Impaired sarcoplasmic calcium release inhibits myocardial contraction in experimental sepsis.

PURPOSE: In septic shock, myocardial dysfunction develops over the course of illness, but the mechanism of this depression is not clear. In this study, mechanisms of myocardial dysfunction were examined in a porcine model of Escherichia coli sepsis. MATERIALS AND METHODS: Animals were subjected to 4 hours of bacteria infusion (n = 5) (septic group) or saline infusion (n = 5) (nonseptic group), after which trabeculae were removed from the right ventricle and placed into a recirculating water bath. Measurements of steady-state contraction (SSC) were obtained at 0.5, 1, and 2 Hz. Indirect indices were used to assess abnormalities in myocardial calcium metabolism in sepsis. Extrasystoles (ES) were used to assess transsarcolemmal (TSL) calcium flux and were measured at 300 milliseconds, 400 milliseconds, and 500 milliseconds after the preceding stimulus. Postrest contraction (PRC) is an indicator of SR recirculation from the uptake to the release site and was obtained after interposing intervals of rest between steady-state beats at 0.5 Hz. Rapid-cooling contracture (RCC) is an indicator of sarcoplasmic reticulum (SR) content and was obtained at 0.5, 1, and 2 Hz and after interposing intervals of rest at 0.5 Hz. RESULTS: SSC was not different between groups at 0.5 Hz, but compared with the nonseptic group, SSC decreased at 1 and 2 Hz in the septic group (P < .05). PRC and TSL were not different between groups. During rest intervals, calcium leaks out of SR through the ryanodine channel (ie, SR calcium release channel). In the septic group, as assessed by RCC, SR calcium leak was less than that found in the nonseptic group. CONCLUSION: These results indicate that myocardial dysfunction in sepsis is frequency dependent, and that the mechanism is most likely caused by inhibition of SR calcium release owing to blockade of the ryanodine channel.

Impaired hepatic extraction and increased splanchnic production contribute to lactic acidosis in canine sepsis.

In septic shock, the extent to which lactic acidosis (LA) is a consequence of splanchnic lactate overproduction (SLP) or impaired hepatic lactate extraction (HLE) is not clear. We examined SLP and HLE in E. coli sepsis in dogs. We further determined the effects of vasopressor treatments, which included phenylephrine, dopamine, norepinephrine, and a combination of dobutamine and norepinephrine treatment, on SLP and HLE in respective groups. The animals were studied while anesthetized and ventilated. During sepsis, SLP increased as compared with presepsis (-0.017 versus 0.07 mmol/min, p < 0.05), but this increase could not be explained by reduced splanchnic oxygen delivery (SOD). During sepsis, HLE increased as compared with baseline (0.8 versus 8%, p < 0.05), but was significantly lower than that found during lactic acid loading in nonseptic dogs. None of the vasopressor treatments had a detrimental effect on SLP. These results indicate that LA in sepsis occurs secondary to an increase in splanchnic lactate production that is not related to reduced splanchnic oxygen delivery, as well as to a decrease in hepatic lactate extraction. Effects of different vasoactive agents did not alter either splanchnic lactate production or hepatic lactate extraction in this sepsis model.

Early but not delayed continuous arteriovenous hemofiltration improves cardiovascular function in sepsis in dogs.

