Frederick J. Pearce

Formal specifications and analysis of the computer-assisted resuscitation algorithm (CARA) Infusion Pump Control System

Reliability of medical devices such as the CARA Infusion Pump Control System is of extreme importance given that these devices are being used on patients in critical condition. The Infusion Pump Control System includes embedded processors and accompanying embedded software for monitoring as well as controlling sensors and actuators that allow the embedded systems to interact with their environments. This nature of the Infusion Pump Control System adds to the complexity of assuring the reliability of the total system. The traditional methods of developing embedded systems are inadequate for such safety-critical devices. In this paper, we study the application of formal methods to the requirements capture and analysis of the Infusion Pump Control System. Our approach consists of two phases. The first phase is to convert the informal design requirements into a set of reference specifications using a formal system, in this case EFSMs (Extended Finite State Machines). The second phase is to translate the reference specifications to the tools supporting formal analysis, such as SCR and Hermes. This allows us to conclude properties of the reference specifications. Our research goal is to develop a framework and methodology for the integrated use of formal methods in the development of embedded medical systems that require high assurance and confidence .

The effect of hypothermia on potassium and glucose changes in isobaric hemorrhagic shock in the rat.

Hypothermia has been shown to decrease oxygen consumption requirements and improve survival during hemorrhagic shock. However, hypothermia applied therapeutically does not prevent the development of a lactic acidosis during hemorrhage. We re-examined the development of a hemorrhage-induced lactic acidosis and other metabolic parameters (glucose, plasma electrolytes, and arterial blood gases) at various temperatures (29–37°C) to better define the protective action of hypothermia in hemorrhagic shock. Five groups of male, Sprague-Dawley rats were bled to a mean arterial blood pressure (MABP) of 40 mmHg over a 15 min period and held there by further blood removal until death. The final level and rate of development of the lactic acidemia was the same in all groups. However, the rate of decline in plasma glucose and rate of rise in plasma potassium were temperature dependent. These results suggest that temperature-dependent changes in serum glucose and potassium may contribute to the protective effect of hypothermia during hemorrhagic shock.

Changes in the intracranial rheoencephalogram at lower limit of cerebral blood flow autoregulation

Cerebral blood flow (CBF) reactivity monitoring is an appropriate primary parameter to evaluate cerebral resuscitation due to a systemic or regional cerebral injury leading to possible irreversible brain injury. Use of the electrical impedance method to estimate CBF is rare, as the methods anatomical background is not well understood. Use of intracranial rheoencephalography (iREG) during hemorrhage and comparison of iREG to other CBF measurements have not been previously reported. Our hypothesis was that iREG would reflect early cerebrovascular alteration (CBF autoregulation). Studies comparing iREG, laser Doppler flowmetry and ultrasound were undertaken on anesthetized rats to define CBF changes during hemorrhage. Blood was removed at a rate required to achieve a mean arterial blood pressure (MABP) of 40 mm Hg over 15 min. Estimation of CBF was taken with intracranial, bipolar REG (REG I; n=14), laser Doppler flowmetry (LDF; n=3) and carotid flow by ultrasound (n=11). Data were processed off-line. During the initial phase of hemorrhage, when MABP was close to 40 mm Hg, intracranial REG amplitude transiently increased (80.94%); LDF (77.92%) and carotid flow (52.04%) decreased and changed with systemic arterial pressure. Intracranial REG amplitude change suggests classical CBF autoregulation, demonstrating its close relationship to arteriolar changes. The studies indicate that iREG might reflect cerebrovascular responses more accurately than changes in local CBF measured by LDF and carotid flow. REG may indicate promise as a continuous, non-invasive life-sign monitoring tool with potential advantages over ultrasound, the CBF measurement technique normally applied in clinical practice. REG has particular advantages in non-hospital settings such as military and emergency medicine.

The role of histamine in mediating the decompensatory phase of hemorrhagic shock in the rat.

