CPR in terminally ill patients?

While limiting and foregoing therapy at the end of life is now accepted on medical, ethical, moral and legal grounds, many Americans continue to die with heroic measures being taken to prevent their death. When the patient does eventually die, attempts are frequently made to revive the patient by performing cardiopulmonary resuscitation (CPR). While CPR may result in the establishment of a perfusing pressure, in almost all instances, the patient succumbs despite advanced life support technology. The widespread adoption of do-not-resuscitate (DNR) protocols has not prevented CPR from being performed on patients, who are unlikely to survive. We present two cases, which highlight the modern American way of dying. We submit that poor end-of-life care may result from physicians discomfort with death, their poor communication skills and their failure to fully comprehend the benefits and limitations of advanced life support technology. Furthermore, we maintain that CPR should only be performed on patients, who are likely to derive benefit from this intervention.

Lipid modulation and systemic inflammation.

N-6 and n-3 PUFAs from the diet are absorbed and reach the cell where they interact with fatty acid binding proteins within cell membranes and cytoplasm. They are processed in the endoplasmic reticulum (desaturation-elongation reactions, lipid synthesis, eicosanoid and epoxide production) and in peroxisomes (beta-oxidation, synthesis, oxidation products). They interact with receptors, ion channels, and nuclear elements; the result is modulation of gene expression. PUFA-induced alterations result in modulation of local and systemic inflammation and inflammatory disease activity.

Hypothalamic-pituitary-adrenal insufficiency.

Adrenal insufficiency is a common and underdiagnosed disorder that develops in critically ill patients. Most forms are acquired and will resolve with treatment of the underlying disease. Hypotension that is refractory to fluids and requires vasopressors is the most common presentation of adrenal insufficiency in the ICU. It is important to make the diagnosis of adrenal insufficiency, because current data suggest that treatment with glucocorticoids improves outcome. Diagnosis usually can be made on the basis of a stress cortisol level. Occasionally, when the level of stress is uncertain, the low-dose corticotropin stimulation test will be required for definitive diagnosis. A therapeutic trial with hydrocortisone should be started in patients with suspected adrenal insufficiency pending results of diagnostic testing.

The effect of aging on circulating levels of proinflammatory cytokines during septic shock. Norasept II Study Investigators.

BACKGROUND: As the proportion of the population that is older continues to rise, infection in older people has become an important healthcare problem. Although aging is associated with multiple abnormalities in immune function, the effect of aging on the production of proinflammatory cytokines has not been well studied under conditions of clinical stress. OBJECTIVES: The aim of this study was to examine the effect of aging on circulating levels of the proinflammatory cytokines in a large cohort of septic shock patients. We hypothesized that aging would be associated with a diminished proinflammatory cytokine response to sepsis. DESIGN: Patients with septic shock who were enrolled in the placebo limb of the North American Sepsis Trial (NORASEPT II) study were analyzed. SETTING: The intensive care units of 105 hospitals in the United States and Canada. PARTICIPANTS: Nine hundred and thirty patients presenting to hospital within 12 hours of the onset of septic shock. MEASUREMENTS: Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble tumor necrosis factor-receptor-55 (sTNF-R55), and soluble tumor necrosis factor-receptor-75 (sTNF-R75) concentrations were measured at enrollment. The study population was broken down into five age groups as follows: less than 50 years (group one), 50 to 64 years (group two), 65 to 74 years (group three), 75 to 84 years (group four), and 85 or older (group five). Clinical, demographic, and cytokine data were extracted to describe each age group. RESULTS: Data were available for 930 patients. The patients' mean age (+/- SD) was 59 +/- 17 years (range, 18 to 102). There were 280 patients in group one, 242 in group two, 210 in group three, 150 in group four, and 48 in group five. The primary diagnoses; clinical characteristics; and IL-6, sTNF-R55, and sTNF-R75 levels were similar among the five age groups. The TNF-alpha levels were significantly higher, however, in the oldest group of patients (group five). The 28-day survival was 49% in patients over the age of 75 and 58% in those under 75 years (P = .03). There was no gender difference in survival or cytokine levels. CONCLUSIONS: Contrary to our expectations, we found that aging was not associated with a decline in the circulating levels of proinflammatory cytokines.

