Arthur P. Wheeler

The effects of ibuprofen on the physiology and survival of patients with sepsis

BACKGROUND In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases, but the pathophysiologic role of these prostaglandins is unclear. In animal models, inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival. In pilot studies of patients with sepsis, treatment with ibuprofen led to improvements in gas exchange and airway mechanics. METHODS From October 1989 to March 1995, we conducted a randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (10 mg per kilogram of body weight [maximal dose, 800 mg], given every six hours for eight doses) in 455 patients who had sepsis, defined as fever, tachycardia, tachypnea, and acute failure of at least one organ system. RESULTS In the ibuprofen group, but not the placebo group, there were significant declines in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis. With ibuprofen therapy there was no increased incidence of renal dysfunction, gastrointestinal bleeding, or other adverse events. However, treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days (mortality, 37 percent with ibuprofen vs 40 percent with placebo). CONCLUSIONS In patients with sepsis, treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever, tachycardia, oxygen consumption, and lactic acidosis, but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival.

Acute lung injury and the acute respiratory distress syndrome: a clinical review

Acute respiratory distress syndrome and acute lung injury are well defined and readily recognised clinical disorders caused by many clinical insults to the lung or because of predispositions to lung injury. That this process is common in intensive care is well established. The mainstay of treatment for this disorder is provision of excellent supportive care since these patients are critically ill and frequently have coexisting conditions including sepsis and multiple organ failure. Refinements in ventilator and fluid management supported by data from prospective randomised trials have increased the methods available to effectively manage this disorder.

Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury

CONTEXT The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with γ-linolenic acid and antioxidants, may modulate systemic inflammatory response and improve oxygenation and outcomes in patients with acute lung injury. OBJECTIVE To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28. DESIGN, SETTING, AND PARTICIPANTS The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up. INTERVENTIONS Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement. MAIN OUTCOME MEASURE Ventilator-free days to study day 28. RESULTS The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vs 17.2; P = .02) (difference, -3.2 [95% CI, -5.8 to -0.7]) and intensive care unit-free days (14.0 vs 16.7; P = .04). Patients in the n-3 group also had fewer nonpulmonary organ failure-free days (12.3 vs 15.5; P = .02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P = .054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P = .11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P = .001). CONCLUSIONS Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00609180.

Randomized trial of initial trophic versus full-energy enteral nutrition in mechanically ventilated patients with acute respiratory failure*

Objective:Enteral nutrition is provided to mechanically ventilated patients who cannot eat normally, yet the amount of support needed is unknown. We conducted this randomized, open-label study to test the hypothesis that initial low-volume (i.e., trophic) enteral nutrition would decrease episodes of gastrointestinal intolerance/complications and improve outcomes as compared to initial full-energy enteral nutrition in patients with acute respiratory failure. Design:Randomized, open-label study. Patients:A total of 200 patients with acute respiratory failure expected to require mechanical ventilation for at least 72 hrs. Interventions:Patients were randomized to receive either initial trophic (10 mL/hr) or full-energy enteral nutrition for the initial 6 days of ventilation. Measurements and Main Results:The primary outcome measure was ventilator-free days to day 28. Baseline characteristics were similar between the 98 patients randomized to trophic and the 102 patients randomized to full-energy nutrition. At enrollment, patients had a mean Acute Physiology and Chronic Health Evaluation II score of 26.9 and a Pao2/Fio2 ratio of 182 and 38% were in shock. Both groups received similar durations of enteral nutrition (5.5 vs. 5.1 days; p = .51). The trophic group received an average of 15.8% ± 11% of goal calories daily through day 6 compared to 74.8% ± 38.5% (p < .001) for the full-energy group. Both groups had a median of 23.0 ventilator-free days (p = .90) and a median of 21.0 intensive-care-unit-free days (p = .64). Mortality to hospital discharge was 22.4% for the trophic group vs. 19.6% for the full-energy group (p = .62). In the first 6 days, the trophic group had trends for less diarrhea (19% vs. 24% of feeding days; p = .08) and significantly fewer episodes of elevated gastric residual volumes (2% vs. 8% of feeding days; p < .001). Conclusion:Initial trophic enteral nutrition resulted in clinical outcomes in mechanically ventilated patients with acute respiratory failure similar to those of early full-energy enteral nutrition but with fewer episodes of gastrointestinal intolerance.

Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome.

What is the problem and what is known about it so far? Elderly people are much more likely to develop respiratory failure and require the use of a respirator than younger people. On the other hand, the results of respirator use in the elderly do not appear to be as good as in younger people, but the exact relationship between age and outcome is uncertain. The National Heart, Lung, and Blood Institute (NHLBI) sponsored a large study on acute lung injury that leads to respiratory failure. The data were made available to other researchers for further analysis. Why did the researchers do this particular study? To find out how advancing age affects survival from acute lung injury and whether recovery takes longer in older patients. Who was studied? 902 patients at 24 U.S. hospitals who participated in the NHLBI study between 1996 and 1999. Patients were included in the study if they had acute lung injury requiring use of a respirator, had low oxygen levels, and had a chest x-ray indicating that the respiratory problem was not due to heart failure. Of the participants, 729 were younger than 70 years of age and 173 were 70 years of age or older. How was the study done? Patients were evaluated each day to see if a respirator was still needed. Depending on the results of these evaluations, patients were allowed to breathe on their own for 5 minutes; if they did well, additional time off the respirator was prescribed and respiratory assistance was eventually discontinued. The time required to reach each landmark of recovery was recorded, as were the length of stay in the intensive care unit and the survival rate. What did the researchers find? Seventy percent of the younger patients and 40% of the older patients were discharged from the hospital alive within the first 180 days. At the time of entry into the study, the severity of lung injury was similar in both age groups. Older patients needed the respirator longer, were more likely to require reinstitution of respirator therapy after initial improvement, and stayed in the intensive care unit longer than younger patients. At 28 days after initiation of respirator use, the survival rate was lower with each decade of advancing age. What were the limitations of the study? Several nonrespiratory health problems (such as brain abnormalities) were not carefully monitored but could have affected the results. In addition, older patients may have been more likely than younger patients to have had life support withdrawn because of poor general condition. Furthermore, preexisting illness was difficult to take into account in interpreting the results. What are the implications of the study? Although elderly patients seem to recover initially from acute lung injury at a rate similar to younger patients, they are more likely to return to mechanical ventilation and are more likely to die of their acute lung illness. Age alone should not be used as a criterion to deny respirator care. Rather, more effort should be made to improve outcomes in elderly people who develop acute lung failure.

A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis.

Objective:To evaluate whether TAK-242, a small-molecule inhibitor of Toll-like receptor-4–mediated signaling, suppresses cytokine levels and improves 28-day all-cause mortality rates in patients with severe sepsis. Design:Randomized, double-blind, placebo-controlled trial. Setting:A total of 93 intensive care units worldwide. Patients:A total of 274 patients with severe sepsis and shock or respiratory failure. Interventions:Patients were randomly assigned to receive a 30-min loading dose followed by 96-hr infusions of placebo, TAK-242 1.2 mg/kg/day, or TAK-242 2.4 mg/kg/day. Measurements and Main Results:The primary pharmacodynamic end point was change in serum interleukin-6 levels relative to baseline, with 28-day all-cause mortality rate the primary clinical end point. The trial was terminated because of a lack of effect of TAK-242 in suppressing serum interleukin-6 levels. A total of 274 subjects were randomly assigned and treated. Clinical parameters at baseline were balanced across the three groups. TAK-242 did not suppress interleukin-6 as measured by 0- to 96.5-hr area under the interleukin-6 concentration curve at either dose. Specifically, the area under the effect curve increased by 9% and 26.9% in the TAK-242 1.2 and 2.4 mg/kg/day groups, respectively, which was not statistically different from placebo (p = .63 and .15, respectively). The 28-day mortality rate was 24% in the placebo, 22% in the low-dose, and 17% in the high-dose group (p = .26 for placebo vs. high dose). A nonsignificant reduction in mortality rate was observed in a subset of patients with both shock and respiratory failure (placebo [n = 51], 33%, vs. high dose [n = 52], 19%, p = .10). Transient, dose-related increases in methemoglobin levels were observed with TAK-242 treatment in 30.1% of the patients. Conclusions:TAK-242 failed to suppress cytokine levels in patients with sepsis and shock or respiratory failure. Treatment with TAK-242 resulted in mild increases in serum methemoglobin levels but was otherwise well tolerated. Although observed mortality rates in patients with both shock and respiratory failure were lower with the 2.4 mg/kg/day dose, differences were not significant.