&NA; Our laboratory has previously reported that plasma histamine levels rise significantly and coincidentally with the onset of the decompensatory phase of isobaric hemorrhagic shock in rats. The histamine levels seen in shock were comparable to those that induce profound vasodilatation in many vascular beds under normovolemic conditions. We, therefore, sought to determine whether the elevation in plasma histamine contributes to the cardiovascular collapse seen in the decompensatory phase of hemorrhagic shock. Sprague‐Dawley rats were bled according to an isobaric bleeding protocol which maintained the mean arterial blood pressure (MAP) at 40 mmHg until death. Selected H1 (diphenhydramine) and/or H2 (cimetidine and famotidine) antagonists were administered at 75% of the estimated peak shed blood volume (PSBV), a point preceding the rise in plasma histamine. Plasma histamine levels in all groups were similar throughout the time course of hemorrhagic shock. None of the histamine receptor antagonists affected the time of onset or the rate of decompensation. Suspecting that hypotension may alter the animals response to histamine, we investigated the effect of exogenous histamine administration on MAP before and after hemorrhage. In unbled animals, bolus histamine infusions (.6 mg/kg) dropped the MAP by 62.0 ± 2.7 mmHg, however, in animals bled to 40 mmHg, histamine dropped the MAP by 7.2 ± 2.7 mmHg (p = .002). On the basis of the results of these two interventions, we conclude that histamine is not an important mediator of the cardiovascular collapse seen in the decompensatory phase of hemorrhagic shock in the rat.

Clinical evaluation of the Life Support for Trauma and Transport (LSTAT) platform

IntroductionThe Life Support for Trauma and Transport (LSTAT™) is a self-contained, stretcher-based miniature intensive care unit designed by the United States Army to provide care for critically injured patients during transport and in remote settings where resources are limited. The LSTAT contains conventional medical equipment that has been integrated into one platform and reduced in size to fit within the dimensional envelope of a North Atlantic Treaty Organization (NATO) stretcher. This study evaluated the clinical utility of the LSTAT in simulated and real clinical environments. Our hypothesis was that the LSTAT would be equivalent to conventional equipment in detecting and treating life-threatening problems.MethodsThirty-one anesthesiologists and recovery room nurses compared the LSTAT with conventional monitors while managing four simulated critical events. The time required to reach a diagnosis and treatment was recorded for each simulation. Subsequently, 10 consenting adult patients were placed on the LSTAT after surgery for postoperative care in the recovery room. Questionnaires about aspects of LSTAT functionality were completed by nine nurses who cared for the patients placed on the LSTAT.ResultsIn all of the simulations, there was no clinically significant difference in the time to diagnosis or treatment between the LSTAT and conventional equipment. All clinicians reported that they were able to manage the simulated patients properly with the LSTAT. Nursing staff reported that the LSTAT provided adequate equipment to care for the patients monitored during recovery from surgery and were able to detect critical changes in vital signs in a timely manner.DiscussionPreliminary evaluation of the LSTAT in simulated and postoperative environments demonstrated that the LSTAT provided appropriate equipment to detect and manage critical events in patient care. Further work in assessing LSTAT functionality in a higher-acuity environment is warranted.

Cerebrovascular Involvement in Liposome-Induced Cardiopulmonary Distress in Pigs

Intravenous administration of liposomes, including Doxil, can cause severe life-threatening hemodynamic changes in pigs. The reaction is due to complement activation, and it is characterized by massive pulmonary hypertension, systemic hypotension, and severe cardiac abnormalities including falling cardiac output, tachy-or bradycardia with arrhythmia. There were no data suggesting the involvement of cerebrovascular changes in this reaction; however, clinical observations allowed this hypothesis. Here we measured the accompanying changes during liposome infusion by monitoring pulsatile electrical impedance (rheoencephalogram- REG) on the skull (n = 24 pigs, 57 trials, 19 types of liposomes). A transient but significant decrease of REG pulse amplitudes followed the injection of liposomes (78.43% in the total sample, and 91.66% in the Doxil subgroup; P = 0.003, n = 12), indicating the involvement of cerebrovascular reaction during liposome infusion.

Cerebrovascular reactivity: rat studies in rheoencephalography

Here we describe a correlative study of cerebral blood flow (CBF) using global, local CBF and carotid flow measurements. The primary objective of this study was to establish a relationship between REG and CBF autoregulation. Rheoencephalography (REG), a rarely used method to measure CBF, is a potential tool of non-invasive continuous life sign monitoring and detection of early cerebrovascular alteration. However, the anatomical background of REG is not clearly understood. Two experimental studies were undertaken on anesthetized rats to define two CBF measurements: (1) CO2 inhalation, and, (2) clamping of common carotid arteries. Measurement of CBF was taken with REG, laser Doppler flowmetry (LDF) and carotid flow by Doppler ultrasound. Data were off-line processed. During CO2 inhalation, the increases in REG and LDF were significant (p = 0.0001), while carotid flow and systemic arterial pressure decreased. During carotid artery clamping, the decrease in REG and Doppler ultrasound was significant (p = 0.0001). REG showed cerebrovascular reactivity, indicating the relationship to arteriolar changes. Compared to LDF and carotid flow, only REG showed the classical CBF autoregulation.

