J. Woodrow Weiss

Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol.

Objectives:To describe the effectiveness of a comprehensive, interdisciplinary sepsis treatment protocol with regard to both implementation and outcomes and to compare the mortality rates and therapies of patients with septic shock with similar historical controls. Design:Prospective, interventional cohort study with a historical control comparison group. Setting:Urban, tertiary care, university hospital with 46,000 emergency department visits and 4,100 intensive care unit admissions annually. Patients:Inclusion criteria were a) emergency department patients aged ≥18 yrs, b) suspected infection, and c) lactate of >4 mmol/L or septic shock. Exclusion criteria were a) emergent operation, b) prehospital cardiac arrest, and c) comfort measures only. Time period: protocol, November 10, 2003, through November 9, 2004; historical controls, February 1, 2000, through January 31, 2001. Intervention:A sepsis treatment pathway incorporating empirical antibiotics, early goal-directed therapy, drotrecogin alfa, steroids, intensive insulin therapy, and lung-protective ventilation. Measurements and Main Results:There were 116 protocol patients, with a mortality rate of 18% (11–25%), of which 79 patients had septic shock. Comparing these patients with 51 historical controls, protocol patients received more fluid (4.0 vs. 2.5 L crystalloid, p < .001), earlier antibiotics (90 vs. 120 mins, p < .013), more appropriate empirical coverage (97% vs. 88%, p < .05), more vasopressors in the first 6 hrs (80% vs. 45%, p < .001), tighter glucose control (mean morning glucose, 123 vs. 140, p < .001), and more frequent assessment of adrenal function (82% vs. 10%, p < .001), with a nonstatistically significant increase in dobutamine use (14% vs. 4%, p = .06) and red blood cell transfusions (30% vs. 18%, p = .07) in the first 24 hrs. For protocol patients with septic shock, 28-day in-hospital mortality was 20.3% compared with 29.4% for historical controls (p = .3). Conclusions:Clinical implementation of a comprehensive sepsis treatment protocol is feasible and is associated with changes in therapies such as time to antibiotics, intravenous fluid delivery, and vasopressor use in the first 6 hrs. No statistically significant decrease in mortality was demonstrated, as this trial was not sufficiently powered to assess mortality benefits.

Physiological basis for a causal relationship of obstructive sleep apnoea to hypertension

Obstructive sleep apnoea (OSA) is causally related to systemic hypertension through sustained sympathoexcitation. The causes of this sympathoexcitation remain uncertain; however, substantial animal and human data suggest that cyclic intermittent hypoxia (CIH), as is experienced at night by patients with OSA, provides the causal link between upper airway obstruction during sleep and sympathetic activation during waking. Direct and indirect evidence indicates that CIH leads to sympathoexcitation by two mechanisms: (1) augmentation of peripheral chemoreflex sensitivity (hypoxic acclimatization); and (2) direct effects on sites of central sympathetic regulation, such as the subfornical organ and the paraventricular nucleus of the hypothalamus. Initial reports suggest that the molecular mechanisms influencing peripheral chemoreflex sensitivity and central sympathetic activity may be the same, involving such neuromodulators as angiotensin II, endothelin and nitric oxide.

Phasic electromyographic activity of the genioglossus increases in normals during slow-wave sleep

Obstructive apneas occur infrequently during Stage 3-4 NREM sleep (SWS), even in patients with severe obstructive sleep apnea. To investigate whether upper airway (UA) dilator muscle activity preferentially increases during SWS as a partial explanation for this phenomenon, we measured phasic electromyogram activity of the genioglossus muscle (EMGgg) during continuous Stage 2 NREM sleep and SWS in 5 healthy males. Subjects were studied supine during a complete cycle of nocturnal NREM sleep after partial sleep deprivation. EMGgg was measured with perorally inserted bipolar electrodes, and quantified as peak phasic inspiratory activity during all continuous epochs of NREM sleep. We found EMGgg to be increased during SWS relative to stage 2 sleep by a mean of 58% among all subjects (P = 0.02); neither end-tidal PCO2 nor inspired minute ventilation varied between these sleep stages. Upper airway resistance, measured in 3 of the subjects on a separate study night, was not different between SWS and Stage 2 sleep. We speculate that the increase in phasic EMGgg during SWS in our normal subjects may reflect a mechanism whereby UA patency tends to be preserved during this stage.

Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans

Recurrent and intermittent nocturnal hypoxia is characteristic of several diseases including chronic obstructive pulmonary disease, congestive heart failure, obesity-hypoventilation syndrome, and obstructive sleep apnea. The contribution of hypoxia to cardiovascular morbidity and mortality in these disease states is unclear, however. To investigate the impact of recurrent nocturnal hypoxia on hemodynamics, sympathetic activity, and vascular tone we evaluated 10 normal volunteers before and after 14 nights of nocturnal sustained hypoxia (mean oxygen saturation 84.2%, 9 h/night). Over the exposure, subjects exhibited ventilatory acclimatization to hypoxia as evidenced by an increase in resting ventilation (arterial Pco(2) 41.8 +/- 1.5 vs. 37.5 +/- 1.3 mmHg, mean +/- SD; P < 0.05) and in the isocapnic hypoxic ventilatory response (slope 0.49 +/- 0.1 vs. 1.32 +/- 0.2 l/min per 1% fall in saturation; P < 0.05). Subjects exhibited a significant increase in mean arterial pressure (86.7 +/- 6.1 vs. 90.5 +/- 7.6 mmHg; P < 0.001), muscle sympathetic nerve activity (20.8 +/- 2.8 vs. 28.2 +/- 3.3 bursts/min; P < 0.01), and forearm vascular resistance (39.6 +/- 3.5 vs. 47.5 +/- 4.8 mmHg.ml(-1).100 g tissue.min; P < 0.05). Forearm blood flow during acute isocapnic hypoxia was increased after exposure but during selective brachial intra-arterial vascular infusion of the alpha-blocker phentolamine it was unchanged after exposure. Finally, there was a decrease in reactive hyperemia to 15 min of forearm ischemia after the hypoxic exposure. Recurrent nocturnal hypoxia thus increases sympathetic activity and alters peripheral vascular tone. These changes may contribute to the increased cardiovascular and cerebrovascular risk associated with clinical diseases that are associated with chronic recurrent hypoxia.

Relationship between bronchial responsiveness to hyperventilation with cold and methacholine in asthma

Twenty-seven subjects with asthma and normal baseline lung function were challenged with aerosols of methacholine (M) and by isocapnic hyperventilation with cold air (HV). Stimulus-effect relationships were determined for each provocational technique on separate days and were expressed as the dose required to produce a 20% fall in forced expired volume in 1 sec (FEV1) obtained by linear interpolation from log stimulus vs. response curves (PD20). Each stimulus was applied with a sufficient intensity to produce a 20% or greater fall in FEV1 in each subject. The PD20 for M correlated significantly with the PD20 for HV (p less than 0.001) when the latter was expressed in liters per minute. The correlation between cumulative M PD20 and HV PD20 expressed as a percent of maximal voluntary ventilation was significant but less strong. We conclude that the airway response to HV reflects nonspecific bronchial hyperresponsiveness and that the dose of HV is best determined as the absolute level of ventilation.

Sustained muscle sympathetic activity after hypercapnic but not hypocapnic hypoxia in normal humans

Exposure to hypercapnic hypoxia (asphyxia), but not hyperoxic hypercapnia, results in increased sympathetic activity that persists after exposure. To determine the contribution of CO2 to the post-hypoxia sympathoexcitation, we exposed 12 normal volunteers to hypocapnic and hypercapnic hypoxia (SaO2 approximately 85%) for 20 min each on different days. We measured plethysmographic forearm blood flow, muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP), and heart rate. MSNA increased during both exposures but remained elevated for 15 min only after asphyxia. Following asphyxia, MAP returned to pre-exposure values, but after hypocapnic hypoxia MAP decreased below baseline for 15 min. There were sustained decreases in heart rate after hypocapnic, but not hypercapnic hypoxia. Forearm vascular resistance (FVR) decreased below baseline during both exposures, reached its highest value above baseline after asphyxia and then declined. After hypocapnic hypoxia FVR rose to baseline after exposure. Hemodynamics are differently altered by hypercapnic relative to hypocapnic 20 min hypoxia, while only hypercapnic hypoxia produces sustained elevation of MSNA during recovery.

