Nitric oxide synthase inhibition in sepsis? Lessons learned from large-animal studies

Nitric Oxide (NO) plays a controversial role in the pathophysiology of sepsis and septic shock. Its vasodilatory effects are well known, but it also has pro- and antiinflammatory properties, assumes crucial importance in antimicrobial host defense, may act as an oxidant as well as an antioxidant, and is said to be a vital poison for the immune and inflammatory network. Large amounts of NO and peroxynitrite are responsible for hypotension, vasoplegia, cellular suffocation, apoptosis, lactic acidosis, and ultimately multiorgan failure. Therefore, NO synthase (NOS) inhibitors were developed to reverse the deleterious effects of NO. Studies using these compounds have not met with uniform success however, and a trial using the nonselective NOS inhibitor N-G-methyl-L-arginine hydrochloride was terminated prematurely because of increased mortality in the treatment arm despite improved shock resolution. Thus, the issue of NOS inhibition in sepsis remains a matter of debate. Several publications have emphasized the differences concerning clinical applicability of data obtained from unresuscitated, hypodynamic rodent models using a pretreatment approach versus resuscitated, hyperdynamic models in high-order species using posttreatment approaches. Therefore, the present review focuses on clinically relevant large-animal studies of endotoxin or living bacteria-induced, hyperdynamic models of sepsis that integrate standard day-today care resuscitative measures.

Evaluation of random plasma cortisol and the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: A prospective study

It is unclear whether a random plasma cortisol measurement and the corticotropin (ACTH) test adequately reflect glucocorticoid secretory capacity in critical illness. This study aimed to determine whether these tests provide information representative of the 24 hour period. Plasma cortisol was measured hourly for 24 hours in 21 critically ill septic patients followed by a corticotropin test with 1 μ g dose administered intravenously. Serum and urine were analysed for ACTH and free cortisol respectively. Marked hourly variability in plasma cortisol was evident (coefficient of variation 8-30%) with no demonstrable circadian rhythm. The individual mean plasma cortisol concentrations ranged from 286 59 nmol/l to 796 &PLUSMN; 83 nmol/l. The 24 hour mean plasma cortisol was strongly correlated with both random plasma cortisol (r(2) 0.9, P< 0.0001) and the cortisol response to corticotropin (r(2) 0.72, P< 0.001). Only nine percent of patients increased their plasma cortisol by 250 nmol/l after corticotropin (euadrenal response). However, 35% of non-responders had spontaneous hourly rises > 250 nmol/l thus highlighting the limitations of a single point corticotropin test. Urinary free cortisol was elevated (865&PLUSMN; 937 nmol) in both corticotropin responders and non-responders suggesting elevated plasma free cortisol. No significant relationship was demonstrable between plasma cortisol and ACTH. We conclude that although random cortisol measurements and the low dose corticotropin tests reliably reflect the 24 hour mean cortisol in critical illness, they do not take into account the pulsatile nature of cortisol secretion. Consequently, there is the potential for erroneous conclusions about adrenal function based on a single measurement. We suggest that caution be exercised when drawing conclusions on the adequacy of adrenal function based on a single random plasma cortisol or the corticotropin test.

The effect of positive end-expiratory pressure level on peak expiratory flow during manual hyperinflation

Including positive end-expiratory pressure (PEEP) in the manual resuscitation bag (MRB) may render manual hyperinflation (MHI) ineffective as a secretion maneuver technique in mechanically ventilated patients. In this study we aimed to determine the effect of increased PEEP or decreased compliance on peak expiratory flow rate (PEF) during MHI. A blinded, randomized study was performed on a lung simulator by 10 physiotherapists experienced in MHI and intensive care practice. PEEP levels of 0-15 cm H2O, compliance levels of 0.05 and 0.02 L/cm H2O, and MRB type were randomized. The Mapleson-C MRB generated significantly higher PEF (P < 0.01, d = 2.72) when compared with the Laerdal MRB for all levels of PEEP. In normal compliance (0.05 L/cm H2O) there was a significant decrease in PEF (P < 0.01, d = 1.45) for a PEEP more than 10 cm H2O in the Mapleson-C circuit. The Laerdal MRB at PEEP levels of more than 10 cm H2O did not generate a PEF that is theoretically capable of producing two-phase gas-liquid flow and, consequently, mobilizing pulmonary secretions. If MHI is indicated as a result of mucous plugging, the Mapleson-C MRB may be the most effective method of secretion mobilization.

Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis

Objective: To investigate the effects of recombinant human activated protein C (rhAPC) on pulmonary function in acute lung injury (ALI) resulting from smoke inhalation in association with a bacterial challenge. Design: Prospective, randomized, controlled, experimental animal study with repeated measurements. Setting: Investigational intensive care unit at a university hospital. Subjects: Eighteen sheep (37.2 +/- 1.0 kg) were operatively prepared and randomly allocated to either the sham, control, or rhAPC group (n = 6 each). After a tracheotomy had been performed, ALI was produced in the control and rhAPC group by insufflation of 4 sets of 12 breaths of cotton smoke. Then, a 30 mL suspension of live Pseudomonas aeruginosa bacteria (containing 2-5 x 10(11) colony forming units) was instilled into the lungs according to an established protocol. The sham group received only the vehicle, i.e., 4 sets of 12 breaths of room air and instillation of 30 mL normal saline. The sheep were studied in the awake state for 24 hrs and were ventilated with 100% oxygen. RhAPC (24 mu g/kg/hr) was intravenously administered. The infusion was initiated 1 hr post-injury and lasted until the end of the experiment. The animals were resuscitated with Ringer's lactate solution to maintain constant pulmonary artery occlusion pressure. Measurements and Main Results., In comparison with nontreatment in controls, the infusion of rhAPC significantly attenuated the fall in PaO2/FiO(2) ratio (control group values were 521 +/- 22 at baseline [BL], 72 +/- 5 at 12 hrs, and 74 +/- 7 at 24 hrs, vs. rhAPC group values of 541 +/- 12 at BL, 151 +/- 29 at 12 hours [p < .05 vs. control], and 118 +/- 20 at 24 hrs), and significantly reduced the increase in pulmonary microvascular shunt fraction (Qs/Qt; control group at BL, 0.14 +/- 0.02, and at 24 hrs, 0.65 +/- 0.08; rhAPC group at BL, 0.24 +/- 0.04, and at 24 hrs, 0.45 +/- 0.02 [p < .05 vs. control]) and the increase in peak airway pressure (mbar; control group at BL, 20 +/- 1, and at 24 hrs, 36 +/- 4; rhAPC group at BL, 21 +/- 1, and at 24 hrs, 28 +/- 2 [p < .05 vs. control]). In addition, rhAPC limited the increase in lung 3-nitrotyrosine (after 24 hrs [%]: sham, 7 +/- 2; control, 17 +/- 1; rhAPC, 12 +/- 1 [p < .05 vs. control]), a reliable indicator of tissue injury. However, rhAPC failed to prevent lung edema formation. RhAPC-treated sheep showed no difference in activated clotting time or platelet count but exhibited less fibrin degradation products (1/6 animals) than did controls (4/6 animals). Conclusions. Recombinant human activated protein C attenuated ALI after smoke inhalation and bacterial challenge in sheep, without bleeding complications.

Effect of smoke inhalation on viscoelastic properties and ventilation distribution in sheep

Smoke inhalation injuries are the leading cause of mortality from burn injury. Airway obstruction due to mucus plugging and bronchoconstriction can cause severe ventilation inhomogeneity and worsen hypoxia. Studies describing changes of viscoelastic characteristics of the lung after smoke inhalation are missing. We present results of a new smoke inhalation device in sheep and describe pathophysiological changes after smoke exposure. Fifteen female Merino ewes were anesthetized and intubated. Baseline data using electrical impedance tomography and multiple-breath inert-gas washout were obtained by measuring ventilation distribution, functional residual capacity, lung clearance index, dynamic compliance, and stress index. Ten sheep were exposed to standardized cotton smoke insufflations and five sheep to sham smoke insufflations. Measured carboxyhemoglobin before inhalation was 3.87 +/- 0.28% and 5 min after smoke was 61.5 +/- 2.1%, range 50-69.4% ( P < 0.001). Two hours after smoke functional residual capacity decreased from 1,773 +/- 226 to 1,006 +/- 129 ml and lung clearance index increased from 10.4 +/- 0.4 to 14.2 +/- 0.9. Dynamic compliance decreased from 56.6 +/- 5.5 to 32.8 +/- 3.2 ml/ cmH(2)O. Stress index increased from 0.994 +/- 0.009 to 1.081 +/- 0.011 ( P < 0.01) ( all means +/- SE, P < 0.05). Electrical impedance tomography showed a shift of ventilation from the dependent to the independent lung after smoke exposure. No significant change was seen in the sham group. Smoke inhalation caused immediate onset in pulmonary dysfunction and significant ventilation inhomogeneity. The smoke inhalation device as presented may be useful for interventional studies.

Applications of transcranial Doppler in the ICU: a review

Objective: Transcranial Doppler (TCD) ultrasonography is a technique that uses a hand-held Doppler transducer (placed on the surface of the cranial skin) to measure the velocity and pulsatility of blood flow within the intracranial and the extracranial arteries. This review critically evaluates the evidence for the use of TCD in the critical care population. Discussion: TCD has been frequently employed for the clinical evaluation of cerebral vasospasm following subarachnoid haemorrhage (SAH). To a lesser degree, TCD has also been used to evaluate cerebral autoregulatory capacity, monitor cerebral circulation during cardiopulmonary bypass and carotid endarterectomies and to diagnose brain death. Technological advances such as M mode, colour Doppler and three-dimensional power Doppler ultrasonography have extended the scope of TCD to include other non-critical care applications including assessment of cerebral emboli, functional TCD and the management of sickle cell disease. Conclusions: Despite publications suggesting concordance between TCD velocity measurements and cerebral blood flow there are few randomized controlled studies demonstrating an improved outcome with the use of TCD monitoring in neurocritical care. Newer developments in this technology include venous Doppler, functional Doppler and use of ultrasound contrast agents.

