Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.

Orlistat-induced fulminant hepatic failure.

Orlistat was approved by the Food and Drug Administration in 1998 and has been shown to be superior to placebo in achieving weight loss. It is generally well tolerated. However, severe liver injury has been reported. We present a case of hepatic failure in a patient taking orlistat. A 54-year-old African-American woman with hypertension presented with hepatic failure. She had noticed increasing fatigue, jaundice and confusion. She used alcohol sparingly and denied tobacco or illicit drug use, but had been taking over-the-counter orlistat for the past two months. Physical examination revealed scleral icterus, jaundice, asterixis and slow speech. Laboratory testing showed markedly abnormal liver function tests with coagulopathy. Acute viral and autoimmune serologies were negative, as was toxicology screen. Liver biopsy showed necrotic hepatic parenchyma likely secondary to drug toxicity. Based upon her clinical presentation and time course, the pattern of liver injury seen on liver biopsy and lack of an alternative plausible explanation, her liver failure was most likely associated with orlistat use. She continued to deteriorate and ultimately underwent orthotopic liver transplantation. Fourteen cases of severe liver injury associated with orlistat use have been reported, four of which are detailed in the literature. This is the second published case of liver failure associated with over-the-counter orlistat usage. Clinicians should be aware of the growing number of cases associating liver injury and orlistat use and carefully monitor their patients on this medication for signs of hepatic dysfunction.

Ventilator associated pneumonia: quality of nonbronchoscopic bronchoalveolar lavage sample affects diagnostic yield.

The importance of predefined criteria for acceptable samples of respiratory therapists obtained lower respiratory samples were studied, using a nonbronchoscopic bronchoalveolar lavage (BAL) protocol for ventilated patients in the intensive care unit. Therapists were instructed and asked to follow guidelines for obtaining samples. Over one year, 219 samples were obtained by respiratory therapists. Of these, 115 were considered to be adequate samples using the following criteria: 60 mL of instilled volume, at least 5 mL of fluid aspirated, specimens sent for semiquantitative culture, a differential cell count of <5% bronchial epithelial cells. Overall, 52 samples grew one or more pathogen at >10,000 colony forming units (cfu).mL(-1) of BAL. The most common pathogen was Staphylococcus aureus (S. aureus) (11 samples), although Gram-negative bacilli were the single pathogen in 21 specimens. Of the 115 acceptable samples, 40 (35%) grew > or =1 pathogen at >10,000 cfu.mL(-1). For the 80 not acceptable samples which were sent for appropriate culture, 12 (15%) grew >10,000 cfu.mL(-1) BAL. This difference was significant (Chi-squared=9.44, p<0.01). Nonbronchoscopic bronchoalveolar lavage can be safely performed by respiratory therapists'. The authors recommend that a protocol be used to evaluate the quality of a bronchoalveolar lavage sample in the same manner sputum samples are screened prior to interpretation.

Standards of laboratory practice: theophylline and caffeine monitoring. National Academy of Clinical Biochemistry.

Theophylline is used in the treatment of asthma and chronic obstructive pulmonary disease. The use of theophylline has declined with the advent of potent steroid inhalants. Because of the therapeutic index of this drug, monitoring of theophylline concentrations in plasma is essential. Monitoring should be done on trough specimens after steady-state has been reached. Non-steady-state concentrations may be indicated in selected situations. Caffeine is used to treat apnea of the newborn because of its low toxicity. Monitoring is often by clinical effect. Monitoring of serum concentrations should be performed in cases where there is no clinical response or if there is suspected toxicity.

Changes in the inflammatory response of the lung during acute respiratory distress syndrome: prognostic indicators.

