Randall C. Wetzel

Hemodynamic responses in brain dead organ donor patients.

Because we have noticed dramatic hemodynamic responses in brain dead patients undergoing surgery for organ donation, we analyzed the anesthetic records of cadaver organ donors. Ten records contain complete data for heart rate, blood pressure, central venous pressure, and time of incision. Systolic pressure increased by a mean of 31 torr (P < 0.01), diastolic pressure by 16 torr (P < 0.02), and heart rate by 23 beats/min (P < 0.01) in response to surgical stimulation, These results demonstrate the occurrence of significant hemodynamic responses to surgical stimuli in patients who fulfill the criteria of brain death, responses that do not, however, invalidate the current criteria for the diagnosis of brain death.

Potential paracrine role of the pericardium in the regulation of cardiac function

OBJECTIVE Both coronary and endocardial endothelium regulate cardiac contractile function via paracrine pathways. We investigated whether pericardial fluid (PF) and pericardial mesothelial cells (PMC) could exert a similar paracrine action. METHODS Both PF and PMC were extracted from sheep pericardial space. Endothelin-1, prostaglandins and atrial natriuretic factor were measured in PF in vivo. In the other hand, PMC were grown on T-75 flasks and microcarrier beads to investigate endothelin-1, nitric oxide and prostaglandin pathways in vitro. In addition, effects of PF and PMC effluent were tested on adult rat cardiac myocyte contraction in vitro. RESULTS In vitro, cultured PMC expressed endothelin-1 mRNA but not the endothelial nitric oxide synthase III, and released endothelin-1 and prostaglandins. Both PF and cultured PMC superfusate induced a potent, rapidly reversible decrease in the shortening of isolated rat cardiac myocytes. This effect was not associated with changes in intracellular calcium. In vivo, prostaglandins, atrial natriuretic factor and endothelin were present in PF. A greater concentration of atrial natriuretic factor was present in PF than in serum, suggesting molecular diffusion from the myocardium to PF. Preliminary results show that the instillation of vasoactive agents into the pericardial space of dogs rapidly alter coronary and systemic vascular tone, consistent with a molecular diffusion of these substances from PF into the myocardium and circulation. CONCLUSIONS In addition to its mechanical role, the pericardium may contribute to the integration and the regulation of cardiovascular function via a paracrine mechanism.

Postoperative Analgesia: Use of Intrathecal Morphine in Children

The identification of opiate receptors in the spinal cord gave rise to the suggestion that the use of intrathecal and epidural narcotics may provide effective and safe postoperative analgesia. The authors retrospectively reviewed the records of ten children who received intrathecal morphine as part of their anesthetic care over the last 2 years. Preservative-free morphine (Duramorph®) in a dose of 0.02 mg/kg was administered to all patients in the lumbar intrathecal space before the start of the surgical procedure. Adequate postoperative analgesia was achieved in the ten children. No patient required supplemental analgesic agents for the initial 15-hour postoperative period. Surgical procedures included exploratory laparotomy, laryngotracheoplasty, and craniofacial reconstruction. As with narcotics administered by any route, intrathecal morphine can cause respiratory depression, and such depression may be delayed for up to 24 hours after the dose. Therefore, the postoperative respiratory status of these children should be monitored for 24 hours after the dose, preferably in an intensive care unit. With this caveat, the use of intrathecal morphine provides safe and effective postoperative analgesia in children undergoing major surgery.

High frequency ventilation

High frequency ventilation (HFV) presents a new respiratory therapy modality that has taught us much about the theories of gas transport in the lung. Both experimental and clinical applications are summarized. Although the future clinical role of HFV remains uncertain, pediatric applications and investigation continue at the forefront of this new technology.

Airway pressure release ventilation in a neonatal lamb model of acute lung injury

