Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy.

BACKGROUND: Coagulopathy has a high prevalence in critically ill patients. An increased International Normalized Ratio (INR) is a common trigger to transfuse fresh frozen plasma (FFP), even in the absence of bleeding. Therefore, FFP is frequently administered to these patients. However, the efficacy of FFP in correcting hemostatic disorders in non-bleeding recipients has been questioned. OBJECTIVES: To assess whether INR prolongation parallels changes in the results of other tests investigating hemostasis, and to evaluate the coagulant effects of a fixed dose of FFP in non-bleeding critically ill patients with a coagulopathy. METHODS: Markers of coagulation, individual factor levels and levels of natural anticoagulants were measured. Also, thrombin generation and thromboelastometry (ROTEM) assays were performed before and after FFP transfusion (12 mL kg(-1) ) to 38 non-bleeding critically ill patients with an increased INR (1.5-3.0). RESULTS: At baseline, levels of factor II, FV, FVII, protein C, protein S and antithrombin were reduced, and thrombin generation was impaired. ROTEM variables were within reference ranges, except for a prolonged INTEM clot formation time. FFP transfusion increased the levels of coagulation factors (FII, 34% [interquartile range (IQR) 26-46] before vs. 44% [IQR 38-52] after; FV, 48% [IQR 28-76] before vs. 58% [IQR 44-90] after; and FVII, 25% [IQR 16-38] before vs. 37% [IQR 28-55] after), and the levels of anticoagulant proteins. Thrombin generation was unaffected by FFP transfusion (endogenous thrombin potential, 72% [IQR 51-88] before vs. 71% [IQR 42-89] after), whereas ROTEM EXTEM clotting time and maximum clot firmness slightly improved in response to FFP. CONCLUSION: In non-bleeding critically ill patients with a coagulopathy, FFP transfusion failed to induce a more procoagulant state.

Evaluation of a multi-center randomised clinical trial on prophylactic transfusion of fresh frozen plasma: implications for future trials.

BACKGROUND: Prophylactic use of fresh frozen plasma (FFP) in critically ill patients with a coagulopathy is common. However, a lack of evidence of efficacy has resulted in a call for trials on the benefit of FFP in these patients. To date, conducting a trial on this subject has not been successful. Recently, a multi-center randomised trial was stopped prematurely due to slow inclusion. OBJECTIVE: To assess clinicians' opinions regarding a trial on prophylactic administration of FFP in coagulopathic critically ill patients who need to undergo an intervention. METHODS: A survey among 55 intensivists who all participated in a randomised trial on the risks and benefits of FFP in critically ill patients. RESULTS: Response rate was 84%. Majority of respondents indicated that international normalised ratio (INR) should be assessed before insertion of a central venous catheter (CVC) (61%), chest tube (89%) or tracheostomy (91%). Reasons to withhold transfusion of FFP to non-bleeding critically ill patients are risk of transfusion-related acute lung injury (TRALI) (46%), fluid overload (39%) and allergic reaction (24%). Although, the majority of respondents expressed the opinion that the trial was clinically relevant, 56% indicated that ≥1 patient subgroups should have been excluded from participation. CONCLUSION: Intensivists express the need for more evidence on the prophylactic use of FFP in coagulopathic critically ill patients. However, lack of knowledge about FFP and personal beliefs about the preferable transfusion strategy among clinicians, resulted in premature termination of a clinical trial on this topic.

The effect of C1-inhibitor in a murine model of transfusion-related acute lung injury.

BACKGROUND AND OBJECTIVE: Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality. Specific therapy is lacking. We assessed whether C1-inhibitor attenuates lung injury in a 'two-hit' TRALI model. METHODS: Mice were primed with lipopolysaccharide, subsequently TRALI was induced by MHC-I antibodies. In the intervention group, C1-inhibitor was infused concomitantly. Mice were supported with mechanical ventilation. After 2 h, mice were killed, lungs were removed and bronchoalveolar lavage fluid (BALF) was obtained. RESULTS: Injection of MHC-I antibodies induced TRALI, illustrated by an increase in wet-to-dry ratio of the lungs, in BALF protein levels and in lung injury scores. TRALI was further characterized by complement activation, demonstrated by increased BALF levels of C3a and C5a. Administration of C1-inhibitor resulted in increased pulmonary C1-inhibitor levels with high activity. C1-inhibitor reduced pulmonary levels of complement C3a associated with improved lung injury scores. However, levels of pro-inflammatory mediators were unaffected. CONCLUSION: In a murine model of TRALI, C1-inhibitor attenuated pulmonary levels of C3a associated with improved lung injury scores, but with persistent high levels of inflammatory cytokines.

