Development and Retrospective Clinical Assessment of a Patient-Specific Closed-Form Integro-Differential Equation Model of Plasma Dilution.

A closed-form integro-differential equation (IDE) model of plasma dilution (PD) has been derived which represents both the intravenous (IV) infusion of crystalloid and the postinfusion period. Specifically, PD is mathematically represented using a combination of constant ratio, differential, and integral components. Furthermore, this model has successfully been applied to preexisting data, from a prior human study, in which crystalloid was infused for a period of 30 minutes at the beginning of thyroid surgery. Using Euler's formula and a Laplace transform solution to the IDE, patients could be divided into two distinct groups based on their response to PD during the infusion period. Explicitly, Group 1 patients had an infusion-based PD response which was modeled using an exponentially decaying hyperbolic sine function, whereas Group 2 patients had an infusion-based PD response which was modeled using an exponentially decaying trigonometric sine function. Both Group 1 and Group 2 patients had postinfusion PD responses which were modeled using the same combination of hyperbolic sine and hyperbolic cosine functions. Statistically significant differences, between Groups 1 and 2, were noted with respect to the area under their PD curves during both the infusion and postinfusion periods. Specifically, Group 2 patients exhibited a response to PD which was most likely consistent with a preoperative hypovolemia. Overall, this IDE model of PD appears to be highly "adaptable" and successfully fits clinically-obtained human data on a patient-specific basis, during both the infusion and postinfusion periods. In addition, patient-specific IDE modeling of PD may be a useful adjunct in perioperative fluid management and in assessing clinical volume kinetics, of crystalloid solutions, in real time.

The use of the oesophageal Doppler in perioperative medicine: new opportunities in research and clinical practice.

The oesophageal Doppler (OD) is a minimally invasive haemodynamic monitor used in the surgical theatre and the ICU. Using the OD, goal-directed therapy (GDT) has been shown to reduce perioperative complications in high-risk surgical patients. However, most GDT protocols currently in use are limited to stroke volume optimisation. In the present manuscript, we examine the conceptual models behind new OD-based measurements. These would provide the clinician with a comprehensive view of haemodynamic pathophysiology; including pre-load, contractility, and afterload. Specifically, volume status could be estimated using mean systemic filling pressure (MSFP), the pressure to which all intravascular pressures equilibrate during asystole. Using the OD, MSFP could be readily estimated by simultaneous measurements of aortic blood flow and arterial pressure with sequential manoeuvres of increasing airway pressure. This would result in subsequent reductions in cardiac output and arterial pressure and would allow for a linear extrapolation of a static MSFP value to a "zero flow" state. In addition, we also demonstrate that EF is proportional to mean blood flow velocity measured in the descending thoracic aorta with the OD. Furthermore, OD-derived indexes of blood flow velocity and acceleration, as well as force and kinetic energy, can be derived and used for continuous assessment of cardiac contractility at the bedside. Using OD-derived parameters, the different components of afterload: inertia, resistance and elastance, could also be individually determined. The integration of these additional haemodynamic parameters could assist the clinician in optimising and individualising haemodynamic performance in unstable patients.

Otocephaly Complex: Case Report, Literature Review, and Ethical Considerations.

Otocephaly complex is a rare and usually lethal syndrome characterized by a set of malformations consisting of microstomia, mandibular hypoplasia/agnathia, and ventromedial malposition of the ears. Those cases that have been diagnosed prenatally have used an ex utero intrapartum treatment procedure to establish a definitive airway. However, prenatal diagnosis continues to be challenging, primarily because of poor diagnostic sensitivity associated with ultrasonography. We present a case of a newborn with an unanticipated otocephaly complex requiring emergent airway management. In this report, we discuss the medical and ethical issues related to the care of a newborn with this frequently fatal condition.

Left Ventricle-Arterial System Interaction in Heart Failure.

Ejection fraction (EF) has been viewed as an important index in assessing the contractile state of the left ventricle (LV). However, it is frequently inadequate for the diagnosis and management of heart failure (HF), as a significant subset of HF patients have been found to have reduced EF (HFrEF) whereas others have preserved EF (HFpEF). It should be noted that the function of the LV is dependent on both preload and afterload, as well as its intrinsic contractile state. Furthermore, stroke volume (SV) is dependent on the properties of the arterial system (AS). Thus, the LV-arterial system interaction plays an important role in those patients with HF. This aspect is investigated through the analysis of the specific parameters involved in the coupling of the LV and AS. This includes contractility and the systolic/diastolic indices of the LV. Furthermore, AS afterload parameters such as vascular stiffness and arterial compliance, and their derived coupling coefficient, are also investigated. We conclude that those parameters, which relate to LV structural changes, are most appropriate in quantifying the LV-AS interaction.