Early enteral nutrition in acutely ill patients: a systematic review.

OBJECTIVE: To evaluate the effect of early enteral nutrition on the outcome of critically ill and injured patients. DATA SOURCES: MEDLINE, citation review of relevant primary and review articles, personal files, and contact with expert informants. STUDY SELECTION: Randomized, controlled studies that compared early with delayed enteral nutrition in hospitalized adult postoperative, trauma, head-injured, burn, or medical intensive care unit (ICU) patients. From 161 articles screened, 27 were identified as randomized, controlled trials comparing early with delayed enteral nutrition and were included for data extraction. Of these, 12 were excluded. None of the studies included medical ICU patients. DATA EXTRACTION: Fifteen studies containing 753 subjects were analyzed. Descriptive and outcome data were extracted independently from the articles by the two reviewers. Main outcome measures were infections, noninfectious complications, length of hospital stay, and mortality. The meta-analysis was performed using the random effects model. DATA SYNTHESIS: Early enteral nutrition was associated with a significantly lower incidence of infections (relative risk reduction, 0.45; 95% confidence interval, 0.30-0.66; p =.00006; test for heterogeneity, p =.049) and a reduced length of hospital stay (mean reduction of 2.2 days; 95% confidence interval, 0.81-3.63 days; p =.004; test for heterogeneity, p =.0012). There were no significant differences in mortality or noninfectious complications between the two groups of patients. CONCLUSIONS: The results of this meta-analysis support the experimental data demonstrating the benefit of the early initiation of enteral nutrition. The results of this meta-analysis must, however, be interpreted with some caution because of the significant heterogeneity between studies.

Inhibition of nitric oxide synthase enhances the myocardial toxicity of phenylpropanolamine.

OBJECTIVE: To investigate the direct and indirect effects of the anorexic agent phenylpropanolamine (PPA) on the heart and to determine whether nitric oxide deficiency exacerbates the myocardial toxicity of PPA. DESIGN: Dose response effects using sequential drug administration. SETTING: Animal research laboratory of a large tertiary academic medical center. SUBJECTS: Isolated hearts (n = 8) from male Sprague-Dawley rats weighing 300-400 g. INTERVENTIONS: Measurement of heart rate, maximal change in pressure over time (dP/dtmax), -dP/dtmax, and coronary blood flow in isolated hearts perfused on a Langendorff apparatus. PPA was infused through the aortic cannula at 0.05, 0.125, 0.25, 0.5, and 1.25 mmol/L before and after inhibition of nitric oxide synthesis with N-nitro-L-arginine methyl ester (L-NAME). RESULTS: PPA had little effect on myocardial contractility of normal hearts until the highest dose of PPA (1.25 mmol/L). However, after L-NAME, PPA significantly depressed contractility at a dose of 0.25 mmol/L. PPA had no significant effects on coronary blood flow. PPA failed to induce arrhythmias in normal hearts. However, after L-NAME, PPA induced ventricular fibrillation in 50% of the hearts. CONCLUSION: PPA causes myocardial contractile depression without altering global coronary artery blood flow. Inhibition of nitric oxide synthesis sensitizes the heart to the myocardial depressant effects of PPA and increases the risk for ventricular fibrillation.

Cardiovascular effects of carnosine.

Carnosine (beta-alanyl-L-histidine) is an endogenous dipeptide found in various cells at millimolar concentration with its specific function(s) largely unknown. Our interests in therapeutic peptides led to the discovery that carnosine dramatically increases contractility when perfused into isolated rat hearts. Carnosine's effects are not mediated by histaminic or beta-adrenergic receptors or by increasing cyclic AMP, but carnosine does cause a rise in myoplasmic Ca(2+) concentration. In chemically skinned cardiac cells, carnosine releases calcium, produces contracture, and alters the contractile protein's tension response to calcium. Carnosine also acts directly on the ryanodine receptor calcium release channel producing large increases in open state probability and dwelltime. In this manuscript, we will review studies which provide a basis for considering carnosine a modulator of calcium-regulated proteins in cardiac muscle cells and consequently an important determinant of contractility and cardiac function.