OBJECTIVE: Continuous arteriovenous hemofiltration (CAVH) has been advocated as treatment to remove inflammatory mediators and thereby to improve hemodynamic parameters in sepsis. However, the results obtained with CAVH have been inconsistent. In a canine model of bacteremic Pseudomonas aeruginosa pneumonia, we tested the hypothesis that the time course of the institution of CAVH may be important in obtaining a beneficial treatment effect. METHODS: Two protocols were performed in phenobarbital-anesthetized dogs. In the early hemofiltration study (EHS), CAVH for 3 h was initiated 2 h post-pneumonia before mean arterial pressure (MAP) fell. In the late hemofiltration study (LHS), CAVH for 3 h was initiated at 5 h post-pneumonia when a decrease in MAP had already occurred. Hemodynamic measurements included cardiac output (CO), stroke volume (SV), and stroke work (SW). Myocardial depressant activity [filterable cardiodepressant substance (FCS)] found in plasma was assessed by bioassay at each measurement interval. RESULTS: In EHS, after 5 h of sepsis, SW, CO, and SV in the hemofiltered pneumonia group were higher as compared with the nonhemofiltered pneumonia group. In contrast, in LHS, no differences in hemodynamic parameters were found between the two pneumonia groups. In both EHS and LHS, plasma FCS activity was decreased to similar extents by CAVH. CONCLUSION: These results suggest the time course of institution of CAVH may be important in obtaining a beneficial treatment effect in sepsis.

Pulmonary pathophysiology of pneumococcal pneumonia.

Respiratory failure is one of the most important causes of death in patients with acute pneumococcal pneumonia. There are two forms that may or may not coexist: ventilatory failure and hypoxemic respiratory failure. Ventilatory failure is principally caused by mechanical changes in the lungs resulting from pneumonia. Inflammatory exudate fills alveoli at slightly less than their normal functional residual capacity (FRC), causing a volume loss at FRC roughly proportional to the extent of the pulmonary infiltrate. Because this consolidated air space does not inflate easily at higher transpulmonary pressures, at higher lung volumes the volume loss is proportionally greater. This loss of volume reduces total lung compliance and increases the work of breathing. There is also evidence that the dynamic compliance of the remaining ventilated lung is reduced in pneumococcal pneumonia, possibly by reduction in surfactant activity, further increasing the work of breathing. Arterial hypoxemia early in acute pneumococcal pneumonia is principally caused by persistence of pulmonary artery blood flow to consolidated lung resulting in an intrapulmonary shunt, but also, to a varying degree, it is caused by intrapulmonary oxygen consumption by the lung during the acute phase and by ventilation-perfusion mismatch later. The persistence of pulmonary blood flow to consolidated lung appears to be caused by a relative failure of the hypoxic pulmonary vasoconstriction (HPV) mechanism during acute pneumonia, which is at least caused by endogenous vasodilator prostaglandins associated with the inflammatory process but also by other as yet undefined mechanisms. During convalescence, arterial oxygenation improves as blood flow to consolidated lung falls. The magnitude of the intrapulmonary shunt may be influenced by a number of factors that modify the distribution of pulmonary blood flow. Factors that tend to increase flow to consolidated lung and worsen shunt include endogenous vasodilator mediators, exogenous systemically administered vasodilator drugs, positioning the patient with the affected lung dependent, and increasing positive airway pressure. Factors that tend to reduce shunt include effective HPV, inhaled locally acting vasodilators that act primarily on ventilated lung, and positioning the patient with the affected lung up. Although thoughtful application of what is known about the pathophysiology of the lung in pneumococcal pneumonia can help the clinician deploy most effectively the available technologies of respiratory support in these patients, even the best intensive supportive measures are frequently inadequate, and mortality rates for patients requiring such support remain unacceptably high.

Histamine H3 activation depresses cardiac function in experimental sepsis.

In the heart, histamine (H3) receptors may function as inhibitory presynaptic receptors that decrease adrenergic norepinephrine release in conditions of enhanced sympathetic neural activity. We hypothesized that H3-receptor blockade might improve cardiovascular function in sepsis. In a canine model of Escherichia coli sepsis, we found that H3-receptor blockade increased cardiac output (3.6 to 5.3 l/min, P < 0.05), systemic blood pressure (mean 76 to 96 mmHg, P < 0.05), and left ventricular contractility compared with pretreatment values. Plasma histamine concentrations increased modestly in the H3-blocker-sepsis group compared with values obtained in a nonsepsis-time-control group. In an in vitro preparation, histamine H3 activation could be identified under conditions of septic plasma. We conclude that activation of H3 receptors may contribute to cardiovascular collapse in sepsis.

Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group.

