The orbitofrontal cortex maps future navigational goals

Accurate navigation to a desired goal requires consecutive estimates of spatial relationships between the current position and future destination throughout the journey. Although neurons in the hippocampal formation can represent the position of an animal as well as its nearby trajectories1–7, their role in determining the destination of the animal has been questioned8,9. It is, thus, unclear whether the brain can possess a precise estimate of target location during active environmental exploration. Here we describe neurons in the rat orbitofrontal cortex (OFC) that form spatial representations persistently pointing to the subsequent goal destination of an animal throughout navigation. This destination coding emerges before the onset of navigation, without direct sensory access to a distal goal, and even predicts the incorrect destination of an animal at the beginning of an error trial. Goal representations in the OFC are maintained by destination-specific neural ensemble dynamics, and their brief perturbation at the onset of a journey led to a navigational error. These findings suggest that the OFC is part of the internal goal map of the brain, enabling animals to navigate precisely to a chosen destination that is beyond the range of sensory perception.

Efficacy and Safety of the Early Addition of Vasopressin to Norepinephrine in Septic Shock

Background: Delays in achievement of target mean arterial pressure (MAP) have been associated with increased mortality in patients with septic shock. Vasopressin may be added to norepinephrine to raise MAP or decrease norepinephrine dosage. The purpose of this study was to determine whether early initiation of vasopressin to norepinephrine resulted in a reduced time to target MAP compared to norepinephrine monotherapy. Methods: This retrospective cohort study compared early addition of vasopressin within 4 hours of septic shock onset to norepinephrine versus initial norepinephrine monotherapy in medically, critically ill patients with septic shock admitted from May 2014 to October 2015. Time to goal MAP was compared using Student t test and examined with Kaplan-Meier curves. Changes in Sequential Organ Failure Assessment (SOFA) scores were evaluated with Wilcoxon rank sum test. Results: Each group contained 48 patients. Mean arterial pressure (61.5 vs 58.6 mm Hg) and intravenous fluid volume received at vasopressor initiation (14.3 vs 25.2 hours, P = .014) were similar. Patients started on early vasopressin achieved and maintained goal MAP sooner (6.2 vs 9.9 hours, P = .023), experienced greater reductions in SOFA scores at 72 hours (−4 vs −1, P = .012), and had shorter hospital durations (343 vs 604 hours, P = .014). Not initiating early vasopressin trended toward an association with increased time to goal MAP ( P = .067). Conclusion: Early initiation of vasopressin in patients with septic shock may achieve and maintain goal MAP sooner and resolve organ dysfunction at 72 hours more effectively than later or no initiation.

Impact of Norepinephrine Weight-Based Dosing Compared With Non–Weight-Based Dosing in Achieving Time to Goal Mean Arterial Pressure in Obese Patients With Septic Shock

Background: Currently, a lack of standardization exists in norepinephrine dosing units, the first-line vasopressor for septic shock. Timely achievement of goal mean arterial pressure (MAP) is dependent on optimal vasopressor dosing. Objective: To determine if weight-based dosing (WBD) of norepinephrine leads to earlier time to goal MAP compared with non-WBD in obese patients with septic shock. Methods: This was a retrospective, multicenter cohort study. Patients had a body mass index (BMI) ≥30 kg/m2 and received norepinephrine for septic shock with either a non-WBD strategy (between December 2009 and January 2013) or WBD strategy (between January 2013 and December 2015). The primary outcome was time to goal MAP. Secondary outcomes were norepinephrine duration, dose requirements, and development of treatment-related complications. Results: A total of 287 patients were included (WBD 144; non-WBD 143). There was no difference in median time to goal MAP (WBD 58 minutes, interquartile range [IQR] = 16.8-118.5, vs non-WBD 60 minutes, IQR = 17.5-193.5; P = 0.28). However, there was a difference in median cumulative norepinephrine dose (WBD 12.6 mg, IQR = 4.9-45.9, vs non-WBD 10.5 mg, IQR = 3.9-25.6; P = 0.04) and time to norepinephrine discontinuation (WBD 33 hours, IQR = 15-69, vs non-WBD 27 hours, IQR = 12-51; P = 0.03). There was no difference in rates of atrial fibrillation (WBD 15.3% vs non-WBD 23.7%; P = 0.07) or mortality (WBD 23.6% vs non-WBD 23.1%; P = 0.92). Conclusion: WBD of norepinephrine does not achieve time to goal MAP earlier in obese patients with septic shock. However, WBD may lead to higher norepinephrine cumulative dose requirements and prolonged time until norepinephrine discontinuation.