Monitoring of unfractionated heparin in critically ill patients.

BACKGROUND: In critically ill patients, dosing of unfractionated heparin (UFH) is difficult due to unpredictable pharmacokinetics, which has an impact on the time to reach therapeutic anticoagulation. We evaluated the quality of UFH therapy in critically ill patients in terms of activated partial thromboplastin time (APTT) test values and time to therapeutic range. METHODS: Patients admitted to the Intensive Care Unit (ICU) and Medium Care Unit (MCU) were screened for intravenous UFH administration. Time to therapeutic range was categorised into 0-12, 13-24 and >24 hours. APTT results were classified into categories of subtherapeutic, supratherapeutic and therapeutic tests. We identified to what extent the sub- and upratherapeutic values were aberrant of the limit of the therapeutic range (15%). RESULTS: In 101 patients admitted to the ICU and MCU, time to therapeutic range was 24 hours in 56% of the population, whereas in 10% of the patients no therapeutic APTT was achieved during UFH treatment. Among the APTT levels, 29% of all test results measured in 24 hours were within the therapeutic range. Subtherapeutic values were found in 53% of the test results, of which 160/203 were more than 15% under the lower limit, whereas 18% of the test results were supratherapeutic, of which 40/69 more than 15% above the upper limit. CONCLUSION: In this cohort of critically ill patients, therapeutic APTT values were reached within 24 hours in 56% of the patients. We conclude that intravenous UFH therapy can be improved in critically ill patients.

Manual hyperinflation is associated with a low rate of adverse events when performed by experienced and trained nurses in stable critically ill patients--a prospective observational study.

BACKGROUND: Manual hyperinflation (MH) can be performed as part of airway management in intubated and mechanically ventilated patients to mobilize airway secretions. Although previous studies demonstrated MH to be associated with hemodynamic and respiratory instability, we hypothesized MH to cause fewer adverse events (AEs) when performed by experienced and trained nurses in stable critically ill patients. METHODS: The incidence and type of AEs associated with MH were studied in a 28-bed mixed medical-surgical Intensive Care Unit. A difference in mean arterial pressure (MAP) or heart rate (HR) >15%, a decrease in peripheral oxygen saturation (SpO2) >5%, and a change in end-tidal (et)-CO2 >20% were considered AEs. A decrease of MAP to ≤60 mmHg, any new arrhythmia, and a decrease of SpO2 ≤90% were all considered severe AEs. Also, all changes in medication were considered severe AEs. RESULTS: A total of 107 MH maneuvers in 74 patients, performed by 57 nurses, were observed and analyzed. A total of 17 MH maneuvers (16%) were associated with any AE; 7 maneuvers (6%) were associated with a severe AE. Overall, MH did not affect MAP. MH caused a statistically significant but clinically irrelevant increase of HR (from 87±24 to 89±22 bpm). In one patient the MAP dropped from 70 mmHg to 60 mmHg, requiring adjustment of vasopressor therapy; one patient developed ventricular tachycardia requiring electric cardioversion. In general, MH did not affect SpO2. In one patient SpO2 dropped below 90%, requiring additional oxygen supply for 10 minutes. MH caused a statistically significant but clinically irrelevant increase of et-CO2 levels (from 4.4±0.9 to 4.5±1.0 kPa). Five patients developed anxiety/agitation during or shortly after MH, mandating additional sedation in four patients. Occurrence of (severe) AEs was not associated with any specific patient or MH characteristic. CONCLUSION: The rate of hemodynamic and respiratory AEs with MH is low when performed by experienced and trained nurses in stable, critically ill patients. MH, however, may induce or increase anxiety/agitation. We consider MH a safe maneuver in stable ICU patients in our setting.

Reliability and accuracy of Sequential Organ Failure Assessment (SOFA) scoring.

OBJECTIVE: The Sequential Organ Failure Assessment (SOFA) score was developed to quantify the severity of patients' illness, based on the degree of organ dysfunction. This study aimed to evaluate the accuracy and the reliability of SOFA scoring. DESIGN: Prospective study. SETTING: Adult intensive care unit (ICU) in a tertiary academic center. SUBJECTS: Thirty randomly selected patient cases and 20 ICU physicians. MEASUREMENTS AND MAIN RESULTS: Each physician scored 15 patient cases. The intraclass correlation coefficient was .889 for the total SOFA score. The weighted kappa values were moderate (0.552) for the central nervous system, good (0.634) for the respiratory system, and almost perfect (>0.8) for the other organ systems. To assess accuracy, the physicians' scores were compared with a gold standard based on consensus of two experts. The total SOFA score was correct in 53% (n = 158) of the cases. The mean of the absolute deviations of the recorded total SOFA scores from the gold standard total SOFA scores was 0.82. Common causes of errors were inattention, calculation errors, and misinterpretation of scoring rules. CONCLUSIONS: The results of this study indicate that the reliability and the accuracy of SOFA scoring among physicians are good. We advise implementation of additional measures to further improve reliability and accuracy of SOFA scoring.

