Waheedullah Karzai

Anti-tumor necrosis factor therapy in sepsis: update on clinical trials and lessons learned.

ObjectiveTumor necrosis factor (TNF) is an important mediator involved in the pathogenesis of sepsis. We review clinical studies investigating the efficacy of anti-TNF therapy in decreasing mortality rates in septic patients. Data Sources We conducted a computerized bibliographic search of randomized, clinical, multicenter trials studying the effects of anti-TNF therapy in the treatment of sepsis. We included all primary studies, reviewed all published meta-analyses, and contacted primary investigators of multicenter trials where necessary. Data SynthesisAlmost all randomized studies targeting TNF during sepsis show a small, albeit nonsignificant, benefit in decreasing mortality. Strategies using monoclonal antibodies are more effective than are strategies using TNF receptor proteins. Analysis of randomized multicenter trials shows a small but significant benefit with anti-TNF therapeutic strategies. Furthermore, a recent study in 2634 septic patients using a murine anti-TNF antibody shows a 3.6% significant benefit in reducing mortality. ConclusionsAnti-TNF strategies are only partially effective in patients with sepsis. Although individual studies show small, nonsignificant benefits, analysis of all trial data as well as data from a recent trial in a large population of septic patients show that anti-TNF strategies may confer a small survival benefit. Better characterization of patients and a more multimodal approach by concomitantly targeting other mediators involved in sepsis may be helpful in enlarging the clinical benefit of anti-TNF therapy.

Procalcitonin — A new indicator of the systemic response to severe infections

Severe infection and sepsis with consecutive multiple organ dysfunction or failure (MODS) are major causes of morbidity and mortality in modern intensive care units [1]. Recent advances in our understanding of the pathogenesis of sepsis have made it clear that uncontrolled infections, whether clinically manifest or occult, are not the only cause of systemic inflammation and organ dysfunction. Other stimuli such as pancreatitis [2], major trauma [3], and burns [4] can also trigger an excessive inflammatory response and lead to MODS. As a result, it is now generally accepted that not all patients displaying the clinical signs of sepsis have an underlying infection. It is therefore frequently difficult to distinguish patients with systemic infection from those who appear septic but have no bacteriological or clinical evidence of infection. Common signs of systemic inflammation such as changes in body temperature, leukocytosis, and tachycardia may have an infectious or noninfectious etiology and are neither ,specific nor sensitive for sepsis. Thus, of 61 patients with sepsis (documented infection and at least two signs of remote organ failure), 35 (57%) presented with leukocytosis, 18 (29%) had leukopenia, and eight (14%) had normal leukocyte counts (unpublished data). Likewise, patients with sepsis may present with fever, hypothermia, or normal body temperature. Bacteriological evidence of infection, although considered a gold standard, may have some drawbacks. Negative blood cultures do not exclude sepsis and multiple samples may be required over extended periods before positive cultures emerge [5]. Furthermore, positive or negative cultures may not develop concurrently with clinical signs of sepsis. Because these common clinical and laboratory parameters lack sensitivity and specificity, others are needed to provide an early marker of the infectious etiology of a generalized inflammatory response and thus allow early diagnosis and the application of more specific therapeutic interventions. Furthermore, new parameters also may help identify subgroups of septic patients who may benefit from proor antiinflammatory therapies. One such parameter, procalcitonin, has recently attracted attention as a possible marker of the systemic inflammatory response to infection.

Sensitivity and specificity of various markers of inflammation for the prediction of tumor necrosis factor-α and interleukin-6 in patients with sepsis

OBJECTIVES To determine correlations and predictive strength of surrogate markers (body temperature, leukocyte count, C-reactive protein [CRP], and procalcitonin [PCT]) with elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in septic patients. DESIGN Prospective consecutive case series. SETTING Surgical intensive care unit (ICU) of a university hospital. PATIENTS A total of 175 patients experiencing intensive care unit stays >48 hrs categorized for sepsis according to ACCP/ SCCM Consensus Conference criteria. MEASUREMENTS AND MAIN RESULTS CRP and PCT were both significantly correlated with TNF-alpha and IL-6. Based on the area-under-the-curve of the receiver operating characteristics curves, predicting capability was highest for PCT (0.814 for TNF-alpha >40 pg/mL and 0.794 for IL-6 >500 pg/mL), moderate with CRP (0.732 and 0.716, respectively), and lowest for leukocyte count (0.493 and 0.483, respectively) and body temperature (0.587 and 0.589, respectively). Sensitivity, specificity, positive, and negative predictive values and test effectiveness all followed this same pattern of being highest for PCT followed by CRP, with leukocyte count and body temperature being lowest. CONCLUSION PCT may be an early and better marker of elevated cytokines than the more classic criteria of inflammation.

Hypoxemia during one-lung ventilation: prediction, prevention, and treatment.

