Michael P. Hutchens

Dexmedetomidine Overdose in the Perioperative Setting

OBJECTIVE To report 3 cases of accidental dexmedetomidine overdose in the perioperative setting and review the pathophysiology of α2-agonist overdose. CASE SUMMARIES Three patients accidentally received overdoses of dexmedetomidine, one intraoperatively (192 μg over 20 min) and 2 postoperatively (4 and 2 rather than 0.4 and 0.2 μg/kg/h; 0.5 μg/kg/min rather than 0.5 μg/kg/h). Hemodynamic parameters remained stable for all 3 patients. The most notable sign was oversedation diagnosed either clinically or using a bispectral index monitor; Naranjo criteria suggest possible or probable association of the reactions with dexmedetomidine. In all 3 cases, oversedation resolved within one hour of drug discontinuation. There were no other sequelae, and the remainder of each patients hospital course was unremarkable. DISCUSSION As of this writing, dexmedetomidine dosing in excess of the label recommendation has been reported, but accidental dexmedetomidine overdose in clinical practice has not been described. Excessive levels of sedation were the only significant finding in all 3 patients. Dexmedetomidines short redistribution half-life of 6 minutes should lead to rapid resolution of oversedation induced by overdoses if the overall duration of infusion is short (≤8 h). While the patients reported here were hemodynamically stable, dexmedetomidine may engender significant hemodynamic changes either because of sympatholysis at normal doses or vasoconstriction at higher than recommended doses. The absence of a significant hypertensive response to high dexmedetomidine concentrations suggests that dexmedetomidine-induced hypertension may be multifactorial, not simply related to plasma drug concentrations. CONCLUSIONS Practitioners presented with dexmedetomidine overdose should be prepared to manage oversedation. While hemodynamic alterations may be seen with dexmedetomidine use, hypertension from high dexmedetomidine plasma concentrations is not a consistent response. Practitioners using dexmedetomidine should carefully note that dosing for this agent is described by the manufacturer in μg/kg/h, not μg/kg/min.

Renal ischemia: does sex matter?

Renal ischemia is a common complication in the perioperative period that leads to a high rate of morbidity and mortality. As in other forms of ischemia (i.e., cardiac, neurologic), the incidence and outcome of renal ischemia is strikingly sex-specific. Sexual dimorphism in response to renal injury has been noted for many years, but is now the subject of both clinical and experimental research. Clinically, women experience a lower incidence of perioperative acute renal failure, with the exception of cardiac surgery. Experimental science is now producing tantalizing clues that sex steroids, both male and female, play a role in the kidneys response to ischemia. In this review, we evaluated sex differences in perioperative renal failure and in the pathophysiology of renal ischemia/reperfusion injury. Although much work remains to characterize the biological mechanisms involved, the data are sufficient to support consideration of gender and the use of medications that impact steroid availability in the perioperative plan of care.

Estrogen protects renal endothelial barrier function from ischemia-reperfusion in vitro and in vivo

Emerging evidence suggests that renal endothelial function may be altered in ischemia-reperfusion injury. Acute kidney injury is sexually dimorphic, and estrogen protects renal tubular function after experimental ischemic injury. This study tested the hypothesis that during ischemia-reperfusion, estrogen alters glomerular endothelial function to prevent hyperpermeability. Glomerular endothelial cells were exposed to 8-h oxygen-glucose deprivation (OGD) followed by 4- and 8-h reoxygenation-glucose repletion. After 4-h reoxygenation-glucose repletion, transendothelial permeability to Ficoll-70 was reduced, and transendothelial resistance increased, by 17β-estradiol vs. vehicle treatment during OGD (OGD-vehicle: 91.0 ± 11.8%, OGD-estrogen: 102.6 ± 10.8%, P < 0.05). This effect was reversed by coadministration of G protein-coupled receptor 30 (GPR30) antagonist G15 with 17β-estradiol (OGD-estrogen-G15: 89.5 ± 6.9, P < 0.05 compared with 17β-estradiol). To provide preliminary confirmation of this result in vivo, Ficoll-70 was administered to mice 24 h after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Blood urea nitrogen (BUN) and serum creatinine (SCr) in these mice were elevated within 12 h following CA/CPR and reduced at 24 h by pretreatment with 17β-estradiol (BUN/SCr 17β-estradiol: 34 ± 19/0.2 ± 0.1 vehicle: 92 ± 49/0.5 ± 0.3, n = 8-12, P < 0.05). Glomerular sieving of Ficoll 70 was increased by CA/CPR within 2 h of injury and 17β-estradiol treatment (θ; 17β-estradiol: 0.74 ± 0.26 vs. vehicle: 1.05 ± 0.53, n = 14-15, P < 0.05). These results suggest that estrogen reduces postischemic glomerular endothelial hyperpermeability at least in part through GPR30 and that estrogen may regulate post CA/CPR glomerular permeability in a similar fashion in vivo.