Efficacy of laser-assisted uvulopalatoplasty

Laser‐assisted uvulopalatoplasty (LAUP) is being used increasingly as a surgical treatment for snoring and obstructive sleep apnea (OSA). There is limited evidence for the success of LAUP in eliminating OSA. This study assesses the efficacy of LAUP in eliminating snoring and OSA and addresses which patients may be the best candidates for LAUP treatment.

Sympathetic response to chemostimulation in conscious rats exposed to chronic intermittent hypoxia

Exposure to cyclic intermittent hypoxia (CIH) is associated with elevated arterial pressure and sustained sympathoexcitation, but the causes of the augmented sympathetic activity remain poorly understood. We recorded arterial pressure, heart rate, and renal sympathetic nerve (RSN) activity in conscious rats previously exposed to either CIH or Sham for 3 weeks during acute exposure to hypoxia (15% and 10% O(2)) or hypercapnia (7% CO(2)). Hemodynamic responses to both hypercapnia and hypoxia were similar between CIH-exposed and Sham-exposed rats, although the pattern of response was different for hypoxia (tachycardia with no change in arterial pressure) and hypercapnia (bradycardia and increased arterial pressure). RSN responses as a percent of the baseline were, however, significantly greater in CIH-exposed animals (CIH-exposed: 15% O(2) - 123.4+/-0.06%; 10% O(2) - 136.7+/-0.12%; 7% CO(2) - 138.3+/-0.18%; Sham-exposed: 15% O(2) - 106.6+/-0.03%; 10% O(2) - 107.6+/-0.01%; 7% CO(2) - 103.0+/-0.14% P<0.01 for all conditions). These data indicate that in conscious rats exposure to CIH enhances sympathetic responses to both hypoxia and hypercapnia.

Airway effects of monosodium glutamate in subjects with chronic stable asthma.

We studied the effect of oral monosodium glutamate (MSG) on airways function in 12 subjects with a history of chronic stable asthma in a double-blind, randomized, crossover protocol. Subjects ingested either 25 mg/kg of MSG or sodium chloride (equimolar to MSG) following a 6-hour fast. Spirometry [forced expiratory volume in 1 second (FEV1) and forced vital capacity] was performed before administration of the test substances and for a minimum of 4 hours thereafter. At no time during the observation period was the mean change in FEV1 more negative following MGS than following placebo. MSG is unlikely to be a contributing factor in bouts of bronchospasm in subjects with asthma, and routine avoidance of MSG by individuals with asthma need not be advised.

Mechanisms of pulsus paradoxus during resistive respiratory loading and asthma

To determine the mechanisms of pulsus paradoxus during asthma, six subjects known to have cold air bronchial hyperreactivity were studied while in a quiescent phase of their disease. All were free of significant airway obstruction at the time of study. After placement of an esophageal balloon to estimate intrathoracic pressure, the subjects were assessed during quiet breathing, resistive airway loading and then during a stable period of airway obstruction induced by cold air. Steady state left ventricular volume and performance were measured using radionuclide ventriculography; right ventricular volume was calculated from the stroke volume ratio and right ventricular ejection fraction. Cardiac cycles were segregated according to their occurrence in inspiration or expiration using a flow signal from a pneumotachograph. Combined inspiratory and expiratory resistance produced pulsus paradoxus and changes in esophageal pressure that were similar to those during asthma and significantly greater than those during quiet breathing. These changes were accompanied by decreases in left ventricular diastolic volume and stroke volume during inspiration, and increases in these variables during expiration; right ventricular volume and stroke volume demonstrated changes reciprocal to those seen in the left ventricle. These data indicate that during periods of increase in airway resistance, abnormal pulsus paradoxus results from an exaggeration in the normal inspiratory-expiratory difference in stroke volume mediated primarily by the effects of intrathoracic pressure on ventricular preload.