Walter R. Hasibeder

Arginine Vasopressin in Advanced Vasodilatory Shock. A Prospective, Randomized, Controlled Study

Background—Vasodilatory shock is a potentially lethal complication of severe disease in critically ill patients. Currently, catecholamines are the most widely used vasopressor agents to support blood pressure, but loss of catecholamine pressor effects is a well-known clinical dilemma. Arginine vasopressin (AVP) has recently been shown to be a potent vasopressor agent to stabilize cardiocirculatory function even in patients with catecholamine-resistant vasodilatory shock. Methods and Results—Forty-eight patients with catecholamine-resistant vasodilatory shock were prospectively randomized to receive a combined infusion of AVP and norepinephrine (NE) or NE infusion alone. In AVP patients, AVP was infused at a constant rate of 4 U/h. Hemodynamic, acid/base, single-organ, and tonometrically derived gastric variables were reported before the study and 1, 12, 24, and 48 hours after study entry. For statistical analysis, a mixed-effects model was used. AVP patients had significantly lower heart rate, NE requirements, and incidence of new-onset tachyarrhythmias than NE patients. Mean arterial pressure, cardiac index, stroke volume index, and left ventricular stroke work index were significantly higher in AVP patients. NE patients developed significantly more new-onset tachyarrhythmias than AVP patients (54.3% versus 8.3%). Gastrointestinal perfusion as assessed by gastric tonometry was better preserved in AVP-treated patients. Total bilirubin concentrations were significantly higher in AVP patients. Conclusions—The combined infusion of AVP and NE proved to be superior to infusion of NE alone in the treatment of cardiocirculatory failure in catecholamine-resistant vasodilatory shock.

The effects of vasopressin on systemic hemodynamics in catecholamine-resistant septic and postcardiotomy shock: A retrospective analysis

We retrospectively investigated the effects of continuous arginine vasopressin (AVP) infusion on systemic hemodynamics, acid/base status, and laboratory variables in patients (mean age [mean ± sd]= 66.3 ± 10.1 yr) with catecholamine-resistant septic (n = 35) or postcardiotomy shock (n = 25). Hemodynamic and acid/base data were obtained before; 30 min after; and 1, 4, 12, 24, 48, and 72 h after the start of AVP infusion. Laboratory examinations were recorded before and 24, 48, and 72 h after the start of AVP infusion. For statistical analysis, a mixed-effects model was used. The overall intensive care unit mortality was 66.7%. AVP administration caused a significant increase in mean arterial pressure (+29%) and systemic vascular resistance (+56%), accompanied by a significant decrease in heart rate (−24%) and mean pulmonary arterial pressure (−11%) without any change in stroke volume index. Norepinephrine requirements could be reduced by 72% within 72 h. During AVP infusion, a significant increase in liver enzymes and total bilirubin concentration and a significant decrease in platelet count occurred. Arginine vasopressin was effective in reversing systemic hypotension. However, adverse effects on gastrointestinal perfusion and coagulation cannot be excluded.

Sympathetic Overstimulation During Critical Illness: Adverse Effects of Adrenergic Stress

The term ‘‘adrenergic’’ originates from ‘‘adrenaline’’ and describes hormones or drugs whose effects are similar to those of epinephrine. Adrenergic stress is mediated by stimulation of adrenergic receptors and activation of post-receptor pathways. Critical illness is a potent stimulus of the sympathetic nervous system. It is undisputable that the adrenergic-driven ‘‘fight-flight response’’ is a physiologically meaningful reaction allowing humans to survive during evolution. However, in critical illness an overshooting stimulation of the sympathetic nervous system may well exceed in time and scope its beneficial effects. Comparable to the overwhelming immune response during sepsis, adrenergic stress in critical illness may get out of control and cause adverse effects. Several organ systems may be affected. The heart seems to be most susceptible to sympathetic overstimulation. Detrimental effects include impaired diastolic function, tachycardia and tachyarrhythmia, myocardial ischemia, stunning, apoptosis and necrosis. Adverse catecholamine effects have been observed in other organs such as the lungs (pulmonary edema, elevated pulmonary arterial pressures), the coagulation (hypercoagulability, thrombus formation), gastrointestinal (hypoperfusion, inhibition of peristalsis), endocrinologic (decreased prolactin, thyroid and growth hormone secretion) and immune systems (immunomodulation, stimulation of bacterial growth), and metabolism (increase in cell energy expenditure, hyperglycemia, catabolism, lipolysis, hyperlactatemia, electrolyte changes), bone marrow (anemia), and skeletal muscles (apoptosis). Potential therapeutic options to reduce excessive adrenergic stress comprise temperature and heart rate control, adequate use of sedative/analgesic drugs, and aiming for reasonable cardiovascular targets, adequate fluid therapy, use of levosimendan, hydrocortisone or supplementary arginine vasopressin.

Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors.

ObjectiveTo report on the incidence and risk factors associated with the development of ischemic skin lesions (ISL) in critically ill patients with catecholamine-resistant vasodilatory shock treated with a continuous infusion of arginine-vasopressin (AVP). DesignRetrospective analysis. SettingTwelve-bed general and surgical intensive care unit in a university hospital. PatientsA total of 63 critically ill patients with catecholamine-resistant vasodilatory shock. InterventionsContinuous AVP infusion. Measurements and Main ResultsDemographic, hemodynamic, laboratory data, and skin status were evaluated 24 hrs before and during AVP therapy (24 and 48 hrs). Patients were grouped according to development of new ISL during AVP therapy. A mixed-effects model was used to compare groups. A multiple logistic regression analysis was used to identify independent risk factors for the development of ISL. ISL developed in 19 of 63 patients (30.2%). Thirteen of 19 patients (68%) developed ISL in distal limbs, two patients (10.5%) developed ISL of the trunk, four patients (21%) developed ISL in distal limbs and in the trunk. Five patients (26%) had additional ischemia of the tongue. Body mass index, preexistent peripheral arterial occlusive disease, presence of septic shock, and norepinephrine requirements were significantly higher in patients developing ISL. ISL patients received significantly more units of fresh frozen plasma and thrombocyte concentrates than patients without ISL. Preexistent peripheral arterial occlusive disease and presence of septic shock were independently associated with the development of ISL during AVP therapy. ConclusionsISLs are a common complication during continuous AVP infusion in patients with catecholamine-resistant vasodilatory shock. The presence of septic shock and a history of peripheral arterial occlusive disease are independent risk factors for the development of ISL.

Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis.

BACKGROUND: Although detailed analyses of the postmortem findings of various critically ill patient groups have been published, no such study has been performed in patients with sepsis. In this retrospective cohort study, we reviewed macroscopic postmortem examinations of surgical intensive care unit (ICU) patients who died from sepsis or septic shock. METHODS: Between 1997 and 2006, the ICU database and autopsy register were reviewed for patients who were admitted to the ICU because of sepsis/septic shock, or who developed sepsis/septic shock at a later stage during their ICU stay and subsequently died from of sepsis/septic shock. Clinical data and postmortem findings were documented in all patients. RESULTS: Postmortem results of 235 patients (84.8%) were available for statistical analysis. The main causes of death as reported in the patient history were refractory multiple organ dysfunction syndrome (51.5%) and uncontrollable cardiovascular failure (35.3%). Pathologies were detected in the lungs (89.8%), kidneys/urinary tract (60%), gastrointestinal tract (54%), cardiovascular system (53.6%), liver (47.7%), spleen (33.2%), central nervous system (18.7%), and pancreas (8.5%). In 180 patients (76.6%), the autopsy revealed a continuous septic focus. The most common continuous foci were pneumonia (41.3%), tracheobronchitis (28.9%), peritonitis (23.4%), uterine/ovarial necrosis (9.8% of female patients), intraabdominal abscesses (9.1%), and pyelonephritis (6%). A continuous septic focus was observed in 63 of the 71 patients (88.7%) who were admitted to the ICU because of sepsis/septic shock and treated for longer than 7 days. CONCLUSIONS: Relevant postmortem findings explaining death in surgical ICU patients who died because of sepsis/septic shock were a continuous septic focus in approximately 80% and cardiac pathologies in 50%. The most frequently affected organs were the lungs, abdomen, and urogenital tract. More diagnostic, therapeutic and scientific efforts should be launched to identify and control the infectious focus in patients with sepsis and septic shock.

