Larry Casey

Sympathetic nervous system "switch off" with severe hypothermia.

Hypothermia occurs frequently in the critically ill patient, yet little is known about the endogenous cate-cholamine response to this stress. To study this problem, we measured heart rate (HR), mean arterial blood pressure (MAP), and plasma levels of norepinephrine (NE) and epinephrine (Epi) in subhuman primates (baboons) during progressive hypothermia from 37° to 29°C and then during rewarming to 37°C. As the core temperature decreased from 37° to 33°C, HR and MAP increased significantly (p < 0.05), but as core temperature further decreased from 33° to 29°C, the HR and MAP fell to prehypothermic levels. Plasma concentrations of NE and Epi increased significantly (p < 0.01) as core temperature fell from 37° to 31°C, but as core temperature dropped from 31° to 29°C, plasma NE and Epi levels decreased towards prehypothermic concentrations. These findings indicate that the sympathetic nervous system (SNS) responds quickly to hypothermia but may be “switched off” at a threshold temperature of about 29°C. We speculate that hypotensive patients with temperatures ° 29°C may benefit from infusions of exogenous catecholamines, especially if there have been only minimal benefits achieved with conventional therapy such as fluids, and an increase in ambient temperature.

IMMUNOLOGIC RESPONSE TO INFECTION AND ITS ROLE IN SEPTIC SHOCK

In summary, the invasion of bacteria across mucosal surfaces is met with a vigorous host response that includes complement, antibody formation (thymus-independent and eventually thymus-dependent), phagocytosis, production of antibacterial peptides and proteins, the production of cytokines that result in activation of phagocytes and endothelial cells to attract more phagocytes, and the formation of fibrin to limit the spread of infection. The best summary of immune response to infection was written by Lewis Thomas in 1974.

Decreased serum angiotensin converting enzyme in adult respiratory distress syndrome associated with sepsis: A preliminary report

Serum angiotensin converting enzyme (ACE) levels were obtained in 24 control patients who were critically ill, in 11 patients with cardiogenic pulmonary edema, in 8 patients with status postcardiopulmonary bypass, and in 12 patients with adult respiratory distress syndrome (ARDS). Mean values in cardiogenic pulmonary edema (24.3 ± 3.9 SD) in cardiopulmonary bypass (19.5 ± 3.1) and in patients with ARDS and no sepsis (n = 7, 19.0 ± 5.5) were not significantly different from controls (20.7 ± 2.8). In contrast, patients with ARDS and sepsis had markedly decreased serum ACE levels which fell outside of control range (n = 5, 8.6 ± 2.3). The authors speculate that decreased ACE levels in the combination of sepsis and ARDS are due to the presence of circulating inhibitors of ACE. The finding of decreased serum ACE can be of potential clinical usefulness by raising the possibility of sepsis as the etiology of ARDS before results of blood cultures are available.

Impaired tumoricidal function of alveolar macrophages from patients with non‐small cell lung cancer

The capacity of alveolar macrophages and peripheral blood monocytes from patients with non‐small cell lung cancer to develop tumoricidal function after in vitro stimulation with different macrophage activators was investigated. Alveolar macrophages were found to be impaired in their ability to develop cytotoxic activity compared with either the peripheral blood monocytes from the same patients or alveolar macrophages from patients with nonmalignant lung disorders. This result was observed consistently under diverse culture conditions and with different macrophage activators including gamma‐interferon (γ‐IFN), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), phorbol myristate acetate, or endotoxin. The impairment in tumoricidal function observed in alveolar macrophages was not associated with reduced target cell binding compared to peripheral blood monocytes. Alveolar macrophages from patients with lung cancer were found to secrete significantly greater amounts of tumor necrosis factor (TNF) and interleukin‐1 (IL‐1) than either peripheral blood monocytes from the same patients or alveolar macrophages from the patients with nonmalignant disorders. These results are consistent with either different regulatory pathways for cytotoxicity and cytokine secretion in the alveolar macrophages of patients with lung cancer or diversity in the subpopulations of cells responsible for these functions.

Medical effectiveness of esophageal balloon pressure manometry in weaning patients from mechanical ventilation.

