Linda A. Kirschenbaum

Microvascular response in patients with cardiogenic shock.

Objective: To examine the mechanisms contributing to decreased microvascular blood flow in cardiogenic shock by comparing patients with cardiogenic shock with critically ill controls and with patients with septic shock. Design: Prospective, consecutive entry of patients meeting the criteria for septic shock, cardiogenic shock, and critical illness without coexisting infection or shock. Setting: University hospital, medical intensive care unit, coronary care unit, and respiratory care unit. Patients: Eight patients with cardiogenic shock secondary to acute myocardial infarction, six critically ill controls, and six patients with septic shock. Measurements and Main Results: Forearm blood flow was measured at rest and during reactive hyperemia by venous air plethysmography. Red cell deformability was determined by filtration. Leukocyte aggregation was detected by the leukergy test. Neutrophil CD11b/CD18 expression and soluble intercellular adhesion molecule‐1 levels were also measured. In cardiogenic shock, forearm arterial resistance was significantly increased at rest and during reactive hyperemia compared with controls and patients with septic shock. The response to reactive hyperemia was attenuated in cardiogenic and septic shock patients, as measured by the absolute change in forearm blood flow from baseline, which was significantly less as compared with controls (p < .01). The percent change in forearm blood flow during reactive hyperemia compared with forearm blood flow at rest was significantly lower in cardiogenic shock (60 ± 10) and in septic shock (50 ± 11) compared with controls at baseline (145 ± 20; p < .01). Red cell deformability was significantly decreased in cardiogenic shock (1.2 ± 0.2 mL/min; p < .05) and septic shock (1.1 ± 0.2 mL/min; p < .05), compared with controls (1.8 ± 0.1 mL/min). Neutrophil CD11b/CD18 expression, leukergy, and serum intercellular adhesion molecule‐1 levels in cardiogenic shock patients were not significantly different from controls. Conclusion: These data suggest that the response to reactive hyperemia is attenuated in cardiogenic shock. This appears to reflect increased vasoconstriction and an impaired capacity for vasodilation. Decreased erythrocyte deformability may also be important in limiting systemic microvascular flow. However, evidence supporting a role for neutrophil‐endothelial cell interactions was not observed.

The experience at St. Vincent's Hospital, Manhattan, on September 11, 2001: preparedness, response, and lessons learned.

St. Vincent’s Hospital in New York City was the primary recipient of patients after the 1993 bombing of the World Trade Center. This experience prompted the drafting of a formal disaster plan, which was implemented during the terrorist attack on the World Trade Center on September 11, 2001. Here, we outline the Emergency Management External Disaster Plan of St. Vincent’s Hospital and discuss the time course of presentation and medical characteristics of the critically injured patients on that day. We describe how the critical care service adapted to the specific challenges presented and the lessons that we learned. We hope to provide other critical care systems with a framework for response to such large-scale disasters.

Mechanisms of platelet-neutrophil interactions and effects on cell filtration in septic shock

We examined the mechanisms and the adhesive molecules mediating platelet-neutrophil adhesion in patients with septic shock. Neutrophils, platelets, and platelet poor plasma (NPPP) were isolated from 12 normal volunteers. Platelets and neutrophils were stimulated with platelet poor plasma (SPPP) removed from 12 patients in septic shock. Cell adhesion was assessed by filtration through 5-&mgr;m pore filters and by flow cytometry. Blocking monoclonal antibodies were used against the platelet and neutrophil surface receptors glycoprotein complex IIb/IIIa, P-selectin, ICAM-2, CD11a, CD11b, and CD18. The filtration pressure (Pi) of cells suspended in SPPP was significantly greater than that of cells suspended in NPPP (24 ± 1.0 mmHg vs. 14 ± 1.0 mmHg;P < 0.05). The difference between the Pi of cells suspended in SPPP or NPPP (&Dgr;Pi SPPP-NPPP) in the presence of monoclonal antibodies anti-CD41, anti-CD62P, abciximab, anti-CD11a, anti-CD11b, and anti-CD18 was significantly less than the &Dgr;Pi SPPP-NPPP of cell suspensions without the addition of these monoclonal antibodies (P < 0.01). The greatest reduction in Pi occurred when platelet receptor P-selectin was blocked simultaneously with the CD11b receptor on the neutrophil as compared to all other single blocking monoclonal antibodies or combinations of monoclonal antibodies. The mean fluorescence of activated platelet CD63-PE binding to neutrophils suspended in SPPP was significantly greater than that of cells suspended in NPPP (780 ± 130 lfu vs. 295 ± 35 lfu;P < 0.05). The greatest attenuation in mean fluorescence occurred by blocking the P-selectin receptor on the platelet simultaneously with CD11b receptor on the neutrophil. We conclude that platelet-neutrophil aggregation is increased in septic shock. This aggregation is mediated by the interaction of multiple platelet and neutrophil surface receptors. The platelet receptor P-selectin and the neutrophil receptor CD11b/CD18 appear to play the most important role in these interactions.