Effects of ibuprofen on the physiology and survival of hypothermic sepsis

OBJECTIVES The objective was to compare the clinical and physiologic characteristics of febrile septic patients with hypothermic septic patients; and to examine plasma levels of cytokines tumor necrosis factor alpha (TNF-alpha and interleukin 6 (IL-6) and the lipid mediators thromboxane B2 (TxB2) and prostacyclin in hypothermic septic patients in comparison with febrile patients. Most importantly, we wanted to report the effect of ibuprofen treatment on vital signs, organ failure, and mortality in hypothermic sepsis. SETTING The study was performed in the intensive care units (ICUs) of seven clinical centers in the United States and Canada. PATIENTS Four hundred fifty-five patients admitted to the ICU who met defined criteria for severe sepsis and were suspected of having a serious infection. INTERVENTION Ibuprofen at a dose of 10 mg/kg (maximum 800 mg) was administered intravenously over 30 to 60 mins every 6 hrs for eight doses vs. placebo (glycine buffer vehicle). MEASUREMENTS AND MAIN RESULTS Forty-four (10%) septic patients met criteria for hypothermia and 409 were febrile. The mortality rate was significantly higher in hypothermic patients, 70% vs. 35% for febrile patients. At study entry, urinary metabolites of TxB2, prostacyclin, and serum levels of TNF-alpha and IL-6 were significantly elevated in hypothermic patients compared with febrile patients. In hypothermic patients treated with ibuprofen, there was a trend toward an increased number of days free of major organ system failures and a significant reduction in the 30-day mortality rate from 90% (18/20 placebo-treated patients) to 54% (13/24 ibuprofen-treated patients). CONCLUSIONS Hypothermic sepsis has an incidence of approximately 10% and an untreated mortality twice that of severe sepsis presenting with fever. When compared with febrile patients, the hypothermic group has an amplified response with respect to cytokines TNF-alpha and IL-6 and lipid mediators TxB2 and prostacyclin. Treatment with ibuprofen may decrease mortality in this select group of septic patients.

Changing pattern of organ dysfunction in early human sepsis is related to mortality.

ObjectiveWe examined the pattern of organ system dysfunction, the evolution of this pattern over time, and the relationship of these features to mortality in patients who had sepsis syndrome. DesignProspective, multicenter, observational study. SettingIntensive care units in tertiary referral teaching hospitals. PatientsA total of 287 patients who had sepsis syndrome were prospectively identified in intensive care units. Materials and MeasurementsCardiovascular, pulmonary, neurologic, coagulation, renal, and hepatic dysfunction were assessed at onset and on day 3 of sepsis syndrome. Organ dysfunction was classified as normal, mild, moderate, severe, and extreme dysfunction. We calculated the occurrence rate and associated 30-day mortality rate of organ dysfunction at the onset of sepsis syndrome. We then measured the change in organ dysfunction from onset to day 3 of sepsis syndrome and determined, for individual organ systems, the associated 30-day mortality rate. ResultsAt the onset of sepsis syndrome, clinically significant pulmonary dysfunction was the most common organ failure, but was not related to 30-day mortality. Clinically significant cardiovascular, neurologic, coagulation, renal, and hepatic dysfunction were less common at the onset of sepsis syndrome but were significantly associated with the 30-day mortality rate. Worsening neurologic, coagulation, and renal dysfunction from onset to day 3 of sepsis syndrome were associated with significantly higher 30-day mortality than with improvement or no change in organ dysfunction. ConclusionsIncreased mortality rate in sepsis syndrome is associated with a pattern characterized by failure of nonpulmonary organ systems and, in particular, worsening neurologic, coagulation, and renal dysfunction over the first 3 days. Although initial pulmonary dysfunction is common in patients with sepsis syndrome, it is not associated with an increased mortality rate.

Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis.

ObjectiveStarling’s equation indicates that reduced oncotic pressure gradients will favor edema formation, and the current consensus definition of acute respiratory distress syndrome (ARDS) excludes only the hydrostatic pressure contribution. We hypothesized that low serum total protein levels might correlate with the likelihood of ARDS in at-risk patients because serum total protein is the chief determinant of oncotic pressure in humans. DesignRegression analysis to compare outcomes in patients with low serum total protein levels with outcomes in patients with normal serum total protein levels with respect to weight change, development of ARDS, and mortality. SettingIntensive care units (ICUs) of seven clinical centers in North America. PatientsA total of 455 ICU patients who met consensus criteria for severe sepsis (178 of whom developed ARDS) from a recently completed prospective clinical trial. InterventionNone. Measurements and Main ResultsWe found that 92% of the patients developing ARDS had low or borderline serum total protein levels (<6 g/dL). Logistic and multiple regression analyses confirmed that of 18 clinical variables, initial serum total protein level and protein change over time were the most statistically significant predictors of weight gain, prolonged mechanical ventilation, ARDS development, and mortality in the study population. This correlation remained significant after adjustment for the other major predictors of outcome present at baseline (ie, Acute Physiology and Chronic Health Evaluation II score). ConclusionsHypoproteinemia is significantly correlated with fluid retention and weight gain, development of ARDS and poor respiratory outcome, and mortality in patients with sepsis. Prospective, randomized trials of serum protein manipulation are needed to establish whether there is a cause-effect relationship to this association.

Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury

Objective: To identify biological and clinical predictors of acute kidney injury in subjects with acute lung injury. Design: Secondary data analysis from a multicenter, randomized clinical trial. Setting: Intensive care units in ten university medical centers. Patients: A total of 876 patients enrolled in the first National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial. Interventions: Study subjects were randomized to receive a low tidal volume ventilation strategy and pharmacologic therapy with ketoconazole or lisofylline in a factorial design. Measurements and Main Results: We tested the association of baseline levels of interleukin‐6, interleukin‐8, interleukin‐10, von Willebrand factor, tumor necrosis factor‐[alpha], type I and II soluble tumor necrosis factor receptors (sTNFR‐I and ‐II), protein C, plasminogen activator inhibitor‐1 (PAI‐1), surfactant protein‐A, surfactant protein‐D, and intracellular adhesion molecule‐1 with subsequent acute kidney injury. Of 876 study participants who did not have end‐stage renal disease, 209 (24%) developed acute kidney injury, defined as a rise in serum creatinine of >50% from baseline over the first four study days. The 180‐day mortality rate for subjects with acute kidney injury was 58%, compared with 28% in those without acute kidney injury (p < .001). Interleukin‐6, sTNFR‐I, sTNFR‐II, and PAI‐1 levels were independently associated with acute kidney injury after adjustment for demographics, interventions, and severity of illness. A combination of clinical and biological predictors had the best area under the receiver operating characteristic curve, and the contribution of sTNFR‐I and PAI‐1 to this model was highly significant (p = .0003). Conclusions: Elevations in PAI‐1, interleukin‐6, and the sTNFRs in subjects with acute kidney injury suggest that disordered coagulation, inflammation, and neutrophil–endothelial interactions play important roles in the pathogenesis of acute kidney injury. The combination of these biological and clinical risk factors may have important and additive value in predictive models for acute kidney injury.