Additional hemodynamic measurements with an esophageal Doppler monitor: a preliminary report of compliance, force, kinetic energy, and afterload in the clinical setting.

The esophageal Doppler monitor (EDM) is a minimally-invasive hemodynamic device which evaluates both cardiac output (CO), and fluid status, by estimating stroke volume (SV) and calculating heart rate (HR). The measurement of these parameters is based upon a continuous and accurate approximation of distal thoracic aortic blood flow. Furthermore, the peak velocity (PV) and mean acceleration (MA), of aortic blood flow at this anatomic location, are also determined by the EDM. The purpose of this preliminary report is to examine additional clinical hemodynamic calculations of: compliance (C), kinetic energy (KE), force (F), and afterload (TSVR(i)). These data were derived using both velocity-based measurements, provided by the EDM, as well as other contemporaneous physiologic parameters. Data were obtained from anesthetized patients undergoing surgery or who were in a critical care unit. A graphical inspection of these measurements is presented and discussed with respect to each patient's clinical situation. When normalized to each of their initial values, F and KE both consistently demonstrated more discriminative power than either PV or MA. The EDM offers additional applications for hemodynamic monitoring. Further research regarding the accuracy, utility, and limitations of these parameters is therefore indicated.

Afterload assessment with or without central venous pressure: a preliminary clinical comparison.

A clinical comparison, of two methods of afterload assessment, has been made. The first method, systemic vascular resistance index (SVR(i)), is based upon the traditional formula for afterload which utilizes central venous pressure (CVP), as well as cardiac index (C(i)), and mean arterial blood pressure (MAP). The second method, total systemic vascular resistance index (TSVR(i)), also uses MAP and C(i). However, TSVR(i) ignores the contribution of CVP. This preliminary examination, of 10 randomly-selected ICU patients, has shown a high degree of correlation (ranging from 90 to 100%) between SVR(i) and TSVR(i) (P < 0.0001). Furthermore, there was also a high degree of correlation (ranging from 94 to 100%) noted between the hour-to-hour change in SVR(i) with the hour-to-hour change in TSVR(i) (P < 0.0001). The results, of this pilot study, support the premise that the use of CVP may not always be necessary for afterload evaluation in the clinical setting. Minimally-invasive means of measuring both C(i) and MAP, without CVP, may be adequate for use in assessing afterload.

Brachial artery differential characteristic impedance: Contributions from changes in young's modulus and diameter.

This examination of brachial artery (BA) differential characteristic impedance, DeltaZ (c), illustrates that changes in Z (c) can occur from changes in either BA wall stiffness (Young's modulus, E) and/or its diameter, D. Furthermore, we assessed how changes in both E and D combine in either an isolated, synergistic, or antagonistic manner to yield the net change in BA Z (c). The basis of this analysis is a partial differential equation which approximates DeltaZ (c) as a total differential. The effects on BA DeltaZ (c) of acetylcholine, atenolol, fenoldapine, nitroglycerin, hydrochlorothiazide and other medications are examined using data from previously published studies. Clinical situations which alter BA Z (c), such as congestive heart failure, hypertension, and hyperemia, are also analyzed. Results illustrate the usefulness of the present approach in differentiating how medications, hyperemia, and pathological conditions affect BA DeltaZ (c) by causing independent changes to E and/or D.

Development and application of a logistic-based systolic model for hemodynamic measurements using the esophageal Doppler monitor.

The esophageal Doppler monitor (EDM) is a clinically useful device for minimally invasive assessment of cardiac output, preload, afterload, and contractility. An empirical model, based upon the logistic function, has been developed. Use of this model illustrates how the EDM could estimate the net effect of aortic and non-aortic contributions to inertia, resistance, and elastance within real time. This is based on an assumed mechanical impedance conceptually resembling that of a series arrangement of a spring, mass, and dashpot. In addition, when used with an invasive radial arterial catheter, the EDM may also estimate aortic pulse wave velocity, as well as aortic characteristic impedance, and characteristic volume. Approximations of left ventricular stroke work and stroke power can also be made. Furthermore, the effects of inertia, resistance, and elastance, on mean blood pressure during systole, can be quantified. These additional parameters could offer insight for clinicians, as well as researchers, and may be beneficial in further examining and utilizing clinical hemodynamics with the EDM. These additional measurements also underscore the need to integrate the EDM with existing and future monitoring equipment.

Labetalol facilitates GABAergic transmission to rat periaqueductal gray neurons via antagonizing beta1-adrenergic receptors--a possible mechanism underlying labetalol-induced analgesia.

