significant pain. Blood samples were obtained and plasma concentrations of an array of inflammatory mediators were analyzed. Residual limb pain intensity and pain catastrophizing were assessed to examine associations with inflammatory mediators. Pro-inflammatory mediators including tumor necrosis factor (TNF)-α, TNF-β, interleukin (IL)-8, ICAM-1, Tie2, CRP, and SAA were elevated in patients with chronic residual limb pain. Across all patients, residual limb pain intensity was associated positively with levels of several proinflammatory mediators (IL-8, TNF-α, IL-12, TNF-β, PIGF, Tie2, SAA, and ICAM-1), and inversely with concentrations of the anti-inflammatory mediator IL-13, as well as IL-2 and Eotaxin-3. Pain catastrophizing correlated positively with IL-8, IL-12, TNF-β, PIGF, and ICAM-1, and inversely with IL-13. Significant associations between catastrophizing and residual limb pain intensity were partially mediated by TNF-α, TNF- β, SAA, and ICAM-1 levels. Results suggest that chronic postamputation residual limb pain is associated with excessive inflammatory response to injury or to inadequate resolution of the postinjury inflammatory state. Impact of pain catastrophizing on residual limb pain may be because of part to common underlying inflammatory mechanisms.
Open Access
DNA methylation profiles are associated with complex regional pain syndrome after traumatic injury.
(Pain, 2019-10) Bruehl, Stephen; Gamazon, Eric R; Van de Ven, Thomas; Buchheit, Thomas; Walsh, Colin G; Mishra, Puneet; Ramanujan, Krishnan; Shaw, Andrew
Factors contributing to development of complex regional pain syndrome (CRPS) are not fully understood. This study examined possible epigenetic mechanisms that may contribute to CRPS after traumatic injury. DNA methylation profiles were compared between individuals developing CRPS (n = 9) and those developing non-CRPS neuropathic pain (n = 38) after undergoing amputation following military trauma. Linear Models for Microarray (LIMMA) analyses revealed 48 differentially methylated cytosine-phosphate-guanine dinucleotide (CpG) sites between groups (unadjusted P's < 0.005), with the top gene COL11A1 meeting Bonferroni-adjusted P < 0.05. The second largest differential methylation was observed for the HLA-DRB6 gene, an immune-related gene linked previously to CRPS in a small gene expression study. For all but 7 of the significant CpG sites, the CRPS group was hypomethylated. Numerous functional Gene Ontology-Biological Process categories were significantly enriched (false discovery rate-adjusted q value <0.15), including multiple immune-related categories (eg, activation of immune response, immune system development, regulation of immune system processes, and antigen processing and presentation). Differentially methylated genes were more highly connected in human protein-protein networks than expected by chance (P < 0.05), supporting the biological relevance of the findings. Results were validated in an independent sample linking a DNA biobank with electronic health records (n = 126 CRPS phenotype, n = 19,768 non-CRPS chronic pain phenotype). Analyses using PrediXcan methodology indicated differences in the genetically determined component of gene expression in 7 of 48 genes identified in methylation analyses (P's < 0.02). Results suggest that immune- and inflammatory-related factors might confer risk of developing CRPS after traumatic injury. Validation findings demonstrate the potential of using electronic health records linked to DNA for genomic studies of CRPS.
Open Access
Epigenetics and the transition from acute to chronic pain.
(Pain medicine (Malden, Mass.), 2012-11) Buchheit, Thomas; Van de Ven, Thomas; Shaw, Andrew
The objective of this study was to review the epigenetic modifications involved in the transition from acute to chronic pain and to identify potential targets for the development of novel, individualized pain therapeutics.Epigenetics is the study of heritable modifications in gene expression and phenotype that do not require a change in genetic sequence to manifest their effects. Environmental toxins, medications, diet, and psychological stresses can alter epigenetic processes such as DNA methylation, histone acetylation, and RNA interference. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, steroid responsiveness, and opioid sensitivity, they are likely key factors in the development of chronic pain. Although our knowledge of the human genetic code and disease-associated polymorphisms has grown significantly in the past decade, we have not yet been able to elucidate the mechanisms that lead to the development of persistent pain after nerve injury or surgery.This is a focused literature review of epigenetic science and its relationship to chronic pain.Significant laboratory and clinical data support the notion that epigenetic modifications are affected by the environment and lead to differential gene expression. Similar to mechanisms involved in the development of cancer, neurodegenerative disease, and inflammatory disorders, the literature endorses an important potential role for epigenetics in chronic pain.Epigenetic analysis may identify mechanisms critical to the development of chronic pain after injury, and may provide new pathways and target mechanisms for future drug development and individualized medicine.
Open Access
Future therapies and the expanding role for diagnostic ultrasound
(Current Opinion in Anaesthesiology, 2016-01-01) Buchheit, Thomas