BACKGROUND: Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock. METHODS: In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days. FINDINGS: 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, p=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, p<0.001; day 28, p=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group. INTERPRETATION: We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.

Tumour necrosis factor-alpha, but not septic plasma depresses cardiac myofilament contraction.

PURPOSE: In sepsis, myocardial depression may be caused by mediators released as part of the inflammatory reaction, lumour necrosis factor alpha (TNF alpha) is one mediator that may contribute to this depression. In the present study, we contrasted the effects of TNF alpha and septic plasma fraction (SP) obtained from an E. coli model on contractile tension in intact and skinned canine ventricular trabecular (VT) preparations. The objectives were to determine whether SP or TNF alpha could impair contractile tension at the level of the myofilaments, and to determine the extent to which TNF alpha may account for myocardial depression found in E. coli sepsis. METHODS: Measurements of isometric tensions were made after TNF alpha and SP (10,000 to 30,000 MW fraction) were added to respective intact or skinned canine VT preparations. In the skinned preparation, trabeculae were chemically skinned with Triton X-100. RESULTS: Septic plasma caused a decrease in contraction in the intact preparation compared with preseptic plasma (50 +/- 7 vs 33 +/- 7%, P < 0.05), but had no effect in the skinned preparation. On the other hand, TNF alpha (30 ng.ml-1) caused an approximately 50% reduction in tension (29 +/- 2 mg vs 16 +/- 5 mg) in the skinned preparation (P < 0.05), but had no effect in the intact preparation. CONCLUSION: These results suggest that TNF alpha and SP act through different mechanisms. While SP requires an intact membrane, TNF alpha impairs function by a direct effect on the myofilaments.

Effect of sodium nitroprusside and diethylcarbamazine on hypoxic pulmonary vasoconstriction and regional distribution of pulmonary blood flow in experimental pneumonia.

The interaction between the effects of indomethacin and sodium nitroprusside or diethylcarbamazine infusion on the efficacy of hypoxic pulmonary vasoconstriction (HPV) and regional distribution of lung blood flow was studied in 15 pentobarbital-anesthetized dogs with acute pneumonia caused by Pseudomonas aeruginosa. After induction of pneumonia central hemodynamics, gas exchange, and regional distribution of lung blood flow (radionuclide-labeled microsphere method) were measured during ventilation of both lungs with oxygen and again with one lung ventilated with nitrogen. The dogs were then randomly assigned to one of three treatment groups: Group I (n = 5) received indomethacin alone (2 mg/kg); Group I-D received indomethacin and diethylcarbamazine (50 mg/kg over 20 min followed by 1 mg/kg/min for the rest of the experiment); Group I-N (n = 5) received indomethacin with sodium nitroprusside to achieve a 20- to 30-mm Hg reduction in mean blood pressure. All measurements were then repeated during both oxygen ventilation and one-lung nitrogen ventilation. In all three groups there was no effect of nitrogen inhalation on distribution of lung blood flow prior to drug treatment, indicating absence of HPV. After treatment, in Group I, perfusion of the pneumonic lung fell from 0.27 +/- 0.08 to 0.10 +/- 0.03 (p < 0.05) of total lung blood flow, and nitrogen ventilation of the left lung reduced perfusion to that region from 0.23 +/- 0.02 to 0.13 +/- 0.02 (p < 0.05), indicating restoration of HPV. In Groups I-D and I-N, HPV was persistently absent or markedly attenuated after treatment, but the percentage of the cardiac output perfusing the pneumonia region fell by an amount similar to that in Group I (0.26 +/- 0.07 to 0.11 +/- 0.04 in Group I-D and 0.35 +/- 0.03 to 0.21 +/- 0.06 in Group I-N, both p < 0.05). Because these two chemically unrelated pulmonary vasodilators effectively blocked HPV restoration but had no effect on vasoconstriction in the pneumonia region after indomethacin, it is concluded that regional lung blood flow redistribution in pneumonia is mediated by a mechanism other than HPV.

