Janice L. Zimmerman

Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock

ObjectiveTo develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis.DesignThe process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along 5 levels to create recommendation grades from A–E, with A being the highest grade. Pediatric considerations were provided to contrast adult and pediatric management.ParticipantsParticipants included 44 critical care and infectious disease experts representing 11 international organizations.ResultsA total of 46 recommendations plus pediatric management considerations.ConclusionsEvidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that will hopefully translate into improved outcomes for the critically ill patient. The impact of these guidelines will be formally tested and guidelines updated annually, and even more rapidly when some important new knowledge becomes available.

Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome : Results of a randomized phase II trial

OBJECTIVES To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). In addition, the effect of various doses of inhaled NO on clinical outcome parameters was assessed. DESIGN Prospective, multicenter, randomized, double-blind, placebo-controlled study. SETTING Intensive care units of 30 academic, teaching, and community hospitals in the United States. PATIENTS Patients with ARDS, as defined by the American-European Consensus Conference, were enrolled into the study if the onset of disease was within 72 hrs of randomization. INTERVENTIONS Patients were randomized to receive placebo (nitrogen gas) or inhaled NO at concentrations of 1.25, 5, 20, 40, or 80 ppm. MEASUREMENTS AND MAIN RESULTS Acute increases in PaO2, decreases in mean pulmonary arterial pressure, intensity of mechanical ventilation, and oxygenation index were examined. Clinical outcomes examined were the dose effects of inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygenation criteria for extubation. A total of 177 patients were enrolled over a 14-month period. An acute response to treatment gas, defined as a PaO2 increase > or =20%, was seen in 60% of the patients receiving inhaled NO with no significant differences between dose groups. Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs. The initial increase in oxygenation translated into a reduction in the FIO2 over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygenation index. There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation criteria for extubation. However, patients receiving 5 ppm inhaled NO showed an improvement in these parameters. In this dose group, the percentage of patients alive and off mechanical ventilation at day 28 (a post hoc analysis) was higher (62% vs. 44%) than the placebo group. There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo. Four patients had methemoglobin concentrations >5%. The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm. CONCLUSIONS From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome.

Use of a Rapid Assay of Subforms of Creatine Kinase MB to Diagnose or Rule Out Acute Myocardial Infarction

BACKGROUND Ruling out myocardial infarction in patients coming to the emergency room with chest pain is hindered by the lack of a specific early diagnostic marker. Less than 30 percent of patients admitted to coronary care units have infarction, resulting in substantial unnecessary expenditures. We developed a rapid assay of the subforms of creatine kinase MB (CK-MB) and prospectively analyzed its sensitivity and specificity in diagnosing myocardial infarction in the first six hours after the onset of chest pain. METHODS In 1110 consecutive patients who came to the emergency room with chest pain, blood samples were collected every 30 to 60 minutes until at least 6 hours after the onset of symptoms; in patients who were then admitted to the hospital, samples were collected every 4 hours for up to 48 hours. The samples were analyzed for CK-MB subforms, and the diagnosis of myocardial infarction was confirmed by conventional CK-MB analysis. RESULTS Of the 1110 patients evaluated, 121 had myocardial infarction. The sensitivity of the assay of CK-MB subforms to detect myocardial infarction in the first six hours after the onset of symptoms was 95.7 per cent, as compared with only 48 percent for the conventional CK-MB assay; the specificity was 93.9 percent among patients hospitalized without myocardial infarction and 96.2 percent among those sent home. Among the patients with myocardial infarction, definitive results of the subform assay were available a mean (+/- SD) of 1.22 +/- 1.17 hours after their arrival in the emergency room. CONCLUSIONS The assay of CK-MB subforms reliably detected myocardial infarction within the first six hours after the onset of symptoms, and its use could reduce admission to the coronary care unit by 50 to 70 percent, thereby reducing costs.

