Treatment of pulmonary hypertension in the general adult intensive care unit: a role for oral sildenafil?

Use of inhaled nitric oxide for treatment of pulmonary hypertension in adult critical illness is limited by its mode of delivery and high costs, prompting evaluation of alternative therapies. We report the use of oral sildenafil in a patient with severe secondary pulmonary hypertension and right ventricular dysfunction. Following reduction in mean pulmonary artery pressure and pulmonary vascular resistance with inhaled nitric oxide, crossover to sildenafil therapy maintained control of pulmonary hypertension, facilitating discontinuation of respiratory and cardiovascular organ support. The relative pulmonary vascular specificity of oral sildenafil, and its low cost, makes it an attractive therapeutic alternative to inhaled nitric oxide, and warrants further study.

Antibiotic-treated infections in intensive care patients in the UK.

The purpose of this audit was to study reasons for starting antibiotic therapy, duration of antibiotic treatment, reasons for changing antibiotics and the agreement between clinical suspicion and microbiological results in intensive care practice. We conducted a multicentre observational audit of 316 patients. Data on demographic details, site, treatment and nature of infection were collected. The median duration of antibiotic therapy was 7 days. Infections were community-acquired in 160 patients (55%). Antibiotics were started on clinical suspicion of infection in 237 patients (75%). Pulmonary infections were the most common, representing 52% of all proven infections. Gram-negative organisms were the most common cause of proven infections (n = 90 (50%)). The antibiotic spectrum was narrowed in light of microbiology results in 78 patients (43%) and changed due to antibiotic resistance in 38 patients (21%). We conclude that the mean duration of treatment contrasts with existing published guidelines, highlighting the need for further studies on duration and efficacy of treatment in intensive care.

The pulmonary physician in critical care * 6: The pathogenesis of ALI/ARDS.

An understanding of the pathogenesis of ARDS is essential for choosing management strategies and developing new treatments. The key mediators involved in the inflammatory and fibroproliferative responses are reviewed and the mechanisms which regulate these responses are highlighted.

Role of plasminogen activators in peritoneal adhesion formation.

Intra-abdominal adhesion formation is a major complication of serosal repair following surgery, ischaemia or infection, leading to conditions such as intestinal obstruction and infertility. It has been proposed that the persistence of fibrin, due to impaired plasminogen activator activity, results in the formation of adhesions between damaged serosal surfaces. This study aimed to assess the role of fibrinolysis in adhesion formation using mice deficient in either of the plasminogen activator proteases, tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA). We hypothesize that, following serosal injury, mice with decreased peritoneal fibrinolytic activity will be more susceptible to adhesion formation. Adhesion formation was induced in tPA- and uPA-deficient and wild-type mice following either surgical trauma to the serosa with haemorrhage and acute or chronic intraperitoneal inflammation. Adhesion formation was assessed from 1 to 4 weeks post-injury. Mice deficient in tPA were more susceptible to adhesion formation following both a surgical insult and a chronic inflammatory episode compared with uPA-deficient and wild-type mice. In addition, the time of maximal adhesion formation varied depending on the nature of the initial insult. It is proposed that the persistence of fibrin due to decreased tPA activity following surgery or chronic inflammation plays a major role in peritoneal adhesion formation.

In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes.

The resolution of acute inflammation requires bulk clearance of extravasated inflammatory cells in an ordered manner. Neutrophils undergo apoptosis and are ingested by macrophages (M psi) via a novel recognition mechanism that fails to provoke proinflammatory responses. Thereafter, the fate of inflammatory M psi themselves remains unclear. We investigated this in vivo, developing a semiallogeneic adoptive transfer system to track the fate of inflammatory M psi in a murine model of resolving peritonitis. Fluorescently labeled M psi from H-2k/d mice were transferred into the peritoneal cavity of H-2k mice at the same stage of resolving inflammation as the donor mice. Dual color flow cytometry permitted discrimination among donor cells, recipient cells, and donor cells that had been phagocytosed by recipient M psi. Despite the absence of significant local phagocytosis, the number of transferred M psi free in the peritoneum of recipient mice declined rapidly, being undetectable by 96 h. These data suggest that inflammatory M psi normally emigrate rapidly from the peritoneal cavity during the resolution of inflammation, contrasting with resident M psi, which persist in the noninflamed peritoneum for weeks. Accordingly, labeled nonphagocytosed cells were detected in the draining lymph nodes, but not in a variety of other tissues. Thus, unlike the polymorphonuclear leukocyte, which dies by apoptosis and is ingested by M psi, the inflammatory M psi itself does not die locally. Having performed its acute inflammatory and scavenging roles, it emigrates in a nonrandom fashion to the draining lymph node, where it may play an important part in the presentation of Ags from the inflamed site.

Hypoxia prolongs neutrophil survival in vitro.

Neutrophil apoptosis represents a major mechanism involved in the resolution of inflammation. Since hypoxia induces apoptosis in several cell lines and is of particular relevance in many disease states, we studied the effect of oxygen concentration on neutrophil survival in vitro. Hypoxia caused a dramatic decrease in neutrophil apoptosis (% apoptosis 20 h: 78.7 +/- 2.2% in 21% O2, 61.4 +/- 6.5% in 2.5% O2, 23.1 +/- 3.2% in 0% O2, n = 5). This was additive to the effect of GM-CSF (50 U/ml), not associated with induction of bcl-2 expression, and was not mimicked by methionine (5 mM), superoxide dismutase (200 micrograms/ml) or Trolox (10 mM) but was mimicked by catalase (250 micrograms/ml). Hence, hypoxia has a bcl-2-independent effect on neutrophil apoptosis that may adversely affect the clearance of these cells from an inflammatory focus.