A randomized, double-blind comparison of methoxamine and epinephrine in human cardiopulmonary arrest.

The beneficial effect of epinephrine has been attributed to its alpha-adrenergic properties. The present study was designed to compare the effects of epinephrine and methoxamine in witnessed cardiac arrests. Consecutive, witnessed cardiac-arrest victims presenting to the emergency room or from the inpatient population of our institution were enrolled in this study. Patients were randomized to receive either epinephrine (2 mg bolus followed by 2 mg every 4 min) or methoxamine (40 mg bolus followed after 4 min by 40 mg) in a blind design. Patients were followed prospectively for survival and neurologic outcome. A total of 199 patients were randomized into the study, but 54 had to be retrospectively dropped from analysis for failure to comply with the study protocol. Of the 145 patients remaining, 77 received methoxamine (M) and 68 epinephrine (E). There was no difference in rate of successful resuscitation (42% versus 53%, M versus E, respectively), or in neurologic outcome as measured by the Glasgow-Pittsburgh Coma Score (GPCS). This study failed to demonstrate any difference in the rate of initial resuscitation, survival to discharge from the hospital, or neurologic status with methoxamine as opposed to epinephrine in the setting of cardiac arrest.

Effect of continuous arteriovenous hemofiltration combined with systemic vasopressor therapy on depressed left ventricular contractility and tissue oxygen delivery in canine Escherichia coli sepsis.

BACKGROUND: In a previous study, we showed that continuous arteriovenous hemofiltration (CAVH) reversed the depression in left ventricular (LV) contractility in canine Escherichia coli sepsis by the removal of a circulating substance the molecular weight of which is less than 30,000. Despite the normalization of LV contractility, however, we were unable to demonstrate an improvement in systemic arterial blood pressure (BP), presumably because the mechanisms underlying the depression in LV contractility and the decrease in BP are different in sepsis. In the current study, we examined the effect of combined treatment with CAVH and the alpha-adrenergic agonist phenylephrine on LV mechanics and tissue oxygen delivery in our canine E. coli model. METHODS: Measurements were obtained at baseline (condition B), after 4 h of sepsis (condition S), and after 2 h of CAVH and phenylephrine (condition P) (total of 6 h of sepsis). During P, phenylephrine was infused to restore BP to that found at baseline. The slope of the end-systolic pressure-dimension relation was used as the index of LV contractility; LV anterior-posterior dimensions were measured by sonomicrometry. RESULTS: During combined CAVH and phenylephrine treatment, the decrease in the slope of the end-systolic pressure-dimension relation otherwise observed at S was reversed. The slope (mean +/- SD) was 57.5 +/- 32 mmHg/mm at B versus 22.2 +/- 8 mmHg/mm at S (P < 0.05, B vs. S) versus 62 +/- 37 mmHg at P (P < 0.05 S vs. P) (analysis of variance). Mean BP was restored to that found at B (123 +/- 19 mmHg versus 82 +/- 14 mmHg (P < 0.05 B vs. S) versus 116 +/- 27 mmHg (P < 0.05 S vs. P). Combination treatment with CAVH and phenylephrine also improved stroke volume (39.3 +/- 13.5 versus 32 +/- 8 versus 44 +/- 12 ml) and tissue oxygen delivery during P compared with results obtained when phenylephrine was given alone. CONCLUSIONS: Our study offers a rationale for the combined use of phenylephrine and CAVH in the reversal of cardiac depression and hypotension in sepsis.

Compression of the left main bronchus between a descending thoracic aortic aneurysm and an enlarged right pulmonary artery.

A man with chronic obstructive lung disease presented to the hospital with respiratory failure and a chest x-ray indicated complete radiopacity of the left hemithorax. An endobronchial malignancy was suspected, but unexpectedly left-main bronchial occlusion was found secondary to compression between a descending thoracic aortic aneurysm and an enlarged right pulmonary artery.

Effects of E. coli sepsis and myocardial depressant factor on interval-force relations in dog ventricle.