Hypothermia and cytokines in septic shock. Norasept II Study Investigators. North American study of the safety and efficacy of murine monoclonal antibody to tumor necrosis factor for the treatment of septic shock.

BACKGROUND: Hypothermic patients with sepsis have been reported to have a higher mortality than febrile septic patients. The failure to mount a febrile response in sepsis is poorly understood. Since the proinflammatory cytokines play a crucial role in the genesis of fever, we postulated that hypothermic patients with sepsis would have lower circulating levels of these cytokines than febrile patients. METHODS: Patients with septic shock who were enrolled into the placebo limb of the North American study of the safety and efficacy of murine monoclonal antibody to tumor necrosis factor for the treatment of septic shock (NORASEPT II) were analyzed. Body temperature, interleukin-6, tumor necrosis factor alpha, soluble tumor necrosis factor receptor-55, and soluble tumor necrosis factor receptor-75 concentrations were measured at enrollment. The study population was divided into a hypothermic (temperature < 35.6 degrees C) and a febrile group (temperature > or = 38.3 degrees C) according to the core temperature at enrollment (normothermia was an exclusion criteria). Clinical, demographic, and cytokine data were extracted, allowing for comparisons between these two groups of patients. In addition, the correlation between the core body temperature and cytokine levels at enrollment was determined. RESULTS: A complete data set was available for 930 patients; 195 patients (21%) were hypothermic at enrollment. The 28-day survival of these patients was significantly lower than that of the febrile patients (34% vs. 59%, p < 0.001). Hypothermia (and enrollment temperature) were independent predictors of mortality. The hypothermic patients had a higher incidence of organ dysfunction at enrollment than the febrile patients. There was no significant difference in the cytokine profile between the two groups of patients. In addition, there was no correlation between the core body temperature at enrollment and the circulating levels of cytokines measured. CONCLUSION: Hypothermic patients with septic shock have a significantly higher mortality with a higher incidence of organ dysfunction than febrile septic shock patients. The hypothermia in these patients cannot be explained by lower levels of circulating proinflammatory cytokines.

Vasodilatory actions of the dietary peptide carnosine.

The objective of this study was to test the hypothesis that the dietary dipeptide carnosine (beta-alanine-L-histidine) causes direct decreases in arterial tone. Isolated descending thoracic aortic rings from male Sprague-Dawley rats were used for all studies. Preconstriction of vessels was accomplished with phenylephrine. Carnosine (0.625-20 mM) produced dose-dependent vascular relaxation (P < 0.05) that was independent of endothelium. The constituent amino acid L-histidine did not produce any significant relaxation over the same dose range, whereas beta-alanine actually produced dose-dependent vasoconstriction (P < 0.05). The soluble guanylate cyclase inhibitor methylene blue (10(-5) M) significantly decreased the relaxation produced by carnosine (P < 0.05). Measurement of cyclic GMP in the presence and absence of methylene blue after carnosine and phenylephrine exposure was also done. Methylene blue 10(-5) M resulted in a decrease in cyclic GMP levels from 65.3 +/- 15.6 fmol/mg protein to 8.6 +/- 0.9 fmol/mg of protein (P = 0.001). We conclude that carnosine produces relaxation of isolated rat aorta independent of endothelium. The effect of carnosine is at least in part mediated via cyclic GMP production and is not reproduced by its constituent amino acids, L-histidine and beta-alanine.

Propofol-containing sedatives increase levels of parathyroid hormone.