Improved Clinical Outcomes Combining House Staff Self-Assessment with an Audit-Based Quality Improvement Program

ABSTRACTBACKGROUNDThere is a focus on integrating quality improvement with medical education and advancement of the American College of Graduate Medical Education (ACGME) core competencies.OBJECTIVETo determine if audits of patients with unexpected admission to the medical intensive care unit using a self-assessment tool and a focused Morbidity and Mortality (M&M) conference improves patient care.DESIGNCharts from patients transferred from the general medical floor (GMF) to the medical intensive care unit (ICU) were reviewed by a multidisciplinary team. Physician and nursing self-assessment tools and a targeted monthly M&M conference were part of the educational component.PARTICIPANTSPhysicians and nurses participated in root cause analysis.MEASURESRecords of all patients transferred from a general medical floor (GMF) to the ICU were audited. One hundred ninety-four cases were reviewed over a 10-month period.RESULTSNew policies regarding vital signs and house staff escalation of care were initiated. The percentage of calls for patients who met medical emergency response team/critical care consult criteria increased from 53% to 73%, nurse notification of a change in a patient’s condition increased from 65% to 100%, nursing documentation of the change in the patients condition and follow-up actions increased from 65% percent to a high of 90%, the number of cardiac arrests on a GMF decreased from 3.1/1,000 discharges to 0.6/1,000 discharges (p = 0.002), and deaths on the Medicine Service decreased from 34/1,000 discharges to 24/1,000 discharges (p = 0.024).CONCLUSIONWe describe an audit-based program that involves nurses, house staff, a self-assessment tool and a focused M&M conference. The program resulted in significant policy changes, more rapid assessment of unstable patients and improved hospital outcomes.

The effect of resuscitation fluids on neutrophil-endothelial cell interactions in septic shock.

Fluid resuscitation is essential in the treatment of septic shock. This study examined the effect of resuscitative fluids (RFs) on sepsis-induced neutrophil-endothelial cell interactions. The RFs studied were 0.9% saline (NS), Ringers lactate (RL), 7.5% saline and dextran-70 (DHS), 5% albumin (AL), and 6% hydroxyethyl starch (HS). Platelets and neutrophils were obtained from normal volunteers, and plasma was obtained from patients with septic shock. Microslides coated with human umbilical endothelial vein cell (HUVEC) and platelet-neutrophil solutions were primed with septic plasma with/without the RF. Neutrophil rolling velocity, leukoaggregation, and neutrophil adherence were determined. Separately, platelet-neutrophil solutions and endothelial cells were exposed to septic plasma with/without RFs, and cellular activation, neutrophil superoxide production, and endothelial cell E-selectin expression were assessed. Ringers lactate decreased neutrophil rolling velocity and increased aggregation and adherence. Normal saline had no effect on these parameters. Hydroxyethyl starch and AL increased neutrophil rolling velocity and decreased adherence and aggregation when HUVECs were preincubated with the RF. Dextran-70 and 7.5% saline decreased neutrophil-endothelial cell interactions in both HUVECs and platelet/neutrophil preincubated experiments. Ringers lactate increased activation of neutrophils and platelets, whereas AL decreased their activation. Other than NS, all the RFs increased neutrophil superoxide production. Ringers lactate increased endothelial cell E-selectin release, whereas AL and HS both decreased its release. These data suggest that fluids used in the resuscitation of septic shock vary in their effects on sepsis-induced neutrophil-endothelial cell interactions. Ringers lactate amplifies the effects of sepsis, while NS appears to have minimal impact. Dextran-70 and 7.5% saline, AL, and HS in varying degrees decrease sepsis-related neutrophil-endothelial cell interactions and activation.

Augmentation of platelet and endothelial cell eNOS activity decreases sepsis-related neutrophil-endothelial cell interactions.