Effect of drug concentration on adsorption of levofloxacin by polyacrylonitrile haemofilters

We studied an in vitro model of continuous venovenous haemofiltration to determine levofloxacin adsorption by polyacrylonitrile (PAN) filters. Four doses of levofloxacin (5, 25, 50 and 100 mg) were used, resulting in circulating concentrations of levofloxacin at 120 min of 3.56 +/- 0.14, 15.84 +/- 2.08, 31.42 +/- 1.95 and 58.23 +/- 1.10 mg/L, respectively. Adsorption at 2 h was 0.65 +/- 0.17, 5.99 +/- 2.49, 12.30 +/- 2.34 and 30.13 +/- 1.32 mg, respectively (P < 0.001). From 2 h to 4 h, increasing the blood pump rate and the ultrafiltration rate had no effect on adsorption. When the concentration was decreased from 3.55 +/- 0.13 mg/L at 4 h to 2.16 +/- 0.11 mg/L at 5 h by addition of lactated Ringer's solution, adsorption decreased from 0.67 +/- 0.16 mg to 0.21 +/- 0.25 mg (P < 0.05). These data show that adsorption of levofloxacin by PAN haemofilters is concentration dependent and reversible in vitro and suggest that adsorption by haemofilters is unlikely to affect levofloxacin pharmacokinetics significantly in vivo. (c) 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Protein contamination of the laryngeal mask airway and its relationship to re-use

The Laryngeal Mask Airway is a reusable device for maintaining the patency of a patient's airway during general anaesthesia. The device can be reused after it has been cleaned and sterilized. Protein contamination of medical instruments is a concern and has been found to occur despite standard sterilization techniques. The reason for the concern relates to the possibility of the transmission of prions and the risk of developing a neurodegenerative disorder such as Creutzveldt-Jacob disease. The purpose of this study was to quantify the amount of protein contamination that occurs, and to relate this to the number of times the Laryngeal Mask Airway has been used. Fifty previously used Classic Laryngeal Masks were collected after routine sterilization and packaging. The devices were immersed in protein detecting stain and then visual inspection performed to assess the degree and distribution of the staining. The researcher was blinded to the number of times the Laryngeal Mask Airway had been used. Linear regression analysis of the degrees of staining of the airway revealed that protein contamination occurs after the first use of the device and this increases with each subsequent use. This finding highlights the concern that the currently used cleaning and sterilization methods do not prevent the accumulation of proteinaceous material on Laryngeal Mask Airways. Consideration should be given to the search for more efficient cleaning and sterilization techniques or the use of disposable devices.

The use of hypertonic saline for treating intracranial hypertension after traumatic brain injury

The past decade has witnessed a resurgence of interest in the use of hypertonic saline for low-volume resuscitation after trauma. Preliminary studies suggested that benefits are limited to a subgroup of trauma patients with brain injury, but a recent study of prehospital administration of hypertonic saline to patients with traumatic brain injury failed to confirm a benefit. Animal and human studies have demonstrated that hypertonic saline has clinically desirable physiological effects on cerebral blood flow, intracranial pressure, and inflammatory responses in models of neurotrauma. There are few clinical studies in traumatic brain injury with patient survival as an end point. In this review, we examined the experimental and clinical knowledge of hypertonic saline as an osmotherapeutic agent in neurotrauma.

The use of recombinant activated factor VII for refractory bleeding post complex cardiothoracic surgery

We reviewed the outcome following use of recombinant activated factor VII (rVIIa) in patients with major bleeding post cardiothoracic surgery in our unit between January 2002 and July 2004. The unit consists of 16 cardiothoracic intensive care beds in a public metropolitan teaching hospital which serves as a referral centre for heart and lung transplant surgery Patients with refactory bleeding following cardiothoracic surgical procedures who were treated with rVIIa were identified. A total of 12 episodes of rVIIa use were recorded in ten patients, including three episodes with ventricular assist devices, and 5 heart and/or lung transplants. The median dose used was 85 mu g/kg. Chest tube drainage decreased in all patients following administration of rVIIa; median chest tube drainage decreased front 445 ml/h to 171 ml/h (P=0.03). Despite cessation of bleeding, mortality was high, when rVIIa was used after more than 24 hours. In six episodes, despite early rVIIa use (within six hours), continued bleeding necessitated return to theatre, where a surgical source of bleeding was found. In this small retrospective study, rVIIa significantly reduced bleeding that was refractory to standard blood product transfusion. In this series of patients., those that did not respond to rVIla early in the postoperative phase were found to have a surgical source of bleeding.