[Monitoring and treatment of patients with shock in the intensive care unit]. / Bewaking en behandeling van patiënten met shock op de intensivecareafdeling.

The controversy surrounding the use of the pulmonary artery catheter, has stimulated research into alternative methods of haemodynamic monitoring. As yet, however, no new gold standard has emerged. In the future, interest in haemodynamic monitoring is likely to focus more on tissue perfusion and metabolism instead of central circulation. Important causes of shock in the ICU, apart from acute blood loss, are sepsis and acute heart failure. Septic shock results from vasodilatation and myocardial dysfunction. Early initiation of aggressive fluid resuscitation, if necessary accompanied by vasoactive and inotropic agents, improves survival. In addition, low dose corticosteroids have a positive impact on mortality. In the treatment of patients with acute heart failure, phosphodiesterase III-inhibitors are becoming part of standard therapy in addition to beta-adrenoceptor agonists, especially in patients who take beta-blockers.

The quality of Intensive Care nursing before, during, and after the introduction of nurses without ICU-training.

OBJECTIVE: The forecasted shortage of nurses specialized in intensive care seriously threatens the service level in the intensive care units (ICUs). This problem might partly be solved by introducing nurses without ICU experience who can provide basic nursing care to relieve the workload of the ICU nurses. This prospective controlled study was set up to determine whether such an introduction causes a significant shift in the quality of care. DESIGN: A prospective observational study was conducted to measure possible changes in the quality of care by examining the number of predefined nursing errors per patient with an observational instrument, the Critical Nursing Situation Index (CNSI). The CNSI was randomly applied during a preassessment period, an intervention period, and a postassessment period. During the intervention period, 16 full time equivalent nurses were employed with the assignment to assist the ICU nurses with basic care activities for 6 months. SETTING: The study was conducted in a 30-bed ICU at the Academic Medical Center in Amsterdam. ANALYSIS: The effect of the employment of nurses was expressed as the difference in the incidence of CNSI scores between the preassessment period and the intervention period on the basis of the relative risk ratios. The results of the comparison between the preassessment and the postassessment period were used to express the consistency of the measure. RESULTS: The researchers completed 600 CNSI observations in 256 patients in 162 days. Overall incidence rates during the preassessment (13%; 1539/12 222) and postassessment (14%; 1554/11 327) period were comparable, whereas the intervention period showed a diminished overall incidence of 9% (1019/11 395). The overall relative risk (95% CL) was 0.70 (0.56/0.86), indicating a significant risk reduction during the intervention period. CONCLUSION: The employment of nurses without ICU training improved the quality of care. This positive effect was primarily explained by the increase in available nursing time.

[The value of the pulmonary-artery catheter: not ruled out, but not proven either]. / Nut van de A.-pulmonaliskatheter: niet uitgesloten, maar ook niet aangetoond.

A number of prospective, randomized trials have recently been published on the effects of using the pulmonary artery (Swan-Ganz) catheter in the peri-operative management of high-risk patients and in the treatment of critically ill patients on the intensive-care unit. These studies show that using the pulmonary-artery catheter does not lead to increased survival. It cannot be excluded that more beneficial effects would have been found with other treatment goals, or if different populations had been studied. However, based on the present evidence from the literature, the routine use of the pulmonary-artery catheter can no longer be defended.

Effects of dobutamine and enoximone on transmitral and pulmonary venous flow characteristics in patients with left ventricular dysfunction after coronary artery bypass grafting.