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication

RATIONALE We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. OBJECTIVES We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. METHODS We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. MEASUREMENTS AND MAIN RESULTS Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). CONCLUSIONS Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

Endotracheal intubation and mechanical ventilation in severe asthma

Objective:To determine the occurrence rate of complications and mortality in patients with severe asthma requiring endotracheal intubation and mechanical ventilation. Design:Retrospective review of medical records from September 1982 to July 1988. Setting:Urban, teaching hospital serving primarily indigent patients. Patients:Fifty-seven adult patients with asthma requiring tracheal intubation and mechanical ventilation.Interventions: None. Measurements and Main Results:Fifty-seven patients requiring tracheal intubation and mechanical ventilation during 69 hospital admissions were identified. Medication noncompliance and upper respiratory tract infections were recorded as the most frequent precipitating events for exacerbation of asthma. Forty-nine intubations were initiated because of a clinical diagnosis of respiratory distress, but multiple indications were present in 42 admissions. One or more complications occurred in 31 episodes of endotracheal intubation and mechanical ventilation (45%). Death occurred in four (6%) of 69 admissions. Three of the four deaths occurred in patients who had a cardiorespiratory arrest before hospital admission. Conclusions:While complications occurred in 45% of patients with severe asthma requiring intubation and mechanical ventilation, the mortality rate was low. We conclude that intubation and mechanical ventilation in patients with life-threatening asthma are safe and beneficial interventions. (Crit Care Med 1993; 21:1727–1730)

Poisonings and overdoses in the intensive care unit: general and specific management issues.

ObjectiveTo provide current information on general and specific interventions for overdoses likely to require intensive care. DesignReview of literature relevant to selected interventions for general management of overdoses and specific poisons. ResultsThe benefit of interventions to decrease absorption or enhance elimination of toxins is limited to a relatively small number of specific agents. Antidotes and certain interventions may be helpful in preventing or treating toxicity in specific poisonings when used appropriately. Intensive supportive care is also necessary to achieve good outcomes. ConclusionKnowledge of the indications and limitations of current interventions for poisonings and overdoses is important for care of the critically ill poisoned patient.

Initial evaluation of a new intra-arterial blood gas system in humans.

ObjectiveTo evaluate the in vivo performance of a continuous intra-arterial blood gas monitor as compared with in vitro arterial blood gases for measurements of Pao2, Paco2, and arterial pH. DesignConsecutive patient enrollment. SettingMedical intensive care unit of a county teaching hospital. PatientsFive critically ill patients. InterventionsAll patients had a fiberoptic sensor placed through a 20-gauge cannula inserted into the radial artery. Sensor and arterial blood gas measurements were monitored up to 68 hrs. Arterial blood gases were analyzed on two blood gas analyzers. Measurements and Main ResultsA total of 104 arterial blood gases were obtained for comparison of sensor measurements with blood gas analyzer values. Comparison of the sensor values with the blood gas analyzer values showed bias and precision values of −0.021 and 0.037 for arterial pH, 1.74 and 6.06 torr (0.23 and 0.81 kPa) for Paco2, and −5.89 and 13.19 torr (-0.79 and 1.76 kPa) for Pao2, respectively. Comparison of the two blood gas analyzer measurements showed bias and precision values of −0.030 and 0.010 for arterial pH, 1.96 and 2.55 torr (0.26 and 0.34 kPa) for Paco2, and −5.77 and 17.15 torr (-0.77 and 2.29 kPa) for Pao2, respectively. No complications attributable to the sensor were detected. ConclusionsThe performance of this fiberoptic continuous intra-arterial blood gas monitor is comparable to that of blood gas analyzers and compares favorably with previously reported studies utilizing other sensors in reliably and reproducibly approximating Pao2, Paco2, and arterial pH values. This monitoring capability was accomplished with no patient morbidity. Further study is indicated to confirm these initial results and to establish the role of a continuous intra-arterial blood gas monitor in critically ill patients. (Crit Care Med 1993;21:495–500)

Phase I trial of the recombinant soluble complement receptor 1 in acute lung injury and acute respiratory distress syndrome.