We examined whether depressed left ventricular (LV) contractility during Escherichia coli sepsis in dogs was due to a decrease in the fractional release of calcium from the sarcoplasmic reticulum (SR) or a reduction in calcium content in this organelle. To indirectly assess SR calcium availability in a right ventricular (RV) trabecular muscle preparation, we utilized functional indexes of cellular myocardial calcium metabolism, which included rapid-cooling contracture (RCC), an indicator of SR calcium content, and postrest contraction (PRC), an index of calcium availability from the release compartment of the SR. Measurements were made during steady-state stimulation at 0.5 and 1.5 Hz, during which time rest intervals of 30-240 s were periodically imposed. SR calcium availability was measured in RV trabeculae of dogs subjected to 4 h of E. coli sepsis and was compared with calcium availability measured in nonseptic dogs. We further characterized a filterable cardiodepressant substance (FCS), which has been previously shown to be associated with LV depression in this model, to determine whether it produced changes in calcium metabolism similar to those found in sepsis. The results showed that calcium availability from the SR of septic dogs was not impaired. Furthermore, FCS was found in the 10,000- to 30,000-mol wt fraction of plasma and produced changes in PRC in canine trabeculae that were similar to those produced during sepsis. We conclude that, as assessed by PRC and RCC, SR calcium content and release are not impaired in sepsis.

Proportional assist ventilation. Results of an initial clinical trial.

The response to proportional assist ventilation (PAV) was tested in four normal subjects during heavy exercise and in five ventilator-dependent patients recovering from assorted medical disorders. The apparatus consisted of a rolling-seal piston coupled to a motor that generated pressure in proportion to inspired flow and inspired volume, with the gains adjusted such that the proportionality between airway pressure (Paw) and instantaneous patient-generated pressure (Pmus) was approximately 1:1 (i.e., machine-amplified patient effort by a factor of 2). Normal subjects responded to PAV by decreasing their own effort, as judged from esophageal pressure, such that the changes in ventilation and breathing pattern were rather small (VE: 64.8 +/- 3.6 during PAV versus 56.0 +/- 4.3, p less than 0.01; VT: 2.39 +/- 0.24 versus 2.02 +/- 0.17, p less than 0.05; f: 27.5 +/- 1.9 versus 28.0 +/- 2.2, NS). In patients, elastance ranged from 20 to 35 cm H2O cm/L, resistance ranged from 5 to 10 cm H2O/L/s, and maximal inspiratory pressure ranged from -16 to -65 cm H2O. After a period of observation during synchronized intermittent mechanical ventilation (SIMV) the patient was switched to PAV and maintained on it for 1 to 3 h. No patient had to be replaced on SIMV because of discomfort or deterioration in any of the monitored variables. During PAV peak airway pressure was less than half the value observed with the IMV breaths (16.6 +/- 2.4 versus 35.4 +/- 3.4 cm H2O, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of an increase in systemic arterial pressure in the newborn with right ventricular hypertension.

To evaluate the effect of an elevation in systemic arterial pressure upon pulmonary blood flow and arterial oxygenation during right ventricular hypertension (RVH), we acutely studied 13 1-d-old piglets. Catheters were positioned in the pulmonary artery, both atria, and the aorta for hemodynamic measurements. An electromagnetic probe was positioned in the main pulmonary artery for pulmonary blood flow measurement. Systemic and regional blood flow were measured with the radiolabeled microsphere technique. A balloon-mounted catheter was advanced in the aorta and maintained at the lower thoracic level. After induction of RVH (pulmonary artery banding), a significant decrease in arterial O2 pressure from 54.4 +/- 1.6 to 10.6 +/- 0.4 kPa (p less than 0.01), a 30% reduction in systemic arterial pressure, and a 44% decrease in pulmonary blood flow were observed. During RVH, partial inflation of the aortic balloon to restore the systemic arterial pressure to its initial value led to an increase in arterial O2 pressure to 23.5 +/- 3.1 kPa (p less than 0.01). Full inflation of the balloon further increased the arterial O2 pressure to 32.6 +/- 2.9 kPa (p less than 0.01). Aortic balloon inflation increased pulmonary blood flow in 11 and systemic O2 delivery in nine of the 13 animals. RVH was associated with a significant increase in cerebral and right ventricular myocardial free-wall blood flow and a decrease in renal and bowel blood flow and O2 delivery (p less than 0.01). Aortic balloon inflation during RVH did not change either the cerebral or myocardial free-wall blood flow, but further significantly decreased renal and bowel blood flow and O2 delivery.(ABSTRACT TRUNCATED AT 250 WORDS)