OBJECTIVES: To assess the effects of dobutamine and enoximone on transmitral (TMF) and pulmonary venous flow (PVF) characteristics. DESIGN: Prospective and randomized. SETTING: A university hospital intensive care unit. PARTICIPANTS: Thirty patients with moderate left ventricular dysfunction after coronary artery bypass grafting (CABG). INTERVENTIONS: Patients received either dobutamine, 10 micrograms/kg/min, or enoximone, 20 micrograms/kg/min, for the treatment of a low cardiac index (CI) (< 2.2 L/min/m2). MEASUREMENTS AND MAIN RESULTS: Both drugs significantly (p < 0.05) increased CI from 1.91 +/- 0.17 (dobutamine) and 1.97 +/- 0.17 (enoximone) at baseline to 2.86 +/- 0.70 and 2.84 +/- 0.39 L/min/m2, respectively. Compared with the enoximone (enox)-treated group, the administration of dobutamine (dob) resulted in significantly (p < 0.05) greater increases in mean arterial pressure (dob: 18 +/- 9% v enox: -2 +/- 7%), heart rate (dob: 24 +/- 13% v enox: 3 +/- 5%) and pulmonary artery pressure (dob: 5 +/- 10% v enox: -4 +/- 9%). In contrast, the increase in stroke volume index was significantly less in the dobutamine-treated group (dob: 22 +/- 27% v enox: 41 +/- 21%). The TMF indices, peak E, and peak A wave increased significantly (p < 0.05) after both dobutamine (baseline: 37.3 +/- 6.7 and 41.1 +/- 9.3; max dose: 42.4 +/- 4.3 and 49.0 +/- 10.2 cm/s) and enoximone (baseline: 36.2 +/- 7.5 and 44.2 +/- 10.9; max dose: 40.5 +/- 5.0 and 49.4 +/- 12.1 cm/s) without significantly altering the E/A ratio. Only dobutamine significantly (p < 0.05) decreased isovolumic relaxation time from 109 +/- 24 to 94 +/- 21 ms. There was no significant change in isovolumic relaxation time between the dobutamine (-12% +/- 17%)- and the enoximone (-4% +/- 21%)- treated group. PVF recordings demonstrated a significant increase in time velocity integrals of the S wave with both dobutamine (12.2 +/- 3.1 v 13.7 +/- 3.2 cm) and enoximone (11.0 +/- 3.0 v 12.2 +/- 3.2 cm). No changes in the systolic fraction of the PVF were noted. CONCLUSIONS: There were no major differences in parameters reflecting diastolic function between the dobutamine- and the enoximone-treated groups.

Myocardial stunning, hibernation, and ischemic preconditioning.

From the present review, it may be concluded that myocardial ischemia results in far more complicated syndromes than previously realized. Although not all aspects of the issues discussed in this review are currently a clinical reality in the daily practice of cardiovascular anesthesiologists, the understanding and application of these concepts are growing rapidly. Indications for revascularization procedures will be adjusted in patients with evidence of hibernating myocardium. In the future, postoperative myocardial dysfunction may be diminished by the prevention of myocardial stunning, for instance by altering the composition of the cardioplegic solution and other interventions. Finally, additional advances may involve reduction of the extent of perioperative myocardial infarctions by application of ischemic preconditioning.

Rate of coronary flow adaptation in response to changes in heart rate before and during anesthesia for coronary artery surgery.

BACKGROUND: The rate of adaptation of coronary blood flow in response to stepwise changes in heart rate (HR) has been extensively studied in dogs and goats to improve our understanding of the dynamics of coronary regulation processes and their pathophysiology and to obtain time constants for mathematical modeling of the coronary regulation. However, little is known about the dynamic characteristics of coronary flow adaptation in humans. In patients undergoing coronary artery surgery, we investigated the rate of coronary adaptation in response to stepwise changes in HR, in the awake and anesthetized states. METHODS: In 11 patients with stable coronary artery disease, arterial blood pressure, right atrial pressure, and coronary sinus blood flow, measured by continuous thermodilution, were calculated per beat. The ratio of beat-averaged arterial blood pressure minus right atrial pressure and coronary sinus blood flow was calculated to obtain an index of coronary resistance. The rate of change of coronary resistance index was quantified by t50, defined as the time required to establish 50% of the total change in coronary resistance index. Responses of coronary resistance index after HR changes, before and after induction of anesthesia, were compared. The anesthesia technique consisted of 100 micrograms.kg-1 fentanyl and 0.1 mg.kg-1 pancuronium bromide in combination with oxygen in air ventilation (FIO2 = 0.5). RESULTS: In the awake situation, t50 values of the dilating and constricting responses, induced by an increase and a decrease in HR were 5.0 +/- 2.1 (SD) s (range 2.6-9.0 s) and 5.7 +/- 1.2 s (range 4.1-7.8 s), respectively. During fentanyl/pancuronium anesthesia, the rate of coronary flow adaptation was significantly slower, with t50 values of 10.2 +/- 2.1 s (range 7.7-13.1 s) after an HR step-up and 9.8 +/- 2.1 s (range 6.6-13.2 s) after an HR step-down. Compared to the awake situation, arterial blood pressure was significantly reduced during anesthesia, but coronary vascular resistance remained unchanged. This implies that the steady-state static regulation of coronary blood flow had not changed. CONCLUSIONS: These preliminary data suggest that, in patients with coronary artery disease, the rate of change in coronary vascular resistance in response to pacing-induced changes in HR is mitigated by fentanyl/pancuronium anesthesia during positive pressure ventilation. A further qualification of our findings in a larger number of patients is warranted.