Labetalol, a combined alpha1, beta1, and beta2 adrenoceptor-blocking drug, has been shown to have analgesic properties in vivo. To determine the underlying mechanisms, we examined its effects on GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous firings of rat ventrolateral periaqueductal gray (PAG) neurons, either mechanically dissociated, or in acute brain slices. These PAG neurons mediate opioid-mediated analgesia and pain transmission and are under tonic control of GABAergic interneurons. An increase in GABAergic transmission to these neurons yields an inhibitory hyperpolarized state and may interrupt pain signal transmission. Using patch clamp techniques, we found that labetalol reversibly increases the frequency of sIPSCs without changing their mean amplitude. This indicates that labetalol enhances GABAergic synaptic transmission by a presynaptic mechanism. Metoprolol, a specific beta1-adrenoceptor antagonist, also reversibly enhanced sIPSC frequency. In the presence of metoprolol, labetalol-induced increase in sIPSC frequency was significantly attenuated or even abolished. These results suggest that labetalol shares the same pathway as metoprolol in enhancing GABAergic transmission via an inhibition of presynaptic beta1-adrenoceptors. We further showed that labetalol reversibly reduced the firing rate of PAG neurons. This reduction was significantly attenuated in the presence of bicuculline, a selective antagonist of GABAA receptors. These data indicate that labetalol-induced inhibition of PAG cell firing is attributable to its potentiation of GABAergic transmission. Based on these data, we postulate that labetalol-induced analgesia is at least in part ascribed to its antagonistic effects on presynaptic beta1-adrenoceptors.

Development of a recursive finite difference pharmacokinetic model from an exponential model: application to a propofol bolus.

Propofol is commonly administered, as a single bolus dose, for the induction of general anesthesia. The purpose of this study was to mathematically assess the ability to model propofol induction-dose serum levels with a recursive finite difference equation (RFDE). Using data obtained from a prior published study, propofol induction pharmacokinetics were accurately modeled, on a subject-specific basis, with a third-order homogeneous finite difference equation with constant coefficients: P((k + 3)) = AP((k + 2)) + BP((k + 1)) + CP((k)). Furthermore, each RFDE model is derived directly from the coefficients of a traditional three-compartment pharmacokinectic exponential equation. Based on this study, third-order RFDE models can have identical accuracy as three-compartment exponential models. In this particular application, it should be noted that each RFDE model required only three coefficients whereas each exponential model required six. Also, there was overall less patient-to-patient variability of the coefficients of the RFDE models. In general, it appears that RFDE models uniquely allow for predicting subsequent drug levels from preexisting ones. However, RFDE models require initial conditions whereas exponential models do not. Additional studies and applications of exponentially-derived RFDE pharmacokinetic models may be warranted.

Combined preemptive and preventive analgesia in morbidly obese patients undergoing open gastric bypass: A pilot study.

PURPOSE: It is difficult to balance adequate pain control against the risk of sedation and depressed breathing in severely obese patients. This study assesses the effects of combined preemptive and preventive analgesia on narcotic use after open gastric bypass. METHODS: Twenty patients were randomized in this prospective double-blind trial comparing preoperative 30 mg intravenous ketorolac (Toradol), 0.25% subcutaneous bupivacaine (Marcaine) with epinephrine along the planned incision, and 0.25% bupivacaine in the rectus fascia before closing with identical injections with 0.9% saline. The patients' self-assessed pain on a visual analogue scale (VAS) and total narcotic use by patient-controlled analgesia (PCA) and rescue medication were recorded. RESULTS: Age, body mass index (BMI), incision length, and operative times were similar between the two groups, as was the average length of hospital stay (2.9 days). Self-reported pain was less in the treatment group 1 hour postoperatively (P = .01). Narcotic use was less in the treatment group during the first 2 hospital days (51% less on day 1 vs 44.5% less on day 2). Total narcotic use during the hospital stay was reduced by 40% (P = .02). CONCLUSIONS: Patients receiving combined preemptive and preventive analgesia used significantly less narcotic pain medication than the patients receiving placebo. The effect lasted beyond the duration of action of the local anesthetic.

A mathematical model of differential tracheal tube cuff pressure: effects of diffusion and temperature.

The tracheal tube cuff performs an important function during anesthesia and critical care situations by allowing positive pressure ventilation and isolating the lungs from aspiration. Other maneuvers, such as pressure support ventilation and positive end-expiratory pressure, are also cuff-dependent. However, excessive cuff pressure, as well as long-term intubation without excessive cuff pressure, have been associated with significant morbidity and mortality. A straightforward mathematical model of differential tracheal tube cuff pressure has been developed. This model incorporates compliance, temperature variation, and net molar diffusion in determining differential tracheal tube cuff pressure. In addition, temperature and diffusion are modeled as separate processes which effect differential cuff pressure independently. Support for the validity of this model is based upon an analysis of existing data from prior studies.