OBJECTIVE To determine the efficacy of a new respiratory monitor, which uses esophageal balloons, in aiding clinicians attempting to wean patients from mechanical ventilation. DESIGN Prospective study of patients who were deemed ready to be weaned after having required mechanical ventilation for a minimum of 3 days. Each of the patients served as his or her own control. SETTING University medical intensive care unit. PATIENTS The series consisted of 23 consecutive patients who were ready to wean from mechanical ventilation. INTERVENTIONS Before the onset of the study, two weaning strategies were developed. One strategy involved using clinically available weaning parameters. The other strategy involved using esophageal balloon data that was recorded via a new respiratory monitor. Each of the weaning strategies resulted in the development of a scoring system that could be rigidly adhered to and which determined, without bias, to what extent the patient could be weaned each day. Rigid criteria were also developed to determine whether the weaning trial was successful or not. The two strategies were then compared to determine the ability of the strategy to shorten ventilatory time. MEASUREMENTS AND MAIN RESULTS Each patient was evaluated daily by the two weaning protocols. At each weaning step, the two protocols were compared with respect to degree of aggressiveness and tolerance of the weaning maneuver by the patient. A protocol was judged superior if it resulted in more aggressive weaning without increased patient intolerance. The clinicians evaluating the patient with the clinical protocol could accelerate or retard the number of weaning steps by one step, based on the patients clinical state and the clinicians experience. There was no such freedom in the esophageal protocol. The major finding was that in 40.5% of the instances, the protocol involving the esophageal balloon resulted in more aggressive weaning without patient intolerance. In 11.6% of the cases, the clinical protocol was more aggressive. Both protocols predicted the same number of weaning steps 39.8% of the time. In all these instances, the patient tolerated the weaning suggested. The use of data from the esophageal protocol resulted in weaning the patients 1.68 days faster than the use of data from the clinical protocol. CONCLUSIONS The respiratory monitor, using esophageal balloon technology, is effective in that it can provide the clinician with data that can result in more aggressive weaning from mechanical ventilation without an increase in patient intolerance. The duration of mechanical ventilation can be shortened when these data are applied via a rigidly controlled weaning strategy.

Reduced alveolar macrophage production of tumor necrosis factor during sepsis in mice and men

Background and MethodsTumor necrosis factor (TNF) has been implicated as a major humoral mediator of sepsis and endotoxin shock. TNF is secreted by cells of the reticuloendothelial system, including alveolar macrophages. Alveolar macrophage TNF production has been postulated to play a pathogenetic role in the development of adult respiratory distress syndrome (ARDS) in sepsis. To evaluate alveolar macrophage production of TNF during sepsis and endotoxin shock, we studied the effects of sepsis and/or in vivo lipopolysac-charide on the in vitro production of TNF by pulmonary alveolar macrophages. Human pulmonary alveolar macrophages were obtained by bronchoalveolar lavage from six septic and five nonseptic patients, cultured in the presence or absence of lipopolysaccharide (1 ng/mL), and assayed for TNF activity in a bioassay using fibroblast lysis. A murine model of sepsis was also utilized to study pulmonary alveolar macrophage TNF production under more controlled conditions. Normal mice were given ip injections of either lipopolysaccharide or saline. After 2 hrs, pulmonary alveolar macrophages were obtained and cultured in saline or various concentrations of lipopolysaccharide (0.001 to 10 μg/mL). ResultsThere was no difference in baseline TNF activity, expressed as per cent lysis at 1:10 dilution, between pulmonary alveolar macrophages from control and septic patients (35.7 ± 5.5% vs. 24.4 ± 9.3%, respectively) (p > .05). However, when stimulated with lipopolysaccharide in vitro, the pulmonary alveolar macrophages from nonseptic patients produced significantly (p < .01) more TNF (82.8 ± 3.6%) than did pulmonary alveolar macrophages from patients with the septic syndrome (35.2 ± 3.8%). Similar findings were obtained using the murine sepsis model. The baseline TNF activity in pulmonary alveolar macrophages from control mice was 22.9 ± 7.0% (mean ± SEM) and from lipopolysaccharide-injected mice was 26.8 ± 3.3% (p > .05). Stimulation with 1 ng/mL lipopolysaccharide in vitro produced an increase in TNF activity in both groups, but the increase was greater in the control mice (68.1 ± 5.7%) than in the lipopolysaccharide-injected mice (47.5 ± 5.3%) (p < .01). When the murine pulmonary alveolar macrophages were stimulated with higher concentrations of lipopolysaccharide (0.1 to 10 ug/mL), pulmonary alveolar macrophages from lipopolysaccharide-injected mice produced <25.5% of the TNF produced by pulmonary alveolar macrophages from control mice. ConclusionsThese studies indicate that sepsis and endotoxin injection result in a rapid decrease in the ability of pulmonary alveolar macrophages from both humans and mice to produce and secrete TNF in response to lipopolysaccharide. We speculate that a downregulation of TNF production or of macrophage responsiveness to lipopolysaccharide has occurred. These results suggest that sustained TNF production by macrophages is not required for lung injury in sepsis.