ObjectiveTo determine the safety, pharmacokinetics, biological effects, and immunogenicity of recombinant soluble complement receptor 1 (TP10) in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). DesignOpen label, ascending dosage, phase I trial. SettingTwo academic teaching hospitals. PatientsA total of 24 patients diagnosed with ALI/ARDS. InterventionA single, 30-min intravenous infusion of 0.1, 0.3, 1, 3, or 10 mg/kg TP10. Measurements and Main ResultsSerum levels of TP10 increased in proportion to the dose. Mean variable estimates (± sd) were half-life of disposition 69.7 ± 39.7 hrs, plasma clearance 2.39 ± 1.32 mL/hr/kg, and volume of distribution 190.6 ± 135.0 mL/kg. Inhibition of complement activity, measured by CH50, was significant for the interaction of dose and time (p = .024). The C3a levels demonstrated a trend for dose which did not reach statistical significance (p = .090) and soluble C5b-9 levels were significant only for dose (p = .023). As expected by the proposed physiologic mechanism, C4a levels were not affected by TP10, dose, or time. The overall mortality rate was 33%. Neither the type nor the frequency rate of specific adverse events were substantially different between dose groups. Seven adverse events in four patients were thought to be possibly related to TP10. ConclusionsTP10 has a half-life of ∼70 hrs and at doses ≥1 mg/kg, significantly inhibits complement activity at the levels of C3 and C5 in patients with ALI/ARDS. Complement inhibition was more prolonged over time with TP10 doses of 3 and 10 mg/kg. TP10 appears to be safe at the doses tested. Further studies will be required to completely assess the impact of TP10 on pathophysiology and clinical outcome in patients with ALI/ARDS.

Cocaine-associated chest pain

STUDY OBJECTIVES To describe the clinical and ECG features of cocaine abusers evaluated in the emergency department and admitted to the medical coronary care unit with chest pain consistent with myocardial ischemia. DESIGN A four-month retrospective review of all cocaine abusers who presented to the ED with chest pain and a diagnosis of possible myocardial infarction. SETTING Urban county hospital. TYPE OF PARTICIPANTS Forty-eight adult cocaine abusers admitted with chest pain. MEASUREMENTS AND MAIN RESULTS Patients included 34 men and 14 women with a mean age of 29 +/- 7.3 years. The average duration of cocaine abuse in 28 patients for whom it was reported was 5 +/- 4.8 years. Chest pain occurred within one hour of cocaine abuse in 13 admissions (27%), more than one hour after abuse in 13 admissions (27%), and it was not recorded in 23 admissions (47%). Initial ECGs were evaluated in all patients and revealed significant repolarization abnormalities consisting of abnormal ST segment elevations in 18 (37%) and T-wave inversions in 20 (41%) that often persisted on subsequent ECGs. Three patients sustained acute myocardial infarctions. CONCLUSIONS Our findings confirm a small but significant incidence of myocardial infarction in cocaine abusers presenting to the ED with chest pain. The chronicity of cocaine abuse, the persistence of ECG abnormalities, and the variable temporal relationship of chest pain to cocaine abuse suggest possible chronic myocardial changes as etiologies of ischemia.

Recommendations for intensive care unit and hospital preparations for an influenza epidemic or mass disaster: Summary report of the European Society of Intensive Care Medicine's Task Force for intensive care unit triage during an influenza epidemic or mass disaster

PurposeTo provide recommendations and standard operating procedures for intensive care units and hospital preparedness for an influenza pandemic.MethodsBased on a literature review and expert opinion, a Delphi process was used to define the essential topics.ResultsKey recommendations include: Hospitals should increase their ICU beds to the maximal extent by expanding ICU capacity and expanding ICUs into other areas. Hospitals should have appropriate beds and monitors for these expansion areas. Establish a management system with control groups at facility, local, regional and/or national levels to exercise authority over resources. Establish a system of communication, coordination and collaboration between the ICU and key interface departments. A plan to access, coordinate and increase labor resources is required with a central inventory of all clinical and non-clinical staff. Delegate duties not within the usual scope of workers’ practice. Ensure that adequate essential medical equipment, pharmaceuticals and supplies are available. Protect patients and staff with infection control practices and supporting occupational health policies. Maintain staff confidence with reassurance plans for legal protection and assistance. Have objective, ethical, transparent triage criteria that are applied equitably and publically disclosed. ICU triage of patients should be based on the likelihood for patients to benefit most or a ‘first come, first served’ basis. Develop protocols for safe performance of high-risk procedures. Train and educate staff.ConclusionsMortality, although inevitable during a severe influenza outbreak or disaster, can be reduced by adequate preparation.