Efficacy and Outcomes After Vasopressin Guideline Implementation in Septic Shock

Background: In septic shock, the dose of norepinephrine (NE) at which vasopressin (AVP) should be added is unknown. Following an increase in AVP price, our medical intensive care unit (MICU) revised its vasopressor guidelines to reserve AVP for patients requiring greater than 50 µg/min of NE. Objective: The purpose of this study is to compare efficacy and safety outcomes for patients admitted before the guideline revision with those for patients admitted after the revision. Methods: This was a single-center, retrospective cohort study of patients admitted to Vanderbilt University Medical Center from November 1, 2014, to November 30, 2015. Before June 1, 2015, the vasopressor guidelines recommended initiation of AVP for patients requiring 10 µg/min of NE or greater. After June 1, 2015, the guidelines recommended initiation of AVP at a NE dose of 50 µg/min or greater. Results: Time to achieve goal mean arterial pressure (MAP) was shorter in the postintervention group (2.0 vs 1.3 hours; P = 0.03) in univariate analysis but not after adjusting for prespecified confounders. Incidence of new arrhythmias was similar between the 2 groups (14.9% vs 10.9%; P = 0.567). In multivariable analysis accounting for baseline severity of illness, admission after the revision was associated with decreased 28-day mortality (odds ratio = 0.34; 95% CI = 0.16-0.71; P = 0.004). Conclusions: Use of a vasopressor guideline restricting AVP initiation in septic patients to those on at least 50 µg/min of NE appeared to be safe and did not affect the time to reach goal MAP.

Effect of initially limited resuscitation in a combined model of fluid-percussion brain injury and severe uncontrolled hemorrhagic shock

Object. Studies of isolated uncontrolled hemorrhage have indicated that initial limited resuscitation improves survival. Limited resuscitation has not been studied in combined traumatic brain injury and uncontrolled hemorrhage. In this study the authors evaluated the effects of limited resuscitation on outcome in combined fluid-percussion injury (FPI) and uncontrolled hemorrhage.Methods. Twenty-four swine weighing 17 to 24 kg each underwent FPI (3 atm) and hemorrhage to a mean arterial pressure (MAP) of 30 mm Hg in the presence of a 4-mm aortic tear. Group I (nine animals) was initially resuscitated to a goal MAP of 60 mm Hg; Group II (nine animals) was resuscitated to a goal MAP of 80 mm Hg; and Group III (control; six animals) was not resuscitated. After 60 minutes, the aortic hemorrhage was controlled and the animals were resuscitated to baseline physiological parameters and observed for 150 minutes.Mortality rates were 11%, 50%, and 100% for Groups I, II, and III, respectively (Fisher's exact test; p = 0.002). The total hemorrhage volume was greater in Group II (69 ± 32 ml/kg), as compared with Group I (41 ± 18 ml/kg) and Group III (37 ± 3 ml/kg) according to analysis of variance (p < 0.05). In surviving animals, cerebral perfusion pressure, cerebral blood flow (CBF), cerebral venous O2 saturation (ScvO2), and cerebral metabolic rate of O2 did not differ among groups. Although CBF was approximately 50% of baseline during the period of limited resuscitation in Group I, ScvO2 remained greater than 60%, and arteriovenous O2 differences remained within normal limits.Conclusions. In this model of FPI and uncontrolled hemorrhage, early aggressive resuscitation, which is currently recommended, resulted in increased hemorrhage and failure to optimize cerebrovascular parameters. In addition, a 60-minute period of moderate hypotension (MAP = 60 mm Hg) was well tolerated and did not compromise cerebrovascular hemodynamics, as evidenced by physiological parameters that remained within the limits of cerebral autoregulation.