Severe phenytoin intoxication in a subject homozygous for CYP2C9*3.

A 31-year-old woman who had a severe head injury was treated with oral phenytoin (100 mg 3 times a day) to prevent posttraumatic seizures. On day 10 of phenytoin treatment, 3 hours after the morning dose, the patient manifested neurologic signs compatible with phenytoin intoxication. Thus drug serum concentrations were monitored daily for 12 days. The elimination half-life was 103 hours, namely, about 5 times longer than the mean value generally quoted (22 hours). In the absence of any acquired predisposing factor for phenytoin toxicity, genetic mutations in the cytochrome P450 (CYP) enzymes responsible for phenytoin metabolism (CYP2C9 and CYP2C19) were suspected. Genotyping revealed that the patient was homozygous for the CYP2C9*3 allele (CYP2C9*3/*3) and heterozygous for the CYP2C19*2 allele (CYP2C19*1/*2). In view of the markedly reduced metabolic activity of CYP2C*3 in comparison with the wild-type enzyme (about one fifth) and of the minor role of CYP2C19 in phenytoin metabolism, it is likely that CYP2C9*3 mutation was largely responsible for drug overdose.

Respiratory physiopathology in surgical repair for large incisional hernias of the abdominal wall.

BACKGROUND: The computerized noninvasive measurement of respiratory mechanics enables new prospects in the study of respiratory physiopathology in surgical repair of large incisional hernias. STUDY DESIGN: We studied 10 patients with COPD ventilated with a Servo Ventilator 900C. We measured inspiratory flow by means ofa pneumotacograph, the volume by integrating the flow signal, and esophageal and airway opening pressure by means of two differential pressure transducers (an esophageal balloon measures, separately, chest wall and lung mechanical properties). The signals were sent by an analogic-digital converter to a personal portable computer to be analyzed. We calculated compliance of total respiratory system (Crs), chest wall (Ccw), and lung (CI); maximum resistance of the total respiratory system (Rmax, Rs), chest wall (Rmax, w), and lung (Rmax, L); and work of breathing (Wob). Statistics were performed using one-way analysis of variance and p = 0.05 was considered significant. RESULTS: At the closure of the peritoneum a reduction of Crs and Wob was recorded in seven patients in whom a PTFE prosthesis widening the abdominal cavity was used to restore the baseline value. Variations in respiratory compliance are from variations in Ccw with unaffected CI (Ccw varied from 0.180 to 0.130 L/cmH2O at peritoneal closure and from 0.130 to 0.170 L/cmH2O by prosthetic peritoneal widening). Respiratory resistances remained unchanged (11.3 cmH2O/ L/s) at any time of measurement. CONCLUSIONS: The intraoperative assessment of respiratory mechanics is useful to evaluate and eventually to decrease the mechanical workload (prosthesis widening peritoneum or fascia incisions). The passive mechanical work performed by the ventilator needs to be kept constant or no higher than 10% basic data: if these conditions are maintained, mostly in patients with COPD, there is no risk of respiratory muscular fatigue during the postoperative period.

A single institution's experience (1982-1999) with plasma-exchange therapy in patients with fulminant hepatic failure.

Fulminant hepatic failure is a rare, but often fatal complication of acute viral hepatitis. This condition, in absence of orthotopic liver transplantation (OLTx) surgery, is associated with a high mortality rate, despite the improvement of general intensive care. Plasma-exchange (PEx) therapy has been long used to treat FHF, in particular by removing toxic substances and correcting the severe coagulopathy. In this study we describe our experience with PEx treatment of FHF, beginning in 1982. Seventy patients affected with FHF due to various causes (HBV = 40; cryptogenic/non-A, non-E = 15; Amanita phalloides = 8; other = 7) were treated with PEx (altogether 348 sessions). Overall survival rate, comprising patients undergoing OLTx, was 51%, a little higher than what we observed in patients (N = 49) treated solely by PEx, i.e., 41%. The best outcome predictor was FHF aetiology, owing to the good survival rate in patients with Amanita phalloides intoxication and the very poor prognosis of patients suffering from cryptogenic/non-A, non-E FHF. Moreover, the marked increase in prothrombin time and alpha-fetoprotein levels after 48 hours from admission was associated with a good prognosis, whereas the patient's age and coma grade were not clearly predictive of survival. Additionally, lymphocyte subpopulation, resulting in a CD4/CD8 ratio lower than 1.0 along with CD8 activation with HLA-DR strong expression, were associated with a high rate of mortality and morbidity. Our data indicate that PEx therapy can improve survival in patients with sufficient residual capacity of liver regeneration. Moreover, the identification of certain prognostic factors may be useful for the rational planning of therapeutic strategy in FHF.