Objective.To determine if airway pressure release ventilation (APRV) is feasible in a neonatal animal model with acute lung injury. Design.Nonrandomized, repeated, bracketed measures. Setting.University research laboratory. Subjects.Seven neonatal sheep (5.6 ± 0.6 kg), <10 days of age. Interventions.Acute lung injury was induced by oleic acid infusion and cardiorespiratory profiles were compared during spontaneous ventilation at ambient airway pressure, continuous positive airway pressure (CPAP), APRV, and conventional positive-pressure ventilation (PPV). Measurements and Results.Oleic acid resulted in acute lung injury with stable cardiorespiratory status during the 3-hr study period. Mean airway pressure (Paw) was comparable for all three positive-pressure modes (CPAP 13.4 ± 1.5, APRV 13.5 ± 1.4, PPV 13.9 ± 1.4 cm H2O, NS). After acute lung injury, CPAP increased arterial oxygenation compared with spontaneous ventilation (77.3 ± 6.9 vs. 57.7 ± 4.2 torr [10.3 ± 0.9 vs. 7.7 ± 0.6 kPa], p < .05), and this increase was maintained during APRV (73.3 ± 5.6 vs. 77.3 ± 6.9 torr [9.8 ± 0.7 vs. 10.3 ± 0.9 kPa], NS). Alveolar ventilation was increased by APRV compared with CPAP (Paco2 29 ± 1 vs. 41 ± 2 torr [3.9 ± 0.1 vs. 5.4 ± 0.3 kPa], p < .05) without impairment of cardiovascular performance (cardiac output 1.18 ± 0.16 vs. 1.20 ± 0.17 L/min, NS). To achieve ventilation equivalent to APRV during PPV, peak Paw was greater (36.4 ± 3.2 vs. 19.7 ± 1.7 cm H2O, p < .05) and cardiac output (0.94 ± 0.11 vs. 1.18 ± 0.16 L/min, p < .05) and mean arterial pressure (91 ± 7 vs. 96 ± 6 mm Hg, p < .05) were decreased during PPV compared with APRV. Conclusions.In this neonatal laboratory model of acute lung injury, APRV maintained oxygenation and augmented alveolar ventilation compared with CPAP. Compared with PPV, APRV provided similar ventilation and oxygenation, but at lower peak Paw than PPV, without compromising cardiovascular performance. (Crit Care Med 1991: 19:373)

THE VIRTUAL PEDIATRIC INTENSIVE CARE UNIT: Practice in the New Millennium

Patients and their families meet with health care providers in a complex marketplace. The information revolution is providing access to vast amounts of information and new ways to understand it. More important, perhaps, is that it also is providing new ways of communicating information not only about health but also about the health care delivery process. This occurrence makes it possible for patients not only to diagnosis and treat themselves but also see how well the professionals do it. Like all marketplaces, asymmetries in information define the value of the interaction. Patients see physicians because they have no way of overcoming this knowledge barrier, and health care is a highly regulated market because of these asymmetries in information. New information technologies in general and telemedicine (which, in this broad sense, include distance learning for patients) can address and erode these information asymmetries. This technology threatens to have a profound effect on health care. Telemedicine offers to increase greatly the reach (connectivity) and richness (bandwidth, customization, and interactivity) of the health care information marketplace. This radically will change the way in which physicians practice critical care. Intensivists must ensure that patients continue to receive high-quality critical care. This practice will require embracing these new technologies. Resisting them will be catastrophic. What is the VPICU? It is a committed group of pediatric intensivits who are dedicated to supporting pediatric critical care medicine in the enhancement of knowledge about pediatric critical care. It includes application of information technologies to support the practice of pediatric critical care. It primarily is focused on understanding the health care delivery process and providing the tools for pediatric intensive care practitioners to better understand the care they deliver. It is the desire of the VPICU to create a virtual community in which pediatric critical care practitioners work together to understand the way they practice and to identify and implement better ways to deliver pediatric critical care. This virtual community will be responsible for clinical and economic performance in the practice of pediatric critical care. The VPICU realizes that this requires the tools to make high-quality decisions and that these decisions depend on data and communication. The author invites all pediatric intensivists to participate in the VPICU to achieve the goals of better practice through the application of information technologies in pediatric critical care.

17 beta-Estradiol inhibits flow- and acute hypoxia-induced prostacyclin release from perfused endocardial endothelial cells.

BACKGROUND Because of the marked difference in the incidence and severity of cardiovascular diseases between men and premenopausal women, several groups have studied the effect of sex steroids, particularly estrogen, on vascular endothelial prostacyclin (PGI2) release. No previous studies have addressed the effect of estrogen on endocardial endothelial cells (EECs), which are involved in the modulation of the myocardium and potentially in downstream pulmonary and systemic vascular tone. Furthermore, all previous studies of estrogen effects on cultured endothelial cell function have used cells grown under standard static cell culture conditions, thereby ignoring the contribution of flow, the ubiquitous environmental endothelial stimulus. METHODS AND RESULTS The effect of 17 beta-estradiol pretreatment (100 ng/mL, 72 hours) on cultured sheep EEC PGI2 release in response to multiple physiologically relevant stimuli was studied. EECs were grown in six-well plates (static conditions) or on microcarrier beads and perfused at a constant flow with normoxic (PO2 = 150 mm Hg, PCO2 = 35 mm Hg) or hypoxic (PO2 = 35 mm Hg, PCO2 = 35 mm Hg) Krebs solution. The stable metabolite of PGI2, 6-keto-PGF1 alpha, was determined in samples from both static and perfusion experiments by direct radioimmunoassay. 17 beta-Estradiol pretreatment did not alter basal or stimulated (arachidonic acid, 1 mumol/L, 10 mumol/L; A23187, 10 mumol/L; and bradykinin, 1 mumol/L) PGI2 release in static conditions. Untreated and acutely treated (100 ng/mL added to perfusate) EECs responded to flow with a time-dependent increase in PGI2 release that plateaued between 60 and 100 minutes. In contrast, 17 beta-estradiol-pretreated, perfused EECs did not increase PGI2 release over time. During perfusion, acute hypoxia increased PGI2 release: 140 +/- 65 (normoxia) to 296 +/- 113 pg (hypoxia) 6-keto-PGF1 alpha/mg per minute. 17 beta-Estradiol inhibited hypoxia-induced PGI2 release: 296 +/- 113 pg (untreated EECs, hypoxia) versus 159 +/- 60 pg (17 beta-estradiol pretreated, hypoxia) 6-keto-PGF1 alpha/mg per minute. CONCLUSIONS This study demonstrates for the first time an inhibitory effect of 17 beta-estradiol on flow- and acute hypoxia-induced increase in PGI2 release from perfused EECs in the absence of any effect on pharmacologically stimulated PGI2 release from static cultures. These effects of 17 beta-estradiol may explain in part the well-recognized gender and estrogen effects in cardiovascular diseases and highlight the importance of flow in studies of endothelial cell function.