Effect of phosphodiesterase inhibitors on human arteries in vitro.

In the present study, we investigated if the relaxant effects of phosphodiesterase (PDE) III inhibitors on human vessels could be inhibited by a nitric oxide synthase blocker, L-NAME, or by a blocker of ATP-sensitive potassium channels (KATP), glibenclamide. The experiments were performed using an isometric myograph in isolated human s.c. small arteries obtained from healthy donors. After a priming procedure consisting of exposure to high potassium (120 mmol litre-1) solutions, phenylephrine 10 mumol litre-1 and an equilibrium period of 30 min, the preparations were contracted with a thromboxane A2 mimetic agent, U46619 1 mumol litre-1. Subsequently, cumulative concentration-response curves were constructed for the selective PDE III inhibitors amrinone, milrinone and enoximone, and for theophylline and dipyridamole, with and without the addition of L-NAME 100 mumol litre-1 or glibenclamide 1 mumol litre-1. Addition of L-NAME to the organ bath resulted in significantly higher pEC50 values (-log of the concentration required for 50% relaxation) for milrinone compared with the control: 2.77 (SEM 0.24) mol litre-1 (n = 5) vs 3.49 (0.17) mol litre-1 (n = 7) (P < 0.05). There was no significant difference between any other group. From our data we conclude that the relaxant properties of amrinone, enoximone, theophylline and dipyridamole are not dependent on nitric oxide release or on interaction with KATP channels. However, the effect of milrinone may be partly endothelium-dependent in human vessels in vitro.

Relaxant effect of levcromakalim in isolated human small subcutaneous arteries.

The effect of levcromakalim, an ATP-sensitive K+ channel opener, on isolated subcutaneous arteries from mammary tissues obtained from female patients undergoing reconstructive breast surgery was investigated. The small arteries were preserved in the University of Wisconsin (UW) solution. The contractile responses to K+ and 9,11-dideoxy-11a,9a-epoxy-methano-prostaglandin F2 alpha (U46619) and the relexant responses to levcromakalim and to the endothelium-dependent vasodilator, methacholine, in these arteries remained fully intact after preservation in UW solution for at least 5 days. The pD2 value and maximal relaxation obtained from the concentration-response curve of levcromakalim (n = 7) were 5.78 +/- 0.23 and 81 +/- 6%, respectively. The vasodilator effect of levcromakalim was significantly antagonised by the ATP-sensitive K+ channel blocker, glibenclamide (1 and 3 microM). In conclusion, isolated human arteries contain ATP-sensitive K+ channels, which can be modulated by K+ channel openers and blockers. Subcutaneous small arteries, as used in our experiments, appear to be very suitable for pharmacological experiments.

Hemodynamic effects of the novel selective cAMP-phosphodiesterase III inhibitor R 80122 in anesthetized patients with moderate left ventricular dysfunction before coronary artery bypass grafting.

OBJECTIVE(S): To investigate the hemodynamic effects and safety of R 80122, a novel selective phosphodiesterase (PDE) III inhibitor, and its solvent hydroxypropyl-beta-cyclodextrin. DESIGN: Prospective, randomized study. SETTING: Operating theater of a university hospital in the Netherlands. PARTICIPANTS: Twelve patients with impaired left ventricular function scheduled for coronary artery bypass grafting after induction of anesthesia were included. INTERVENTIONS: R 80122 (n = 6) or its solvent (n = 6) was administered using the same infusion regimen. A bolus of 0.1 mL/kg (= 0.1 mg/kg R 80122) was infused over 10 minutes followed by a maintenance infusion of 5 microliters/kg/min (5 micrograms/kg/min R 80122) over 20 minutes. MEASUREMENTS AND MAIN RESULTS: Compared with the solvent, patients receiving R 80122 did not show any significant changes in heart rate, arterial blood pressure, or pulmonary artery pressures. However, R 80122 produced a marked increase (P < 0.05) in cardiac output (thermodilution) and echocardiographically obtained percentage area reduction. No arrhythmias or ischemic episodes occurred during the infusion period. The plasma half-life of R 80122 was 10.6 +/- 1.9 minutes. CONCLUSIONS: R 80122 appears to be a potent positive inotropic agent in these patients. Its use is not associated with marked vasodilation, it is devoid of positive chronotropic effects, and it can be administered safely in patients with impaired left ventricular function.