Flow-triggering reduces inspiratory effort during weaning from mechanical ventilation.

OBJECTIVE: To investigate whether a new flow-triggered (FT) system can reduce the patient's inspiratory effort compared to a traditional pressure-triggered (PT) system during weaning from mechanical ventilation. DESIGN: Prospective study. SETTING: Intensive care unit of a General Hospital. PATIENTS AND PARTICIPANTS: 10 mechanically ventilated patients, without chronic airway disease, ready to wean. MEASUREMENTS: Minute ventilation, breathing pattern, lung mechanics, inspiratory work of breathing (WI) and pressure time product (PTP) of Ppl were obtained in two conditions: 1) unsupported spontaneous breathing through the ventilator circuit (SB); 2) spontaneous breathing with continuous positive airway pressure set at 5 cmH2O (CPAP). Two triggering systems, namely PT and FT, were used in each condition. RESULTS: Though there was no change in breathing pattern, minute ventilation, and lung mechanics, the magnitude of the inspiratory effort decreased significantly with FT compared to PT in both instances. The added resistance (total flow resistance minus pulmonary resistance) decreased by 37% on average when FT replaced PT. PTP decreased, on average, 27% and 15% during SB and CPAP, respectively, with FT compared to PT (p < 0.05). A similar significant decrease was observed in WI. CONCLUSION: The new FT system, i.e. flow-by system, reduces the unintentional ventilatory workload upon the patients' inspiratory muscles compared to traditional PT system during weaning from mechanical ventilation.

Effects of intrinsic PEEP on pulmonary gas exchange in mechanically-ventilated patients.

The aim of the study was to assess the impact of the intrinsic positive end-expiratory pressure (PEEPi) on pulmonary gas exchange in mechanically-ventilated patients, by comparing the effects of similar levels (0.8-0.9 kPa) of positive end-expiratory pressure (PEEP) and PEEPi. Ten patients with acute respiratory failure, without chronic airway disease, were studied with three ventilatory modes: 1) intermittent positive pressure ventilation with zero end-expiratory pressure (ZEEP mode); 2) continuous positive pressure ventilation with PEEP set by the ventilator (PEEP mode); and 3) intrinsic PEEP elicited by adequate shortening of the expiratory time (PEEPi mode). Cardiorespiratory variables (e.g. respiratory compliance and resistance, arterial and mixed venous blood gases, cardiac output, pulmonary capillary pressure, oxygen delivery) were measured during each ventilatory mode. Compared to ZEEP, both PEEP and PEEPi decreased cardiac output while increasing arterial oxygen tension (PaO2). However, the improvement of PaO2 was more consistent (8 out of 10 patients), and larger (+2.1 kPa, on average, p < 0.05) with PEEP than with PEEPi (5 out of 10 patients, and +1.4 kPa, on average, NS). Since the effects of PEEP and PEEPi on ventilation, lung volume, compliance, cardiac output (QT), mixed venous oxygen tension (PvO2) and oxygen consumption (VO2) were similar, we attributed the less favourable impact of PEEPi on PaO2 to a less homogeneous distribution of PEEPi between lung units with different time constant, and hence to a more uneven distribution of the inspired gas.

Partitioning of respiratory mechanics in mechanically ventilated patients.