Influence of volume and flow change on the electrical impedance signal (in vitro)

On the basis of preliminary results, rheoencephalography (REG) shows promise as a practical, noninvasive and continuous monitoring modality of brain injuries. However, REG literature reflects uncertainty about whether the signal reflects flow or volume. Presented here are results of in vitro studies manipulating flow/volume to model clinical conditions (such as brain ischemia and vasospasm) while recording the electrical impedance signal. A loop was created using tubing filled with 0.9 % NaCl. This loop was comprised of a Doppler in-line flow probe connected to an ultrasound flow meter, a peristaltic pump, a pressure transducer and home-made electrical impedance measuring cell, incorporating a balloon catheter. Bipolar impedance amplifiers were used for measuring impedance pulse waves. Data were stored on a PC and processed off-line. This in vitro study confirmed that 1) Doubling flow rate influenced the pulse amplitude and mean flow of the Doppler signal; 2) Doubling flow rate had no influence on the amplitudes of the pressure or electrical impedance signals; 3) An increase in amplitude was observed in the pressure and electrical impedance signals when the first derivative was taken. 4) Balloon inflation decreased electrical impedance and Doppler flow pulse amplitudes; 5) With balloon inflation, Doppler and electrical impedance signals showed an identical relationship to decreased flow (R2=0.966).

Rheoencephalogram Reflects Cerebral Blood Flow Autoregulation In Pigs

Cerebral blood flow autoregulation (CBF AR) is the phenomenon that makes blood flow constant within a physiological range regardless of blood pressure variations. When systemic arterial pressure (SAP) increases, vasoconstriction is taking place in the brain. The objective of the present study was to compare SAP, rheoencephalogram (REG), and carotid flow (CF) measured by Doppler ultrasound. Twentyeight anesthetized Yorkshire pigs were measured to evaluate CBF AR during several CBF manipulations: haemorrhage, positive end-expiratory pressure (PEEP), and transitory SAP decrease and increase. Data were sampled with 200 Hz and processed off-line. 1) Haemorrhage elicited a decrease in SAP and transitory increases in REG and CF amplitude; 2) PEEP resulted in a decrease in SAP and increases in REG and CF amplitude; 3) PEEP after haemorrhage caused decreases in SAP, REG and CF amplitudes. When CBF AR was present, it was detected by both REG and carotid flow. Following haemorrhage, CBF AR was lost; CF and REG passively followed SAP. The clinical importance of these findings is that REG can be measured more conveniently and continuously in humans than can Doppler ultrasound. Therefore, measurement of CBF autoregulation by REG has potential for use as a life sign monitoring modality.

In vivo cerebral blood flow autoregulation studies using rheoencephalography

Acute management of patients with traumatic brain/blast injury is a challenge. To minimize secondary injury and improve outcome, it is critical to detect neurological deterioration early, when it is potentially reversible. One potential monitoring method is cerebral electrical impedance (rheoencephalography-REG) because of its non-invasiveness and good time resolution. Reported here are the results of cerebral blood flow (CBF) manipulations comparing electroencephalogram (EEG) with REG (both intra-cerebral) and measuring with surface and skull REG electrodes. Our hypothesis was that REG would reflect spreading depression and CBF autoregulation. Animal experiments were performed using one rat (four trials with intracerebral electrodes), monkeys (n=8, with surface electrodes) and pigs (n = 24 pigs with skull electrodes; 57 trials, 19 types of liposomes). Challenges included intracranial pressure (ICP) elevation, liposome infusion, and hemorrhage. Data were stored on a PC and evaluated off line. CBF autoregulation was evaluated both by visual inspection and by a Matlab script. These studies confirmed that REG reflects CBF autoregulation and that REG is useful for detecting spreading depression (SD), vasospasm and the lower limit of CBF autoregulation. These findings have clinical relevance for use in noninvasive neuro-monitoring in the neurosurgery intensive care and during transportation of patients with brain injury.