We studied paired bronchoalveolar lavage (BAL) in patients with sepsis-associated acute respiratory distress syndrome (ARDS). Patients were evaluated at one institution and underwent bronchoscopy with BAL within 48 h of the onset of ARDS. Patients were restudied with bronchoscopy and BAL after 4 d of treatment. Fifty-eight patients were initially studied, with 44 patients having follow-up bronchoscopy after 4 d. The overall 30-d survival for the ARDS group was 60%. In the initial lavage, there was no difference in the neutrophils between the survivors and nonsurvivors (survivors: 59 [0-98]%; Median [Range]; nonsurvivors: 55 [0-92]%). The follow-up lavage demonstrated a significant drop in the neutrophils for the survivors (36 [4-89]%, p < 0.002) which was not seen for the nonsurvivors (70 [26-95]%). Initial IL-8 concentrations in the BAL fluid were not significantly different between the two groups. In the follow-up lavage, there was a significant fall for the IL-8 concentrations for the survivors but not the nonsurvivors. We conclude that neutrophil influx in ARDS may rapidly resolve within a week of the onset of ARDS. The resolution of neutrophils was associated with a good prognosis.

Plasma catecholamine levels in cyclic antidepressant overdose.

Cyclic antidepressant overdose is a major cause of morbidity and mortality in self-poisoned patients. The major cause of mortality with cyclic antidepressant overdose is cardiotoxicity. We determined plasma catecholamine levels in 41 symptomatic acute overdose patients to identify interactions between QRS duration (a marker for cardiotoxicity) and a presumed hyper-adrenergic state. Using a linear multivariable regression analysis, QRS duration correlated with the presence of cyclic antidepressant, plasma norepinephrine levels, the ratio of norepinephrine to epinephrine level, and pulse rate (p less than 0.001, r2 = 0.42). Commensurate physiologic changes were not found in the presence of elevated catecholamine levels in the cyclic antidepressant overdose group. One possible explanation for the blunted systemic response to the elevated catecholamine levels is adrenergic desensitization. Investigation of serial catecholamine levels during cyclic antidepressant overdose may lead to modification of our current theories of cardiotoxicity and therapy.

Prospective evaluation of gastric emptying in the self-poisoned patient.

The authors prospectively studied the effect of gastric emptying (GE) and activated charcoal (AC) upon clinical outcome in acutely self-poisoned patients. Presumed overdose patients (n = 808) were treated using an alternate day protocol based on a 10-question cognitive function examination and presenting vital sign parameters. Asymptomatic patients (n = 451) did not receive GE. AC was administered to asymptomatic patients only on even days. GE in the remaining symptomatic patients (n = 357) was performed only on even days. On emptying days, alert patients had ipecac-induced emesis while obtunded patients received gastric lavage. AC therapy followed gastric emptying. On nonemptying days, symptomatic patients were treated only with AC. No clinical deterioration occurred in the asymptomatic patients treated without GE. AC use did not alter outcome measures in asymptomatic patients. GE procedures in symptomatic patients did not significantly alter the length of stay in the emergency department, mean length of time intubated, or mean length of stay in the intensive care unit. Gastric lavage was associated with a higher prevalence of medical intensive care unit admissions (P = .0001) and aspiration pneumonia (P = .0001). The data support the management of selected acute overdose patients without GE and fail to show a benefit from AC in asymptomatic overdose patients.

Lithium toxicity and myxedema coma in an elderly woman.

The development of hypothyroidism as a side effect of lithium therapy is a well recognized phenomenon. However, the presentation of myxedema coma after lithium intoxication has not been previously documented. In this case lithium toxicity may have exacerbated preexisting hypothyroidism to the point of respiratory arrest. Based on this case, we recommend periodic monitoring of thyroid function in an effort to detect preexisting hypothyroidism or lithium-induced hypothyroidism.

Serial physiologic studies of a chronic obstructive pulmonary disease patient in acute respiratory failure: clues for weaning?