NO is an important mediator of microvascular patency and blood flow. The purpose of this study was to examine the role of enhanced eNOS activity in attenuating sepsis-induced neutrophil-endothelial cell interactions. Microslides coated with human umbilical vein endothelial cells were stimulated with plasma from patients with septic shock. Neutrophil and platelets from control subjects were also stimulated with plasma from patients in septic shock and perfused over stimulated endothelial cells. l-Arginine (LA) with and without NG-monomethyl l-arginine (LNMMA), a nonselective NOS inhibitor, and N-(3-(aminomethyl) benzyl acetamide) ethanimidamide dihydrochloride (1400W), a highly selective iNOS inhibitor, were added to the septic plasma. The number of neutrophils adherent to endothelial cells, neutrophil rolling velocity, and the number of neutrophil aggregates were determined. Cell activation and the formation of platelet-neutrophil aggregates were assessed by flow cytometry. Separate experiments were done with isolated platelets using platelet aggregometry. l-Arginine significantly decreased sepsis-related neutrophil adhesion and aggregation and increased rolling velocity. The addition of LNMMA to LA and cell suspensions reversed the effects of LA on these parameters, whereas the addition of 1400W had no effect on LA-related changes. Platelet-neutrophil aggregation, platelet aggregation, platelet activation, and neutrophil activation induced by septic plasma were also significantly decreased by LA. Again, the addition of LNMMA reversed the effects of LA on these parameters, whereas 1400W had no effect on LA-related changes. These data suggest that enhancement of platelet and endothelial cell eNOS activity decreases sepsis-induced neutrophil-endothelial cell interactions and may play a role in maintaining microvascular patency in septic shock.

Effect of recombinant activated protein C and low-dose heparin on neutrophil-endothelial cell interactions in septic shock

Objective:To examine the effects of recombinant activated protein C (rhAPC) and low-dose heparin on neutrophil-platelet-endothelial cell interactions in septic shock. Design:Controlled experiments using phase contrast microscopy to study neutrophil, platelet, and endothelial cell interactions in flowing cell suspensions under simulated physiologic conditions. Setting:University research laboratory. Patients:Adult patients with septic shock and normal volunteers. Interventions:Neutrophils and platelets removed from control subjects were stimulated with plasma and serum from 21 patients in septic shock and perfused over endothelial cells. Activated protein C, low-dose heparin, and low-dose heparin with rhAPC were added to cells suspended in septic plasma. Neutrophil rolling velocity and the number of neutrophils adherent to endothelial cells and in aggregates were determined. Flow cytometric analysis of CD11b/CD63 cells was used to identify platelet-neutrophil aggregates. Measurements and Main Results:Activated protein C significantly decreased neutrophil adhesion and aggregation and increased rolling velocity in cells stimulated with both septic serum and septic plasma. Significant decreases in platelet-neutrophil aggregates induced by septic plasma were also observed. Low-dose heparin alone had no effects on these variables. The addition of low-dose heparin to cells suspended in septic plasma and rhAPC attenuated the benefits observed with rhAPC alone in each of these variables. Conclusions:These data suggest that the in vitro addition of rhAPC decreases sepsis-induced interactions between isolated platelets, neutrophils, and endothelial cells. Low-dose heparin attenuates the benefits observed with rhAPC. The changes in neutrophil-endothelial cell interactions demonstrated with rhAPC may play a role in preserving microvascular patency in patients with septic shock.

The effect of anticoagulants and the role of thrombin on neutrophil-endothelial cell interactions in septic shock.

To examine the effects of anticoagulants and the role of thrombin on neutrophil-platelet-endothelial cell interactions in septic shock. Controlled experiments using phase-contrast microscopy to study neutrophil, platelet, and endothelial cell interactions in flowing cell suspensions under simulated physiologic conditions. University research laboratory. Adult patients with septic shock and normal volunteers. Microslides were coated with human umbilical vein endothelial cells. Neutrophils and platelets removed from control subjects were stimulated with plasma from patients in septic shock and perfused over endothelial cells. Heparin (H), argatroban (A), antithrombin III (ATIII), and recombinant human activated protein C (rhAPC) with and without thrombin were added to cells suspended in septic plasma and normal plasma. The number of neutrophils adherent to endothelial cells, neutrophil rolling velocity, and the number of neutrophils in aggregates were determined. Flow cytometric analysis of cells was used to identify cell activation and the formation of platelet-neutrophil aggregates. Heparin, A, ATIII, rhAPC all significantly decreased neutrophil adhesion and aggregation, and increased rolling velocity of neutrophils suspended in septic plasma. These results are similar to those observed with normal plasma but present greater absolute changes. Platelet-neutrophil aggregation, platelet activation, and neutrophil activation were significantly decreased by each of the anticoagulants. The addition of thrombin to cell suspensions containing anticoagulants reversed the effects of H, A, ATIII, rhAPC on neutrophil adhesion, adherence, and rolling velocity. In addition, thrombin attenuated the effects of each of these agents on platelet-neutrophil aggregation, platelet activation, and neutrophil activation. These data suggest that H, A, ATIII, and rhAPC decrease sepsis-induced neutrophil-endothelial cell interactions. The reversal of this effect by thrombin suggests that these agents alter neutrophil-endothelial interactions through their anticoagulant effects and the resulting decrease in thrombin activity.

Acute pancreatitis: a possible role for activated protein C?

Acute pancreatitis results from a sequence of events that involve the systemic inflammatory response. Activated C has multiple anti-inflammatory activities and may attenuate the degree of pancreatic injury and systemic organ dysfunction when infused early in pancreatitis