In ten mechanically ventilated patients, six with chronic obstructive pulmonary disease (COPD) and four with pulmonary edema, we have partitioned the total respiratory system mechanics into the lung (l) and chest wall (w) mechanics using the esophageal balloon technique together with the airway occlusion technique during constant-flow inflation (J. Appl. Physiol. 58: 1840-1848, 1985). Intrinsic positive end-expiratory pressure (PEEPi) was present in eight patients (range 1.1-9.8 cmH2O) and was due mainly to PEEPi,L (80%), with a minor contribution from PEEPi,w (20%), on the average. The increase in respiratory elastance and resistance was determined mainly by abnormalities in lung elastance and resistance. Chest wall elastance was slightly abnormal (7.3 +/- 2.2 cmH2O/l), and chest wall resistance contributed only 10%, on the average, to the total. The work performed by the ventilator to inflate the lung (WL) averaged 2.04 +/- 0.59 and 1.25 +/- 0.21 J/l in COPD and pulmonary edema patients, respectively, whereas Ww was approximately 0.4 J/l in both groups, i.e., close to normal values. We conclude that, in mechanically ventilated patients, abnormalities in total respiratory system mechanics essentially reflect alterations in lung mechanics. However, abnormalities in chest wall mechanics can be relevant in some COPD patients with a high degree of pulmonary hyperinflation.

The role of PEEP in patients with chronic obstructive pulmonary disease during assisted ventilation.

In patients with acute respiratory failure (ARF) due to acute exacerbation of chronic obstructive pulmonary disease (COPD), the intrinsic positive end-expiratory pressure (PEEPi) can significantly increase workload for ventilation. It has been suggested that, in the presence of expiratory flow limitation, application of low levels of PEEP by the ventilator can be used to reduce PEEPi and therefore the magnitude of the inspiratory effort during assisted mechanical ventilation (or pressure support) and weaning. Clearly, pulmonary hyperinflation should not be further enhanced in order not to counteract the beneficial effect of removing PEEPi by decreasing respiratory muscle length and force. This use of PEEP in COPD patients is supported not only by theory, but also by recent experimental work, although sufficient clinical information is not yet available to provide a guideline for titration of the PEEP level. Therefore, application of PEEP in COPD patients requires close monitoring of the end-expiratory lung volume. This can be accomplished, among other noninvasive ways (e.g. the inductive plethysmography), by inspection of flow/volume curves during application of increasing levels of PEEP. The shape of the expiratory limb of the flow/volume curve can also suggest the presence of dynamic hyperinflation and expiratory flow limitation.

Dose-response effects and time course of effects of inhaled fenoterol on respiratory mechanics and arterial oxygen tension in mechanically ventilated patients with chronic airflow obstruction.

To investigate the dose-response relationship and the time course of the effects of fenoterol (a selective beta 2-adrenergic agonist) on respiratory function in mechanically ventilated patients with acute respiratory failure due to exacerbation of chronic airflow obstruction (CAO), seven consecutive acutely ill patients were studied within 3 days of the onset of mechanical ventilation. Airflow, airway pressure, and changes in lung volume were measured with the transducers of the 900 C Servo Ventilator, the last by electronic integration. The end-expiratory lung volume (EELV), the intrinsic positive end-expiratory pressure (PEEPi), the static respiratory compliance (Cstrs), maximum and minimum respiratory resistance (Rrsmax and Rrsmin), and arterial oxygen tension (PaO2), were measured under control conditions (all patients were receiving aminophylline infused at a constant rate) 5, 15, and 30 min after administration of 4 ml aerosolized saline solution and 5, 15, and 30 min after inhalation of 0.4, 0.8, and 1.2 mg fenoterol. After the last dose, measurements were repeated at 60, 120, and 180 min. We found that, on average, while saline did not cause any significant change in respiratory mechanics, a low dose (0.4 mg) of inhaled fenoterol was followed by a rapid (5 min) and significant decrease in Rrsmax (-33%), Rrsmin (-28%), EELV (-34%), and PEEPi (-44%), with a slight but not significant further fall with higher doses. However, changes were short-lasting, and by 2 h after the end of administration were no longer significant. PaO2 dropped significantly on average, with a maximum mean fall of 15 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)

Doxofylline and respiratory mechanics. Short-term effects in mechanically ventilated patients with airflow obstruction and respiratory failure.