A patient with severe chronic obstructive pulmonary disease was studied during acute respiratory failure. On the day of intubation his respiratory rate was 42, the tidal volume 295 ml, and the maximal inspiratory pressure 8 cm H2O. These parameters improved with rest by mechanical ventilation to 16, 620 ml, and 30 cm H2O, respectively, on the day of successful weaning. Daily tidal volumes correlated significantly with maximal inspiratory muscle pressures (r = 0.936; p less than 0.001). Respiratory system compliances and resistances were measured by the inflation, the end-inspiratory occlusion, and the interrupter methods. In general, inflation compliance and occlusion compliance were comparable and significantly smaller than the interrupter compliance (p less than 0.002 and p less than 0.003, respectively), whereas inflation resistance and occlusion maximal resistance were also comparable but significantly smaller than the interrupter resistance (p less than 0.0008 and p less than 0.0006, respectively). The former was due to increased hysteresis of the pressure volume curves and the latter due to expiratory compression of airways. The compliance was low, and the resistance was high on the day of intubation and became much higher and lower, respectively, on the day of successful extubation. These physiological changes were associated with weaning difficulty. We conclude that respiratory failure and weaning are complex physiologic events under the influence of muscle strength, lung mechanics, gas exchange, and control of breathing. Therefore, prediction of weaning success based upon one or two measured parameters as has been done is probably inadequate in difficult patients.

Pressure flow characteristics of commonly used heat-moisture exchangers.

Heat-moisture exchangers or "artificial noses" are commonly used to humidify the inspired air in intubated or tracheostomized patients. These devices add resistance to breathing that may be significant in critically ill and weak patients, especially when the devices are humidified. Three of each six commonly used types (Portex, SH 150, SH 151, NCC, Engström, and PaII) were tested to define the pressure flow characteristics. Known flows were passed through these devices, and the pressure drops across them were measured. The devices were tested when they were dry and when they were humidified with 100% saturated water vapor for 8, 16, and 24 h. The amount of water added to the devices was measured. The pressure flow characteristics of the devices could be described by a power function: P = aVb, where P is pressure, V is flow, and a and b are constants determined by the characteristics of the devices. In addition, the resistance increased with the increasing weight of the devices from added moisture clogging the pores of the felt pads contained inside.

Hyperthermia, hypertension, hypertonia, and coma in a massive thioridazine overdose.

This report characterizes an atypical presentation of a thioridazine overdose. Clinical manifestations included wide Q.R.S. complex, hyperthermia, hypertension, hypertonia, and coma. Plasma catecholamine levels were markedly elevated. The patient was treated with dantrolene sodium and supportive care. The patient's condition improved over time, with questionable response to dantrolene sodium. Supportive care was the mainstay of treatment.

Factors influencing the production of wheezes during expiratory maneuvers in normal subjects.

We recorded wheezes, pleural pressure, plethysmographic lung volumes and mouth flow rates in 6 healthy subjects during maximal expiratory maneuvers breathing air and a mixture of 80% He-20% O2 (He) before and after methacholine inhalation. During expiratory flow maneuvers a critical pleural pressure was needed before wheezes occurred. All but one wheeze occurred in the last two thirds of vital capacity during forced exhalation where flow limitation existed. At a flow rate of 2 liters/s, the critical pleural pressure breathing air was 21 +/- 5.8 cm H2O (mean +/- SD), whereas that of breathing He was higher: 32 +/- 7.8 cm H2O (p less than 0.02). In addition the wheezes occurred at lower lung volumes (associated with small airway diameters) when He was breathed instead of air. This was seen both before (p less than 0.02) and after (p less than 0.01) methacholine. These findings suggested that for a given flow rate a lighter gas such as He had to acquire a higher linear velocity so that the convective acceleration was sufficient to produce wheezes. This was achieved by either an increase in the driving critical pleural pressure or narrowing of bronchi by a larger compressing pleural pressure or smaller lung volumes.

Pentobarbital treatment of refractory status epilepticus.

We studied nine patients with status epilepticus refractory to standard therapy. In all patients so treated, IV pentobarbital terminated seizure activity. Mortality was high (77%) in those treated, but was attributed to underlying pathology and possibly to duration of status epilepticus. Pentobarbital therapy should be initiated within 0 to 2 hours after onset of seizures, with continuous EEG monitoring in an intensive care unit.