Age-dependent effects of indomethacin on hypoxic vasoconstriction in neonatal lamb lungs

ABSTRACT: Although smooth muscle is abundant in the pulmonary vessels of young animals at birth, it is not clear if these vessels respond more vigorously to hypoxia than the less muscular vessels of older neonates. To determine the effect of age on the pulmonary vascular response to hypoxia during the neonatal period in a single species, we measured the steady-state stimulus-response relationship between inspired oxygen tension (200, 50, 30 and 0 mm Hg) and pulmonary artery pressure-flow curves in isolated blood perfused lungs from 2− to 4− and 12− to 14-day-old lambs. Hypoxic vasoconstriction was attenuated in the younger newborns at an inspired oxygen tension of 50 mm Hg, but not at the other oxygen tensions. To determine if this age-related difference was due to differences in modulation of hypoxic vasoconstriction by cyclooxygenase products, we assayed the metabolite of prostacyclin, 6-keto-prostaglandin F1α in the perfusate and determined the effects of indomethacin (40 μg/ml) on the hypoxic stimulus-response relationship. There was no age-related difference in perfusate concentration of 6-keto-prostaglandin F1α at any oxygen tension. However, indomethacin reversed the age-dependent attenuation of hypoxic vasoconstriction at inspired oxygen tension = 50 mm Hg such that in indomethacin-treated lungs pulmonary vasomotor tone was higher in 2− to 4-day-old lungs than in 12− to 14-day-old lungs. This marked enhancement of hypoxic reactivity by indomethacin in the younger lambs suggests that in isolated neonatal lamb lungs cyclooxygenase products exerted a vasodilatory modulation of hypoxic vasoconstriction that decreased with age.

Endotoxin induces organ-specific endothelial cell injury.

Endothelial cell (EC) injury is observed in clinically important pathological processes, including bacterial endotoxemia. We hypothesized that such pathological processes may exhibit target organ heterogeneity due to organ-specific heterogeneity of endothelial cells. To test this hypothesis, endothelial cells of aorta (AO), pulmonary artery (PA), left ventricle (LV), and right ventricle (RV) were cultured from individual sheep and exposed to bacterial endotoxin. Marked heterogeneity in endotoxin-induced cytotoxicity was observed. AOEC were the most sensitive, followed by PAEC, LVEC, and RVEC. This cytotoxicity was manifested as programmed cell death (apoptosis). All cells were able to express both interleukin-6 and endothelin-1 (ET-1) transcripts. Following exposure to bacterial endotoxin, interleukin-6 transcripts accumulated in all cells, whereas ET-1 expression was constant or slightly decreased. These data suggest that organ-specific heterogeneity of EC responsiveness to endotoxin is a potential determinant of organ-specific resistance to endotoxin and other mediators of injury.

Arterial blood gas derived variables as estimates of intrapulmonary shunt in critically ill children

Oxygen transport data, prospectively collected from 52 critically ill children, were analyzed to determine whether any derived variable accurately estimated intrapulmonary shunt (Qsp/Qt). Arterial hemoglobin saturation was more closely correlated with Qsp/Qt than was Pao2, alveolar-arterial oxygen gradient, arterial mixed venous oxygen difference (C[a-v]o2), arterial/alveolar oxygen ratio, and the ratio of Pao2 to inspired oxygen (FIO2) (r = 0.8, p < .0001). When C(a-v)o2 was normal, hemoglobin saturation became a very accurate (r = 0.96) assessment of Qsp/Qt.We conclude that various arterial blood gas derived variables do not accurately reflect Qsp/Qt in critically ill children. In these patients, a pulmonary artery catheter is needed to accurately assess intrapulmonary shunt.