Eric A. Bedell

Percutaneous venovenous perfusion-induced systemic hyperthermia for advanced non-small cell lung cancer: initial clinical experience.

BACKGROUND Venovenous perfusion-induced systemic hyperthermia raises core body temperature by extracorporeal heating of the blood. Five patients with advanced non-small cell lung carcinoma stage IV (4.4+/-1 months after initial diagnosis) received venovenous perfusion-induced systemic hyperthermia to 42.5 degrees C (core temperature) to assess technical and patient risks. METHODS After general anesthesia and systemic heparinization (activated clotting time > 300 seconds), percutaneous cannulation of the right internal jugular vein (15F) for drainage and common femoral vein (15F) for reinfusion allowed extracorporeal flow rates up to 1,500 mL/min (20 mL x kg(-1) x min(-1)) with the ThermoChem System. This device uses charcoal-based sorbent for electrolyte homeostasis. Six monitored sites (rectal, bladder, tympanic x2, nasopharyngeal, and esophageal) determined average core temperature. RESULTS All patients achieved a core target temperature of 42.5 degrees C for 2 hours. Electrolyte balance was maintained throughout hyperthermia (mean) in mmol/L: Na+, 136.2+/-2.2 mmol/L; K+, 4.0+/-0.3 mmol/L; Ca2+, 4.1+/-0.2 mg/dL; Mg2+, 1.9+/-0.1 mg/dL; PO4-, 4.5+/-0.9 mg/dL). Plasma cytokine concentration revealed significant heat-induced activation of proinflammatory and antiinflammatory cascades. All patients exhibited systemic vasodilation requiring norepinephrine infusion, 4 of 5 patients required vigorous diuresis, and 3 of 5 required intubation for 24 to 36 hours because of pulmonary edema or somnolence, with full recovery. Average length of hospital stay was 5.4 days. Serial tumor measurements (1 patient withdrew) revealed a decrease (64.5%+/-18%) in tumor size in 2 patients, no change in 1, and enlargement in 1, with no 30-day mortality. Median survival after hyperthermia treatment was 172 days (range, 40 to 271 days). CONCLUSIONS Venovenous perfusion-induced systemic hyperthermia is feasible and provides the following potential advantages for better tumoricidal effect: (1) homogeneous heating, and (2) a higher sustained temperature.

Should induced hypertension be beneficial after traumatic brain injury

raumatic brain injury (TBI) is a major source of morbidity and mortality: approximately 80,000 patients become permanently disabled, and 52,000 die each year in the United States alone (1). The management of these patients remains controversial, in part because of the limited number of definitive clinical studies relating interventions to improved out- comes. One critical issue that has been addressed ex- perimentally (2,3) and clinically (4) is the role of hy- potension in aggravating TBI. Although most clinical investigators would avoid hypotension, only a few argue-based on experimental and clinical observa- tions-that arterial blood pressure should be aggres- sively increased (5). In the September issue, Talmor et al. (6) reported the influence on brain edema and short-term behavior of a 15-min infusion of phenyl- ephrine started 65 min after experimental TBI using a weight-drop model in rats. Control of systemic physiologic variables represents one of the primary therapeutic goals for patients suf- fering from TBI. Investigators have studied blood pressure management (4,5), therapeutic hypothermia (7,8), appropriate targets for Pace, (9-12), and man- agement of serum glucose (13,14). Each of these areas has the potential to influence outcome after TBI. Arterial blood pressure management after TBI is one of the most commonly targeted areas for interven- tion. Cerebral perfusion pressure (CPP), the potential pressure decrease across the vascular bed of the brain, is mean arterial pressure minus intracranial pressure (ICI’) or cerebral venous pressure, whichever is higher. After TBI, short-term neuronal function and long-term outcome are related to maintenance of a minimal CPP. Animal (2,3) and human (15,16) studies suggest that cerebral blood flow (CBF) autoregulation in response to blood pressure alterations is altered by TBI. After TBI, cerebral vascular dilation is impaired at previously “normal” blood pressures, which leads to decreases in CBF. Alterations in CBF autoregulation

Veno-venous perfusion-induced systemic hyperthermia: case report with perfusion considerations.