When switching from two-lung to one-lung ventilation (OLV), shunt fraction increases, oxygenation is impaired, and hypoxemia may occur. Hypoxemia during OLV may be predicted from measurements of lung function, distribution of perfusion between the lungs, whether the right or the left lung is ventilated, and whether the operation will be performed in the supine or in the lateral decubitus position. Hypoxemia during OLV may be prevented by applying a ventilation strategy that avoids alveolar collapse while minimally impairing perfusion of the dependent lung. Choice of anesthesia does not influence oxygenation during clinical OLV. Hypoxemia during OLV may be treated symptomatically by increasing inspired fraction of oxygen, by ventilating, or by using continuous positive airway pressure in the nonventilated lung. Hypoxemia during OLV may be treated causally by correcting the position of the double-lumen tube, clearing the main bronchi of the ventilated lung from secretions, and improving the ventilation strategy.

Total plasma antioxidant capacity is not always decreased in sepsis

OBJECTIVE To compare total plasma antioxidant capacity and selected individual antioxidants in patients with varying degrees of severity of sepsis. DESIGN A prospective, observational, consecutive case study. SETTING A 16-bed intensive care unit (ICU) in a university teaching hospital. INTERVENTIONS None. PATIENTS Forty-six healthy controls, ten ICU patients, nine patients with systemic inflammatory response syndrome (SIRS), 11 septic patients, and 14 septic shock patients. Plasma was obtained in healthy patients scheduled for minor surgery immediately before anesthesia and in ICU patients within 24 hrs of admittance to the unit or diagnosis of SIRS, sepsis, or septic shock. MEASUREMENTS AND MAIN RESULTS Using the total peroxyl radical trapping method, we found plasma antioxidant capacity to be lower in septic patients but higher in septic shock patients, as compared with controls. Bilirubin was the greatest contributor to the increase with shock, followed by uric acid. Neopterin also correlated with the peroxyl radical trapping antioxidant parameter values. CONCLUSION Although total plasma antioxidant capacity is decreased from normal levels in septic patients, an increase in some oxidants contributes to an increased total antioxidant capacity in septic shock patients.

Oxygenation during one-lung ventilation: the effects of inhaled nitric oxide and increasing levels of inspired fraction of oxygen.

We studied whether inhaled nitric oxide (NO) would improve arterial oxygen tension (Pao2) and reduce the occurrence of oxygen saturation of hemoglobin (O2Hb) <90% during one-lung ventilation (OLV). One-hundred-fifty-two patients were ventilated either with or without NO (20 ppm) with an inspired fraction of oxygen (Fio2) of either 0.3, 0.5, or 1.0 during OLV. Anesthesia was induced and maintained with propofol, remifentanil, and rocuronium IV, and lung separation was achieved with a double-lumen tube. During OLV, we set positive end-expiratory pressure at 5 cm H2O, peak pressure at 30 cm H2O, and end-tidal CO2 at 30 mm Hg. The nonventilated lung was opened to room air and collapsed. During OLV, three consecutive measurements were performed every 10 min. The operated lung was temporarily ventilated if pulse oximetric saturation (Spo2) decreased to <91%. Spo2 <91% occurred in 2 of the 152 patients. Spo2 overestimated O2Hb by 2.9% ± 0.1%. NO failed to improve oxygenation or alter occurrence of O2Hb <90% during OLV across all time points and all levels of Fio2. Increasing Fio2 increased oxygenation and decreased occurrence of O2Hb <90% (P < 0.001). At Fio2 = 1, Pao2 was higher (P < 0.01) and O2Hb <90% rate tended to be lower (P = 0.1) during right versus left lung ventilation. Pao2 was higher in patients undergoing pneumonectomy and lobectomy than in those undergoing metastasectomy or video-assisted operations (P < 0.05).

Extravasation injury in the perioperative setting.

Extravasation is an unintentional injection or leakage of fluid in the perivascular or subcutaneous space. Extravasation injury results from a combination of factors, including solution cytotoxicity, osmolality, vasoconstrictor properties, infusion pressure, regional anatomical peculiarities, and other patient factors. We reviewed the hospital files of patients who had sustained a significant extravasation injury in the perioperative setting at two German hospitals. These cases highlight the risk of devastating consequences from extravasation injury. Vasoactive drugs and hyperosmolar and concentrated electrolyte solutions are the predominant vesicants in the perioperative setting. Prompt and appropriate intervention is important for avoiding or minimizing extensive tissue injury.