To assess the short-term effects of a methylxanthine (doxofylline) on respiratory mechanics in mechanically ventilated patients with airway obstruction and respiratory failure, nine consecutive patients were examined within three days from the onset of mechanical ventilation. Flow, changes in pulmonary volume, and Paw were measured using a ventilator (Servo 900C). End-expiratory and end-inspiratory airway occlusion was performed to measure PEEPi, Cstrs, Rrsmax, and Rrsmin. Measurements were performed before and at 5, 15, and 30 minutes after an intravenous loading dose of doxofylline (5 to 6 mg/kg). We found that doxofylline determined, on the average, a marked decrease in respiratory resistance (Rrsmax and Rrsmin, -27.2 percent and -36.5 percent, respectively) without significant changes in Cstrs and Pmax. The PEEPi, reflecting pulmonary dynamic hyperinflation, was also significantly decreased by doxofylline (-41 percent, on the average). The Pmax was not reliable for evaluation of a single patient, since changes in the elastic pressure can offset changes in the resistive one. No patient experienced significant side effects due to doxofylline. We conclude that (1) the effects of therapy can be assessed noninvasively at bedside in critically ill patients; (2) doxofylline is a rapid and efficient bronchodilator in mechanically ventilated patients with ARF and airflow obstruction; and (3) the decrease in the respiratory resistance and PEEPi, associated with an improved mechanical efficiency of the respiratory muscles at a lower pulmonary volume, can provide better conditions for the patient-ventilator interaction and for weaning.

Respiratory resistance and intrinsic positive end-expiratory pressure (PEEPi) in patients with the adult respiratory distress syndrome (ARDS).

Fourteen consecutive ARDS patients were examined within 24 h from the onset of mechanical ventilation to determine respiratory resistance (Rrs) and compliance (Cstrs), and to assess the influence of "intrinsic" positive end-expiratory pressure (PEEPi) on the measurement of Cstrs. Flow, pressure, and changes in lung volume were measured with the transducers of the Servo 900C Siemens ventilator. Airway occlusion was performed with the end-inspiratory and end-expiratory buttons of the ventilator. We found PEEPi (3.0 +/- 2.6 cm H2O) in ten of the fourteen patients. Without the correction for PEEPi, Cstrs was underestimated by 13.9 +/- 10% on average in the group as a whole (fourteen patients), and by 19.5 +/- 5.9% in the ten ARDS patients with PEEPi. Maximum and minimum respiratory resistance (Rrsmax and Rrsmin), and frequency-dependence of Rrs were also measured. On average, there was a marked frequency-dependence of resistance, as manifested by the difference between Rrsmax and Rrsmin, with an increase of both Rrsmin (7.7 +/- 4.2 cm H2O.l-1.s) and Rrsmax (14.3 +/- 5.0 cm H2O.l-1.s). The added resistance of the endotracheal tubes and ventilator tubings was flow dependent, and averaged 13.2 +/- 2.9 cm H2O.l-1.s.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory mechanics during the first day of mechanical ventilation in patients with pulmonary edema and chronic airway obstruction.

We investigated the early changes of respiratory mechanics in mechanically ventilated patients with acute respiratory failure (ARF): 8 patients after acute exacerbation of chronic airway obstruction (CAO), 8 patients with cardiogenic pulmonary edema (CPE), and 8 patients with adult respiratory distress syndrome (ARDS). The patients were studied within the first day from the onset of mechanical ventilation. Flow, changes in lung volume, and airway pressure were measured using the 900C Servo Ventilator. End-inspiratory and end-expiratory occlusions of the airway were performed to obtain respiratory compliance and resistance. We found that: (1) acute exacerbation of CAO was characterized by high respiratory resistance (reflecting in part time-constant inequalities within the lung) and severe pulmonary hyperinflation, with "intrinsic" PEEP (PEEPi) up to 22 cm H2O (mean [SD], 13.5 [6.7] cm H2O); (2) PEEPi, even if not high, was present in almost all patients with pulmonary edema, averaging 3.8 and 3.0 cm H2O in ARDS and CPE, respectively; (3) respiratory resistance was increased in patients with CPE and ARDS who had no history of airway disease; (4) patients with ARDS were characterized also by low compliance (mean [SD], 0.035 [0.005] L/cm H2O) and high resistance, the latter also reflecting a substantial component caused by time-constant inequalities; (5) in all 24 patients, static respiratory compliance (and its reciprocal, elastance) was significantly correlated with the pulmonary oxygenation index, i.e., the PaO2/PAO2 ratio. We conclude that early assessment of respiratory mechanics in mechanically ventilated patients with ARF can provide better understanding of the patients' conditions as well as guidelines for therapeutic approach and weaning attempts.