Estrogen Is Renoprotective via a Nonreceptor-dependent Mechanism after Cardiac Arrest In Vivo

Background:Severe ischemia induces renal injury less frequently in women than men. In this study, cardiac arrest and cardiopulmonary resuscitation were used to assess whether estradiol is renoprotective via an estrogen receptor (ER)-dependent mechanism. Materials and Methods:Male and female C57BL/6 and ER gene-deleted mice underwent 10 min of cardiac arrest followed by cardiopulmonary resuscitation. Serum chemistries and renal stereology were measured 24 h after arrest. Results:Estrogen did not affect mean arterial pressure, regional renal cortical blood flow, and arterial blood gases. Hence, female kidneys were protected (mean ± SEM: blood urea nitrogen, 65 ± 21 vs.149 ± 27 mg/dl, P = 0.04; creatinine, 0.14 ± 0.05 vs. 0.73 ± 0.16 mg/dl, P = 0.01; volume of necrotic tubules, 7 ± 1% vs. 10 ± 0%, P = 0.04). Estrogen also reduced renal injury. In intact females (n = 5), ovariectomized/vehicle-treated (n = 8), and ovariectomized/estrogen-treated (n = 8) animals, blood urea nitrogen was 65 ± 21, 166 ± 28, and 50 ± 14 mg/dl (P = 0.002); creatinine was 0.14 ± 0.05, 0.74 ± 0.26, and 0.23 ± 0.27 mg/dl (P = 0.014); necrotic tubules were 2.5 ± 0.25%, 12.0 ± 1.9%, and 5.0 ± 1.6% (P = 0.004), respectively. In ER-α and ER-β gene-deleted mice and controls estradiol-reduced functional injury (blood urea nitrogen: estradiol 117 ± 71, vehicle 167 ± 56, P = 0.007; creatinine: estradiol 0.5 ± 0.5, vehicle 1.0 ± 0.4, P = 0.013), but the effect of estradiol was not different between ER-α or ER-β gene-deleted mice. Adding ICI 182,780 to estradiol did not alter injury. Conclusions:In women, kidneys were protected from cardiac arrest through estrogen. Estradiol-mediated renoprotection was not affected by ER deletion or blockade. Estradiol is renoprotective after cardiac arrest. The results indicate that estradiol renoprotection is ER-α and ER-β independent.

Propofol for sedation in neuro-intensive care

Interventions in the intensive care unit often require that the patient be sedated. Propofol is a widely used, potent sedative agent that is popular in critical care and operating room settings. In addition to its sedative qualities, propofol has neurovascular, neuroprotective, and electroencephalographical effects that are salutory in the patient in neurocritical care. However, the 15-year experience with this agent has not been entirely unbesmirched by controversy: propofol also has important adverse effects that must be carefully considered. This article discusses and reviews the pharmacology of propofol, with specific emphasis on its use as a sedative in the neuro-intensive care unit. A detailed explanation of central nervous system and cardiovascular mechanisms is presented. Additionally, the article reviews the literature specifically pertaining to neurocritical care use of propofol.

Postcardiac arrest temperature management: infectious risks.

Purpose of reviewTherapeutic hypothermia following out-of-hospital cardiac arrest improves neurological recovery. Coupled with neurological benefit, multiple complications including infection have been associated with therapeutic hypothermia following out-of-hospital cardiac arrest. In this review, we will discuss therapeutic hypothermia, and more broadly, temperature management, as a risk for ICU infection. Recent findingsThe application of therapeutic hypothermia following out-of-hospital cardiac arrest has been associated with infectious complications. Studies of hypothermic animal models have provided useful insights into mechanisms by which therapeutic hypothermia confers neuroprotection. Ironically, the same mechanisms through which therapeutic hypothermia provides neuroprotection have been implicated in the risk of infection associated with therapeutic hypothermia. Studies have demonstrated types of infections, pathogens, and the impact of infections on mortality and neurological recovery. SummaryStudies demonstrate increased rate of pneumonia and bacteremia but decreased rate of other infections, suggesting redistribution but no overall increased risk of infection per se. The diagnosis of infection during therapeutic hypothermia does not impact mortality or neurological recovery.

Therapeutic Hypothermia After Perioperative Cardiac Arrest in Cardiac Surgical Patients

BACKGROUND: Therapeutic hypothermia (TH) has been established as an effective treatment for preserving neurological function after out of hospital cardiac arrest (CA). Use of TH has been limited in cardiac surgery patients in particular because of concern about adverse effects such as hemorrhage and dysrhythmia. Little published data describe efficacy or safety of TH in cardiac surgical patients who suffer unintentional CA. However, the benefits of TH are such as may suggest clinical equipoise, even in this high risk patient population. OBJECTIVE: To report a series of three patients in our institutions cardiac surgery intensive care unit who suffered unintentional CA within 48 hours of cardiac surgery and were treated with TH. METHODS: After institutional review board approval, study patients were identified by diagnosis of undesired intraoperative CA or arrest on ICU days 1-2, as well as having documented TH. The institutions electronic medical record and the Society of Thoracic Surgeons database were retrospectively reviewed for demographic information, comorbid diagnoses, surgical procedure, and outcomes including hemorrhage, re-warming dysrhythmias, infection, in-hospital mortality, and neurologic outcome were assessed. TH was initiated and monitored using active cooling pads according to written institutional protocol. RESULTS: Four patients received TH after perioperative arrest. One patient was inadequately cooled and had massive surgical bleeding, and was therefore excluded from this review. The remaining three patients had a predicted mortality of 14.6% (±13.3) based on Euroscore calculation, and were cooled for 17.6±4.0 hours after CA. Coagulopathy, hypovolemia, severe electrolyte abnormalities, and re-warming dysrhythmias were not identified in any patient. 2 patients were discharged home and 1 was discharged to a long-term care facility. CONCLUSION: Herein we report the safe and successful use of TH after unintentional perioperative CA in 3 cardiac surgery patients. These data suggest that further investigation of this therapy may be warranted given the potential benefit and apparent safety in a small series.