Use of the protected specimen brush in patients with endotracheal or tracheostomy tubes.

Twenty-one patients on mechanical ventilators for greater than 48 hours who had new localized infiltrates were evaluated using a quantitative culture technique of the involved lung compared to the non-involved lung. Based on the clinical course, response to antibiotics, or subsequent analysis of pathologic specimens, eight patients were felt to have acute bacterial pneumonia, while the remaining 13 were felt to have an alternative cause of their infiltrate. Cultures of the protected brush specimen of the involved lung in all eight cases of bacterial pneumonia had one or more organisms grown at a greater than 100 colony forming units (cfu) per ml while only one of the 13 cases of non-pneumonia had a culture from the involved area having greater than 100 cfu per ml (p less than 0.001). The non-involved area always grew fewer organisms than the involved area, and in 16 cases, there was no growth from the specimen obtained from the non-involved area.

Acute complications of endotracheal intubation. Relationship to reintubation, route, urgency, and duration.

Sixty-one consecutive medical intensive care unit patients who were intubated for more than three days were prospectively studied for complications. Patients who were reintubated had a higher incidence of all complications (chi square = 5.4; p less than .025), as did those with prolonged intubation (chi square = 16.1; p less than .005). Neither route nor urgency had an adverse clinical effect. In contrast there was a 13 percent incidence of acute tracheolaryngeal complications, but no association was found with reintubation, route, urgency, or total duration of endotracheal intubation.

Oxygen delivery in critically ill patients. Relationship to blood lactate and survival.

Forty-four critically ill patients with or without adult respiratory distress syndrome (ARDS) were studied in an attempt to define critical levels of oxygen delivery. Blood lactate was used as the indicator of tissue hypoxia independent of cardiac output. Survival was good (55 percent) and blood lactate near normal for those with oxygen delivery more than 8 ml/kg/min. Below this level, survival was poor (14 percent) and blood lactate markedly increased. There were significant nonlinear correlations of lactate with O2 delivery (r = - .735, p less than .001) and cardiac output (r = - .602, p less than .001). Mixed venous oxygen was not a reliable indicator of blood lactate, survival, oxygen delivery, or oxygen consumption.

Changes in fatty acids in phospholipids of the bronchoalveolar fluid in bacterial pneumonia and in adult respiratory distress syndrome.

Fatty acids of the phospholipid fraction of bronchoalveolar lavage fluid from patients with bacterial pneumonia or with the adult respiratory distress syndrome were chromatographed and the patterns compared with those for a control group. In the control group, palmitic acid (16:0) was the predominant fatty acid, accounting for 58.0% (SD 8.25%) of the total fatty acid, a proportion significantly higher (p less than 0.001) than in the distress-syndrome group (42.1%, SD 4.88%) or the acute pneumonia group (32.1%, SD 1.73%). There was a greater proportion of oleic acid (18:1) in the disease groups; thus the ratio of palmitic to oleic acid was useful in distinguishing these three groups. No patient with a palmitic/oleic acid ratio greater than 2.45 had evidence of parenchymal inflammation. Of those with a ratio less than 1.3, 89% had acute bacterial pneumonia.

Bronchoalveolar lavage in patients with the acquired immune deficiency syndrome (AIDS).

The lymphocytes retrieved by bronchoalveolar lavage (BAL) of three patients with the acquired immune deficiency syndrome were studied to determine the local immune status of these patients. These results were compared to those of patients with pulmonary sarcoidosis, who have similar systemic immune response (anergy, hypergammaglobulinemia). In these AIDS patients, the T4/T8 ratio in the BAL was 0.44 +/- 0.20. In eleven patients with pulmonary sarcoidosis, the bronchoalveolar lavage showed a T4/T8 ratio of 7.51 +/- 2.14. It is possible that patients with AIDS are unable to change the local immune response in the lung and thus are at risk for unusual infections.