Intensive care management of pneumonia in the elderly.

Arterial hypoxemia, hypercapnic respiratory failure, hypotension, and depressed level of consciousness are the usual reasons for admitting a patient with pneumonia to an intensive care unit (ICU). Once the decision has been made to manage the patient in the ICU, age has little effect on the immediate goals of therapy, which include correction of hypoxemia, maintenance of adequate alveolar ventilation, and provision of sufficient blood pressure and cardiac output to support organ function until physiological homeostasis is restored as the pneumonia is controlled by appropriate antimicrobial therapy. Age-related decreases in physiological reserve are the major reasons specifically to consider ICU management of elderly pneumonia patients. These physiological changes increase the probability of major organ system failure with the development of pneumonia, and increase the likelihood that pneumonia will require ICU management. This has implications for the clinician regarding the selection and timing of therapeutic interventions. Unfortunately, the reduction of physiological reserve and the increased prevalence of coexistent chronic disease also result in significant mortality rates for elderly patients with pneumonia, potentially limiting the benefits of intensive care in this population. This raises a second issue: When, if ever, should intensive care not be used in the management of an elderly patient with severe pneumonia? A full discussion of the ethical issues surrounding this question is beyond the scope of this article, however, good medical ethics begin with sound medical judgment and are based upon solid clinical data. Accordingly, this article will also address the implications of age and underlying disease in the assessment of prognosis and use of the ICU in patients with pneumonia.

The effects of methoxamine and epinephrine on survival and regional distribution of cardiac output in dogs with prolonged ventricular fibrillation.

This study compares the effects of methoxamine, a pure alpha 1-agonist, and epinephrine on cerebral and myocardial blood flow, central hemodynamics, and survival in a randomized placebo-controlled fashion during prolonged ventricular fibrillation (VF) in a canine model. Twenty-four anesthetized and ventilated adult mongrel dogs were instrumented for regional blood flow determinations using radio-labeled microspheres. The dogs were randomized to receive either 20 mg of methoxamine as a single intravenous bolus or repeated boluses of 0.02 mg/kg of epinephrine, 0.2 mg/kg of epinephrine, or normal saline solution placebo beginning at three minutes following induction of VF and initiation of closed chest cardiac massage (CCCM). Organ blood flow measurements were determined during normal sinus rhythm and after five and 20 minutes of VF. All six dogs receiving methoxamine were successfully resuscitated in contrast to only one in each of the epinephrine-treated groups and none of the dogs receiving placebo (p less than .01). Although epinephrine was associated with significantly higher blood pressures than placebo during cardiopulmonary resuscitation (CPR), blood pressures achieved with methoxamine were significantly higher than those observed in the other three treatment groups (p less than .001). Cerebral blood flow was significantly higher with both methoxamine and high-dose epinephrine (p less than .05). Mean left and right ventricular myocardial flows were highest with methoxamine but this did not achieve statistical significance. In contrast, organ flows measured in the animals receiving the lowest dose of epinephrine were not significantly higher than those associated with placebo. Cardiac output after 20 minutes of CPR was significantly lower with high-dose epinephrine than with methoxamine or placebo (p less than .05). Our results suggest that methoxamine significantly improves regional cerebral blood flow and survival during CPR and although high-dose epinephrine is associated with comparable improvements in regional cerebral blood flow, this treatment is associated with deterioration in central hemodynamics during prolonged VF and does not enhance survival.