Percutaneous transtracheal ventilation: effects of a new oxygen flow modulator on oxygenation and ventilation in pigs compared with a hand triggered emergency jet injector

The application of percutaneous transtracheal jet ventilation for emergency ventilation depends on special equipment which is often not available outside the operating room. The oxygen flow modulator is a new specially designed device for emergency ventilation using a low pressure oxygen supply. We studied the effects of the new device in comparison with a hand triggered emergency jet injector on oxygenation and ventilation in six pigs (21+/-1 kg). The animals were anaesthetized, tracheally intubated, and mechanically ventilated. Following central venous and pulmonary artery catheterization, a Paratrend 7 sensor was placed in the left femoral artery for continuous measurements of PaO(2) and PaCO(2). Then an emergency transtracheal airway catheter was inserted into the trachea after surgical exposure. In randomized order each animal was ventilated via the transtracheal airway catheter with the hand triggered emergency jet injector (inspiratory/expiratory (I/E) ratio of 1:1; respiratory rate of 60 min(-1); driving pressure 1.5 bar; FjetO(2) 1.0) and the oxygen flow modulator (FiO(2) 1.0 at an oxygen flow of 15 l min(-1); respiratory rate of 60 min(-1); I/E ratio of approximately 1:1) for 15 min each. After each phase of the experiment respiratory and hemodynamic variables were measured. Whereas PaO(2) was not significantly different between the two devices, PaCO(2) was higher during the hand-triggered jet ventilation. Thus, the efficacy of the oxygen flow modulator during the experiment was comparable with the efficacy of the hand triggered emergency jet injector.

Protection with antibody to tumor necrosis factor differs with similarly lethal escherichia coli versus staphylococcus aureus pneumonia in rats

Background Differing factors may alter the effects of antibody to tumor necrosis factor (TNF) in infection and sepsis. The authors tested whether bacteria type or treatment route alters antibody to TNF in a rat model of bacterial pneumonia. Methods Rats (n = 231) received similarly lethal doses of either intratracheal Escherichia coli or Staphylococcus aureus followed by treatment with either intratracheal or intraperitoneal antibody to TNF or control serum. Animals received antibiotics (cefotiam daily dose, 100 mg/kg) starting 4 h after inoculation and were studied for up to 96 h. Results Compared with S. aureus, E. coli increased serum TNF and interleukin-6 concentrations, lung lavage TNF concentrations, neutrophil counts, and alveolar-to-arterial oxygen gradients and decreased circulating neutrophils and lymphocytes (P ≥ 0.05 for all). Compared with controls, with both bacteria, except for lung lavage TNF concentrations (which decreased with intratracheal but not with intraperitoneal antibody to TNF), treatment route did not alter the effects of antibody to TNF on any parameter (P = not significant for all). Antibody to TNF reduced mortality rates (relative risk of death ± SEM) with both E. coli (−1.6 ± 0.6;P = 0.006) and S. aureus (−0.5 ± 0.04;P = 0.185), but these reductions were greater with E. coli than with S. aureus in a trend approaching statistical significance (P = 0.09). Compared with controls, similarly (P = not significant) with both bacteria, antibody to TNF decreased lung lavage and tissue bacteria concentrations (both P < 0.05) and serum TNF concentration (P < 0.09) and increased circulating neutrophils and lymphocytes (both P ≤ 0.01). Compared with S. aureus, with E. coli antibody to TNF decreased alveolar-to-arterial oxygen gradients (P = 0.04) and increased serum interleukin-6 concentrations (P = 0.003). Conclusion Antibody to TNF improved host defense and survival rates with both lethal E. coli and S. aureus pneumonia, but protection was greater with E. coli, where TNF concentrations were higher than with S. aureus. The efficacy of antiinflammatory agents in sepsis may be altered by bacteria type.

The effects of increasing concentrations of isoflurane and desflurane on pulmonary perfusion and systemic oxygenation during one-lung ventilation in pigs.

During one-lung ventilation (OLV), hypoxic pulmonary vasoconstriction (HPV) reduces venous admixture and attenuates the decrease in arterial oxygen tension by diverting blood from the nonventilated lung to the ventilated lung. In vitro, desflurane and isoflurane depress HPV in a dose-dependent manner. Accordingly, we studied the effects of increasing concentrations of desflurane and isoflurane on pulmonary perfusion, shunt fraction, and Pao2 during OLV in vivo. Fourteen pigs (30–42 kg) were anesthetized, tracheally intubated, and mechanically ventilated. After placement of femoral arterial and thermodilution pulmonary artery catheters, a left-sided double-lumen tube (DLT) was placed via tracheotomy. After DLT placement, Fio2 was adjusted at 0.8 and anesthesia was continued in random order with 3 concentrations (0.5, 1.0, and 1.5 minimal alveolar concentrations) of either desflurane or isoflurane. Differential lung perfusion was measured with colored microspheres. All measurements were made after stabilization at each concentration. Whereas mixed venous Po2, mean arterial pressure, cardiac output, nonventilated lung perfusion, and shunt fraction decreased in a dose-dependent manner, Pao2 remained unchanged with increasing concentrations of desflurane and isoflurane during OLV. In conclusion, increasing concentration of desflurane and isoflurane did not impair oxygenation during OLV in pigs.