Normothermic Cardiac Arrest and Cardiopulmonary Resuscitation: A Mouse Model of Ischemia-Reperfusion Injury

Acute Kidney Injury (AKI) is a common, highly lethal, complication of critical illness which has a high mortality and which is most frequently caused by whole-body hypoperfusion. Successful reproduction of whole-body hypoperfusion in rodent models has been fraught with difficulty. Models which employ focal ischemia have repeatedly demonstrated results which do not translate to the clinical setting, and larger animal models which allow for whole body hypoperfusion lack access to the full toolset of genetic manipulation possible in the mouse. However, in recent years a mouse model of cardiac arrest and cardiopulmonary resuscitation has emerged which can be adapted to model AKI. This model reliably reproduces physiologic, functional, anatomic, and histologic outcomes seen in clinical AKI, is rapidly repeatable, and offers all of the significant advantages of a murine surgical model, including access to genetic manipulative techniques, low cost relative to large animals, and ease of use. Our group has developed extensive experience with use of this model to assess a number of organ-specific outcomes in AKI.

Estrogen-mediated renoprotection following cardiac arrest and cardiopulmonary resuscitation is robust to GPR30 gene deletion.

Introduction Acute kidney injury is a serious,sexually dimorphic perioperative complication, primarily attributed to hypoperfusion. We previously found that estradiol is renoprotective after cardiac arrest and cardiopulmonary resuscitation in ovariectomized female mice. Additionally, we found that neither estrogen receptor alpha nor beta mediated this effect. We hypothesized that the G protein estrogen receptor (GPR30) mediates the renoprotective effect of estrogen. Methods Ovariectomized female and gonadally intact male wild-type and GPR30 gene-deleted mice were treated with either vehicle or 17β-estradiol for 7 days, then subjected to cardiac arrest and cardiopulmonary resuscitation. Twenty four hours later, serum creatinine and urea nitrogen were measured, and histologic renal injury was evaluated by unbiased stereology. Results In both males and females, GPR30 gene deletion was associated with reduced serum creatinine regardless of treatment. Estrogen treatment of GPR30 gene-deleted males and females was associated with increased preprocedural weight. In ovariectomized female mice, estrogen treatment did not alter resuscitation, but was renoprotective regardless of GPR30 gene deletion. In males, estrogen reduced the time-to-resuscitate and epinephrine required. In wild-type male mice, serum creatinine was reduced, but neither serum urea nitrogen nor histologic outcomes were affected by estrogen treatment. In GPR30 gene-deleted males, estrogen did not alter renal outcomes. Similarly, renal injury was not affected by G1 therapy of ovariectomized female wild-type mice. Conclusion Treatment with 17β-estradiol is renoprotective after whole-body ischemia-reperfusion in ovariectomized female mice irrespective of GPR30 gene deletion. Treatment with the GPR30 agonist G1 did not alter renal outcome in females. We conclude GPR30 does not mediate the renoprotective effect of estrogen in ovariectomized female mice. In males, estrogen therapy was not renoprotective. Estrogen treatment of GPR30 gene-deleted mice was associated with increased preprocedural weight in both sexes. Of significance to further investigation, GPR30 gene deletion was associated with reduced serum creatinine, regardless of treatment.

Hyperglycemia abolishes the protective effect of ischemic preconditioning in glomerular endothelial cells in vitro

In preclinical investigations, ischemic preconditioning (IPC) protects kidneys from ischemia/reperfusion injury. The direct effects of IPC on glomerular endothelial cells have not been studied in detail. Most investigations of IPC have focused on healthy cells and animals, and it remains unknown whether IPC is renoprotective in the setting of medical comorbidities such as diabetes. In this study, we determined the preventive potential of IPC in healthy glomerular endothelial cell monolayers, and compared these results to monolayers cultured under hyperglycemic conditions. We exposed glomerular endothelial monolayers to 1 h of IPC 24 h prior to oxygen–glucose deprivation (OGD), an in vitro model of ischemia/reperfusion injury. Glomerular endothelial monolayer integrity was assessed by measuring transendothelial electrical resistance, albumin flux, and cell survival. We found that IPC protected healthy but not hyperglycemic glomerular endothelial monolayers from ischemia/reperfusion injury. Furthermore, not only was the protective effect of IPC lost in the setting of hyperglycemia, but IPC was actually deleterious to the integrity of hyperglycemic glomerular endothelial cell monolayers.