Oxygen and 99mTc-MAA shunt estimations in patients with pulmonary arteriovenous malformations: effects of changes in posture and lung volume.

BACKGROUND: Patients with arteriovenous malformations are routinely monitored with arterial oxygen saturation (SaO2) estimations (breathing air) from which an oxygen shunt fraction can be calculated. This simple estimation has been compared with an anatomically defined estimate of the right to left shunt using a radioisotopic method. The fall in SaO2 which occurs in patients with pulmonary arteriovenous malformations in the erect posture and at high lung volumes was used to test the ability of SaO2 alone to follow changes in right to left shunt. METHODS: Radiolabelled albumin macroaggregates (99mTc-MAA) or microspheres (MS) were injected intravenously and kidneys and lungs were imaged. The shunt fraction (QS/QTTc) in the supine position at functional residual capacity (baseline) was obtained by quantifying right kidney radioactivity. On standing or while breath holding at total lung capacity, shunt fraction was calculated from baseline QS/QTTc and from lung counts and the injected dose. Arterial oxygen saturation (SaO2) was recorded by a pulse oximeter for calculation of the oxygen shunt (QS/QTO2) (breathing air). RESULTS: In the postural study (n = 8) SaO2 decreased from a mean (SD) value of 89 (5)% supine to 80 (6)% erect, corresponding to QS/QTO2 28 (8)% and 44 (8)% respectively. QS/QTTc increased from 28.7 (10.3)% to 39 (14.3)%. In the lung volume study (n = 8) QS/QTTc increased from 16.6 (11.5)% at functional residual capacity to 23.3 (11.9)% at total lung capacity while QS/QTO2 increased from 19.5 (7.5)% to 25.9 (10.6)% respectively. When all measurements were compared for QS/QTTc% and QS/QTO2% (n = 32) the difference in the mean values was 2.5% (absolute) and the limits of agreement between the two methods were +38% to -18% (relative). In neither the postural nor the volume study did delta (QS/QTO2) reliably predict delta (QS/QTTc)%. CONCLUSIONS: In pulmonary arteriovenous malformations the simple physiological shunt calculated from SaO2 breathing air agreed well with the anatomical right to left shunt measured with 99mTc-MAA, but predicted poorly the changes in anatomical shunt induced by postural or lung volume changes.

Quantification of right to left shunt at rest and during exercise in patients with pulmonary arteriovenous malformations.

BACKGROUND: Current treatment of patients with pulmonary arteriovenous malformations requires serial embolisations by means of steel coils or balloons. Measurement of right to left shunt is the most specific index of response to treatment. A new method of measuring shunt has been developed that is less invasive than traditional methods. METHODS: Right to left pulmonary shunt (expressed as percentage of cardiac output) was measured at rest in 19 patients with pulmonary arteriovenous malformations and six normal subjects by using intravenously injected albumin microspheres labelled with technetium-99m. The technique was compared with a simultaneous shunt measurement in subjects breathing 100% oxygen while they rested. The microsphere technique was adapted to measure the right to left shunt during exercise in 12 patients and five normal subjects with a new method of quantification. RESULTS: The mean (SD) shunt at rest as measured by the microsphere method was 23.2% (15.6%) in the patients and 2.7% (1.2%) in the normal subjects. When these values were compared with those of the 100% oxygen method the difference in mean values was 1% and the limits of agreement between the two methods -32% to +45%. The microsphere method is less invasive (arterial blood gas sampling is not required), quicker, and more comfortable for patients than the 100% oxygen method. In five of the normal subjects the mean (SD) 99mTc microsphere shunt increased from 2.9% (1.3%) at rest to 5.1% (2.9%) during exercise. In the 12 patients studied during exercise the shunt increased from 33.7% (12.7%) at rest to 41.7% (13.3%) during exercise in eight but decreased from 22.6% (2.4%) at rest to 17.6% (2.2%) during exercise in four. Arterial desaturation during exercise correlated with change in the size of the right to left shunt during exercise (r = +0.80). CONCLUSIONS: The microsphere method allows measurement of right to left shunt at rest and during exercise. Serial measurements at rest provide a simple, safe assessment of the physiological response to embolisation in patients with pulmonary arteriovenous malformations.

Inhibition of inhaled metabisulphite-induced bronchoconstriction by inhaled frusemide and ipratropium bromide.

1. The effect of inhaled frusemide and high dose inhaled ipratropium bromide on bronchoconstriction induced by inhaled metabisulphite was studied in 10 atopic volunteers. 2. Frusemide (40 mg), ipratropium bromide (0.5 mg) or saline placebo were administered by nebuliser in a double-blind fashion, prior to construction of a dose-response curve to metabisulphite (2.5-100 mg ml-1). 3. Geometric mean of the provocative dose of metabisulphite that caused a 35% fall in specific airways resistance (sGaw) after placebo was 13 (95% confidence intervals CI 4-36 mumol) compared with 36 (16-78) mumol after ipratropium bromide and 45 (22-94) mumol after frusemide. 4. Mean maximum fall in sGaw was 49 (40-57)% after placebo, 11 (0-22)% after frusemide and -1 (-25-22)% after ipratropium bromide. 5. Frusemide significantly protected against metabisulphite induced bronchoconstriction (P less than 0.005). The protection from high dose ipratropium bromide was also significant (P less than 0.05), but the response was more variable between subjects.