Hemorrhagic hypotension increases plasma beta-endorphin concentrations in the nonhuman primate

The role which beta-endorphin plays in the pathogenesis of hemorrhagic hypotension is controversial. In the present experiment, 20 ml/kg of blood was bled from ten healthy male baboons (Papio anubis) over 60 min and then retransfused over the next 30 min. We found that the mean plasma beta-endorphin level increased 109% above baseline (p < .05) within 15 min after starting hemorrhage, and rapidly returned to a baseline concentration with retransfusion. We conclude that in a primate species, circulating endogenous opioid peptide concentrations increase rapidly in response to sublethal hemorrhagic hypotension and normalize with restoration of the baseline intravascular volume. These findings support the concept that endogenous opioid peptides may mediate the hypotension of shock states.

The in vitro development of cytotoxicity in response to granulocyte/macrophage-colony-stimulating factor or interferon γ in the peripheral blood monocytes of patients with solid tumors: Modulation by arachidonic acid metabolic inhibitors

SummaryThe capacity of granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interferon γ (IFN γ) to elicit monocyte cytotoxicity in vitro in the peripheral blood monocytes of patients with solid tumors was investigated. The cytotoxicity elicited by IFN γ was significantly reduced in cancer patient monocytes compared to normal monocytes. The cytotoxicity elicited by GM-CSF, however, was comparable between cancer patient monocytes and normal monocytes, but was lower than that induced by IFN γ. Indomethacin, a cyclooxygenase inhibitor, significantly augmented IFN γ-elicited cytotoxicity in cancer patient monocytes, but not in normal monocytes. In contrast, indomethacin augmented GM-CSF-elicited cytotoxicity in both cancer patient monocytes and normal monocytes. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, was found to suppress cytotoxicity in response to IFN γ and GM-CSF in both cancer patient monocytes and normal monocytes. The addition of leukotrienes to NDGA-treated cultures restored the development of cytotoxicity. Thus there are differences in the in vitro response of cancer patient monocytes and normal monocytes to distinct biological activators. Furthermore, these responses can be manipulated by agents that modulate arachidonic acid metabolism.

Modulation of tumoricidal function in alveolar macrophages from lung cancer patients by interleukin-6

Previous studies have demonstrated that alveolar macrophages from lung cancer patients are impaired in their ability to develop tumoricidal function when stimulated by activators such as interferon γ + lipopolysaccharide. However, these same macrophages have been shown to develop significant tumoricidal function when precultured with macrophage-depleted allogeneic peripheral blood lymphocytes from normal donors, an effect that was lost by the elimination of natural killer cells from the allogeneic lymphocyte population. In the present study, the effect of each activation condition on the expression of mRNA for interleukin-1α (IL-1α), IL-1β, tumor necrosis factor α (TNFα) and IL-6 was determined using reverse transcription/polymerase chain reaction. The results show that the non-permissive activation condition is associated with the expression of mRNA for IL-6 while the permissive activation condition is not. Antibodies against IL-6 were subsequently shown to permit the development of tumoricidal function in alveolar macrophages stimulated with interferon γ + lipopolysaccharide while IL-6 protein was shown to inhibit the stimulatory action of allogeneic lymphocytes on the development of tumoricidal function in the same alveolar macrophages. Neither the permissive (i.e. allogeneic lymphocyte stimulation) nor the non-permissive (i.e. interferon γ + lipopolysaccharide) activation condition had any effect on the capacity of alveolar macrophages from lung cancer patients to express mRNA for IL-1α, IL-1β or TNFα These results show that IL-6 can regulate the ability of alveolar macrophages from lung cancer patients to be stimulated by interferon γ + lipopolysaccharide to develop significant tumoricidal function. They also show that allogeneic lymphocytes have the capacity to downregulate IL-6 mRNA synthesis by alveolar macrophages thereby permitting the development and/or expression of macrophage tumoricidal function.

Augmentation of impaired tumoricidal function in alveolar macrophages from lung cancer patients by cocultivation with allogeneic, but not autologous lymphocytes

It has been reported that the in vitro development of tumoricidal function in alveolar macrophages from lung cancer patients is reduced significantly when compared to that in peripheral blood monocytes from the same patients or alveolar macrophages from control patients. In the present investigation, a method for potentiating the development of tumoricidal function in alveolar macrophages from lung cancer patients is described. This method, which relies on priming the macrophages with purified, allogeneic peripheral blood lymphocytes from normal donors, could not be demonstrated when autologous lymphocytes from lung cancer patients were used in the priming coculture. The augmentation of tumoricidal function appears to be mediated by one or more soluble factors, since supernatants from cocultures of alveolar macrophages and allogeneic peripheral blood lymphocytes could enhance the cytotoxic function of freshly obtained alveolar macrophages. Furthermore, it appears that NK cells are necessary for this effect, since depletion of CD56+/CD57+ cells from allogeneic lymphocytes eliminated their capacity to enhance alveolar macrophage cytotoxic function. The augmentation of cytotoxic function elicited in alveolar macrophages by this method was not associated with changes in the secretion of tumor necrosis factor α, or interleukin 1β.