OBJECTIVE: To evaluate the effects of propofol and propofol containing disodium edetate (ethylenediaminetetraacetic acid [EDTA]) on the parathyroid-calcium axis in normal subjects. DESIGN: Randomised, double-blind, age-stratified, crossover trial. SETTING: Single centre. PATIENTS: A total of 50 healthy subjects. INTERVENTIONS: Each subject was randomised to receive propofol or propofol containing EDTA on day 1 and the alternate treatment between days 15 and 29, with a 2-week wash-out period in between. On the day of treatment, subjects received a bolus of trial medication (1 or 2 mg/kg) followed by a 60-minute observation period. At the end of 60 minutes, subjects received trial medication infused for 60 minutes at 1 of 4 randomised infusion rates (25, 50, 100, or 200 microg/kg per min). Subjects were monitored for an additional 60 minutes following the infusion. MEASUREMENTS AND RESULTS: Blood pressure, heart rate, respiratory rate, oxygen saturation, blood ionised calcium concentration, serum total magnesium concentration, serum intact parathyroid hormone (PTH) level, and plasma EDTA level were assessed at periodic intervals during and following the bolus and continuous infusion of trial medication. Mean arterial pressure significantly decreased (p < 0.05) following the bolus injection of both trial medications and returned to baseline at 60 minutes; it significantly decreased again during the continuous infusion and returned to baseline during recovery. Heart rate and respiratory rate fluctuated in both groups with significant increases and decreases throughout the study period following the bolus injection; both returned to baseline during the recovery period in each group. Ionised calcium and total magnesium concentrations remained within normal limits and were unchanged in response to both study medications. PTH levels significantly increased following the bolus injection of both study drugs. The increase in PTH levels was greater with higher doses of study medication during the infusion period. There was no difference in the response of blood pressure, heart rate, respiratory rate, or PTH levels between propofol and propofol with EDTA. EDTA levels increased significantly during the infusion of propofol with EDTA, reaching mean levels of 240 ng/mL. CONCLUSIONS: The results of this study indicate that propofol increases PTH levels in normal subjects; however, propofol with EDTA does not alter ionised calcium or total magnesium concentrations.

Trace element homeostasis during continuous sedation with propofol containing EDTA versus other sedatives in critically ill patients.

OBJECTIVE: To evaluate changes in serum and urinary zinc, cobalt, copper, iron, and calcium concentrations in critically ill patients receiving propofol containing disodium edetate (disodium ethylenediaminetetraacetic acid [EDTA]) versus sedative agents without EDTA. DESIGN: This was a randomised, open-label, parallel-group study with randomisation stratified by baseline Acute Physiology and Chronic Health Evaluation (APACHE II) scores. SETTING: Intensive care units (ICU) in 23 medical centres. PATIENTS: Medical, surgical, or trauma ICU patients 17 years of age or older who required mechanical ventilator support and sedation. INTERVENTIONS: A total of 106 patients received propofol containing 0.005 % EDTA (propofol EDTA), and 104 received other sedative agents without EDTA (non-EDTA). Only the first 108 patients were assessed for urinary trace metal excretion. Twenty-four-hour urine samples were collected on days 2, 3, and 7 and every 7 days thereafter for determination of zinc, cobalt, copper, iron, and calcium excretion; EDTA levels; urine osmolality; albumin levels; and glucose levels. The first 143 patients were assessed for serum concentration of zinc, cobalt, copper, iron, and calcium; creatinine; blood urea nitrogen; and albumin at baseline and once during each 24-hour urine collection. MEASUREMENTS AND RESULTS: For the assessment of trace metals, patients receiving propofol EDTA demonstrated increased mean urinary excretion of zinc, copper, and iron compared with the normal range. All patients receiving sedatives demonstrated increased urinary excretion of zinc and copper above normal reference values. Compared with the non-EDTA sedative group, the propofol EDTA group demonstrated increased urinary excretion of zinc and iron. Mean serum concentrations of zinc and total calcium were decreased in both patient groups. Serum zinc concentrations increased from baseline to day 3 in the non-EDTA sedative group but not in the propofol EDTA group. Renal function, measured by blood urea nitrogen, serum creatinine, and creatinine clearance, did not deteriorate during ICU sedation with either regimen. CONCLUSION: This study showed that critical illness is associated with increased urinary losses of zinc, copper, and iron. Propofol EDTA-treated patients had greater urinary losses of zinc and iron and lower serum zinc concentrations compared with the non-EDTA sedative group. No adverse events indicative of trace metal deficiency were observed in either group. The clinical significance of trace metal losses during critical illness is unclear and requires further study.

Cation metabolism during propofol sedation with and without EDTA in patients with impaired renal function.