Cancer cells are more susceptible to destruction by heat than are their normal counterparts. However, optimization of this hyperthermic susceptibility for selective cancer cell kill has been difficult to define and technically difficult to achieve. A whole-body hyperthermic technique - veno-venous perfusion-induced systemic hyperthermia (VV-PISH) was designed in in vitro and in swine experiments to achieve selective hyperthermic cancer cell destruction. In this case report, VV-PISH is studied for its safety and therapeutic efficiency in a Food and Drug Administration (FDA) approved phase-I study, where hyperthermia is used to treat advanced (Stage III B or IV) lung cancer. VV-PISH, utilizing the ThermoChem™ HT system in an extracorporeal circuit, was used to induce hyperthermia to 42.5°C sustained for 120 min. Cooling returned the body temperature to 37°C. After completion of the treatment, the patient was transferred to the intensive care unit on a ventilator, norepinephrine and diuretics. The patient remained somnolent for 36 h, developed pulmonary congestion requiring an additional 48 h before extubation, was transferred to the intermediate unit on day 4 and discharged in good condition on day 8. He did experience hyperthermia-related shrinkage of his lung cancer; however, he succumbed 270 days after this treatment from further progression of this disease. Hyperthermia is not a benign therapy; management techniques have been developed that have ameliorated many of the problems associated with extremely high temperatures, but pathophysiology still exists. Using these techniques, VV-PISH can be safety implemented, albeit not without temporary sequelae and further hospitalization.

Is reduced cerebral perfusion pressure better tolerated during hypothermia

The finite tolerance of the brain for reduced cerebral perfusion pressure (CPP) is one of the key issues that complicates management of the critically ill neurologic or neurosurgical patient. Traumatic brain injury (TBI) intensifies the problem by apparently increasing the vulnerability of the traumatized adult (1) or pediatric (2, 3) brain to reductions in CPP. In this issue of Critical Care Medicine, Dr. Bauer and colleagues (4) present data suggesting that mild hypothermia (~32C) improves the tolerance of the brain for reduced CPP, produced in juvenile swine by increasing intracranial pressure while controlling mean arterial pressure (MAP). That conclusion, however, must be viewed in the context of other studies of cerebral pressure autoregulation under normothermic and hypothermic conditions in the normal and traumatized brain.

Fentanyl infusion preserves cerebral blood flow during decreased arterial blood pressure after traumatic brain injury in cats

Hypotension after traumatic brain injury (TBI) has been associated with significant reductions in cerebral blood flow (CBF) in experimental animals. In humans, posttraumatic hypotension is associated with significantly worsened outcome, possibly because of cerebral hypoperfusion. The existence of opioid receptor-mediated cerebrovascular dilatory effects in humans has been theorized. We studied the systemic and cerebral vascular effects of fentanyl after fluid-percussion injury (FPI) TBI in isoflurane-anesthetized cats. In an approved protocol, 17 fasted cats were anesthetized, mechanically ventilated with 1-1.5% isoflurane in 70% N2O/30% O2, and prepared for FPI. Electroencephalogram (EEG) and intracranial pressure (ICP) were monitored. Cerebral blood flow and cardiac output were measured with radiolabelled microspheres. Animals received moderate FPI (2.2 atm) followed by 15 min of stabilization. Cats were then randomized to control (isoflurane anesthesia plus saline placebo) or fentanyl (isoflurane anesthesia plus fentanyl 50 microg x kg(-1) h(-1)) groups. CBF, EEG, and ICP were recorded at baseline (Baseline), 15 min post-FPI (post-FPI), and at 15, 75, and 135 min after beginning fentanyl or saline placebo infusions (INF 15, INF 75, INF 135). EEG, ICP, PaCO2, PaO2, pH, and temperature were similar between groups. Mean arterial pressure was significantly lower than in the control group after fentanyl administration, while total CBF was not significantly different from control values. In a previous study, decreasing MAP to 80 mm Hg after TBI in isoflurane-anesthetized cats resulted in a 30% decrease in CBF. In this study, fentanyl after TBI significantly decreased MAP but not CBF. Fentanyl administration was associated with preservation of CBF despite hypotension. Further research is necessary to evaluate the effects of fentanyl on cerebral autoregulation after TBI.

Management of traumatic brain injury

&NA; The goal of research in traumatic brain injury (TBI) is to identify processes that contribute to mortality and morbidity and that are amenable to intervention. Recent observations that neural loss progresses for weeks to months after TBI suggest a prolonged interval during which interventions could be accomplished. Cell dysfunction and death after TBI are related to a variety of posttraumatic vascular and cellular processes. After TBI, cerebral blood flow progresses through three phases: phase I, decreased cerebral blood flow and cerebral metabolic rate for oxygen; phase II, increased cerebral blood flow with unchanged cerebral metabolic rate for oxygen; and phase III, cerebral vasospasm. In severely head injured patients, impaired cerebrovascular autoregulation correlates with poor outcome. Impaired brain tissue oxygenation after TBI can be measured by intraparenchymal probes that have also been used to define changes in tissue oxygenation in response to pharmacologically increasing cerebral perfusion pressure, mannitol, and hyperventilation.