OBJECTIVE: To compare the effects of propofol with and without disodium edetate (EDTA) on cation metabolism in intensive care unit (ICU) patients with renal insufficiency who received propofol or propofol plus EDTA (propofol EDTA) for sedation and mechanical ventilation. DESIGN: Double-blind, randomised, multicentre study. SETTING: Medical and surgical ICUs from 5 hospitals. PATIENTS: Thirty-nine ICU patients with acute and chronic renal impairment expected to require at least 24 hours of continuous sedation and respiratory failure necessitating mechanical ventilation. INTERVENTIONS: Propofol or propofol EDTA administered for sedation by continuous intravenous infusion. MEASUREMENTS AND RESULTS: The depth of sedation, as measured by the Modified Ramsay Sedation Scale, was similar in the 2 groups, when adjusted for dosing differences. The amount of propofol required to maintain adequate sedation was decreased in both groups compared to propofol requirements in ICU patients with normal renal function. EDTA levels were elevated at baseline in both groups. In the propofol EDTA group, the EDTA levels increased further by 20 % but decreased to below baseline EDTA levels at 48 hours after sedation. In the propofol group, EDTA levels decreased during sedation and remained below baseline levels at 48 hours after sedation. PATIENTS in both groups were hypocalcaemic and hyperphosphataemic at baseline with low levels of 1,25-dihydroxyvitamin D and elevated parathyroid hormone (PTH) levels. Other than a slight difference in ionised serum calcium levels at 4 h after the start of sedation, there were no significant differences observed in serum calcium levels between the two groups. There were no significant differences in 1,25-dihydroxyvitamin D or PTH levels over time between the two groups. There was no significant effect on renal function in either group. CONCLUSIONS: The results of this study suggest that adding EDTA to propofol does not adversely affect cation homeostasis or renal function when used for sedation of ICU patients with renal insufficiency. Although EDTA levels increased over time from baseline levels in patients with renal insufficiency who receive propofol EDTA, this increase does not appear to be clinically significant, and EDTA levels return to below baseline levels within 48 hours of discontinuing the propofol EDTA infusion. The efficacy of propofol with and without EDTA also appears comparable in these patients.

Safety and efficacy of propofol with EDTA when used for sedation of surgical intensive care unit patients.

OBJECTIVE: To compare propofol with disodium edetate (EDTA) and propofol without EDTAwhen used for the sedation of critically ill surgical intensive care unit (ICU) patients. DESIGN: Prospective, randomised, multicentre trial. PATIENTS: A total of 122 surgical ICU patients who required intubation and mechanical ventilation. INTERVENTIONS: Patients were randomised to receive either propofol or propofol plus EDTA (propofol EDTA) by continuous infusion for sedation. MEASUREMENTS AND RESULTS: The addition of EDTA to propofol had no effect on calcium or magnesium homeostasis, renal function, haemodynamic function, or efficacy when used for the sedation of surgical patients in the ICU. The most common adverse events were hypotension, atrial fibrillation, and hypocalcaemia. In this trial, a greater number of serious adverse events and adverse events leading to withdrawal occurred in the propofol group relative to the propofol EDTA group. There was a significantly lower crude mortality rate at 7 and 28 days for the propofol EDTA group compared with the propofol group. There were no statistically significant differences between groups with respect to depth of sedation. CONCLUSION: The propofol EDTA formulation had no effect on calcium or magnesium homeostasis, renal function, or sedation efficacy compared with propofol alone when used for sedation in critically ill surgical ICU patients. There was a significant decrease in mortality in the propofol EDTA group compared with the propofol group. Further investigations are needed to validate this survival benefit and elucidate a possible mechanism.

Pine oil ingestion: a common cause of poisoning.

Pine oil is a common component of household cleaning solutions. We present the case of an elderly woman with dementia who ingested a household cleaning solution that contained pine oil and review the treatment of pine oil ingestion. The patient developed CNS depression and respiratory failure that required intubation and mechanical ventilation. A chest radiograph revealed diffuse alveolar interstitial infiltrates consistent with pneumonitis. The patient improved with supportive care. However, she developed nosocomial pneumonia, sepsis, and multiple organ failure and subsequently died. This case is illustrative of the increased risk for ingestion of toxic household compounds in the growing population of elderly and demented individuals, who are being cared for in the home. Pine oil ingestions are one of the most common accidental ingestions encountered in clinical practice. Clinical features of ingestion include depressed mentation, respiratory failure, and GI dysfunction. The treatment is supportive, and the ingestions are rarely fatal.