Causes of death and determinants of outcome in critically ill patients

IntroductionWhereas most studies focus on laboratory and clinical research, little is known about the causes of death and risk factors for death in critically ill patients.MethodsThree thousand seven hundred patients admitted to an adult intensive care unit (ICU) were prospectively evaluated. Study endpoints were to evaluate causes of death and risk factors for death in the ICU, in the hospital after discharge from ICU, and within one year after ICU admission. Causes of death in the ICU were defined according to standard ICU practice, whereas deaths in the hospital and at one year were defined and grouped according to the ICD-10 (International Statistical Classification of Diseases and Related Health Problems) score. Stepwise logistic regression analyses were separately calculated to identify independent risk factors for death during the given time periods.ResultsAcute, refractory multiple organ dysfunction syndrome was the most frequent cause of death in the ICU (47%), and central nervous system failure (relative risk [RR] 16.07, 95% confidence interval [CI] 8.3 to 31.4, p < 0.001) and cardiovascular failure (RR 11.83, 95% CI 5.2 to 27.1, p < 0.001) were the two most important risk factors for death in the ICU. Malignant tumour disease and exacerbation of chronic cardiovascular disease were the most frequent causes of death in the hospital (31.3% and 19.4%, respectively) and at one year (33.2% and 16.1%, respectively).ConclusionIn this primarily surgical critically ill patient population, acute or chronic multiple organ dysfunction syndrome prevailed over single-organ failure or unexpected cardiac arrest as a cause of death in the ICU. Malignant tumour disease and chronic cardiovascular disease were the most important causes of death after ICU discharge.

Blunted erythropoietic response to anemia in multiply traumatized patients.

ObjectivesTo assess the relations between anemia, serum erythropoietin (EPO), iron status, and inflammatory mediators in multiply traumatized patients. DesignProspective observational study. SettingIntensive care unit. PatientsTwenty-three patients suffering from severe trauma (injury severity score ≥30). InterventionsNone. Measurements and Main Results Blood samples were collected within 12 hrs after the accident (day 1) and in the morning on days 2, 4, 6, and 9 to determine blood cell status, serum EPO, tumor necrosis factor-&agr; (TNF-&agr;), soluble tumor necrosis factor-receptor I (sTNF-rI), interleukin-1 receptor antagonist (IL1-ra), interleukin-6 (IL-6), neopterin, and iron status, respectively. Hemoglobin concentration was low at admission (mean, 10.0 g/dL; range, 6.8–12.9 g/dL) and did not increase during the observation time. Serum EPO concentration was 49.8 U/L (mean value) on day 1 and did not show significant increases thereafter. No correlation was found between EPO and hemoglobin concentrations. TNF-&agr; remained within the normal range. sTNF-rI was high at admission and increased further. IL1-ra was above the normal range. IL-6 was very high at admission and did not decrease thereafter. The initial neopterin concentration was normal, but increased until day 9. Serum iron was significantly decreased on day 2 posttrauma and remained low during the study. Serum ferritin increased steadily from day 2, reaching its maximum on day 9. In contrast, concentrations of transferrin were low from admission onward. ConclusionsMultiply traumatized patients exhibit an inadequate EPO response to low hemoglobin concentrations. Thus, anemia in severe trauma is the result of a complex network of bleeding, blunted EPO response to low hemoglobin concentrations, inflammatory mediators, and a hypoferremic state.

Tachyarrhythmias in a surgical intensive care unit: a case-controlled epidemiologic study.

Objective: Incidence, types, and factors associated with new onset tachyarrhythmias (TA) in surgical intensive care patients.¶Design: Pairwise-matched case-controlled study. Setting: Surgical intensive care unit (ICU) with nine intensive care beds. Patients: During a 1-year period, all TA patients (n = 89) were included in the study. Control patients (n = 82) without TA were matched according to age, sex, and surgical region. Methods: TA workup included: 12-lead ECG, arterial blood gas, serum electrolyte (K+, Mg2+), and serum CK/CKMB isoenzyme analysis. Pre-existing cardiovascular and pulmonary disease, cardiovascular risk factors, preoperative regular medication, and admission SAPS were recorded in all patients. A multiple organ dysfunction syndrome (MODS) score, the presence or absence of SIRS or sepsis, and hemodynamics (MAP and CVP) before onset of TA were evaluated in TA patients, while in control patients highest MODSscore, the presence or absence of SIRS or sepsis, mean hemodynamic and laboratory values calculated from highest and lowest readings during ICU stay were used for statistical comparison. Logistic regression analysis was performed to identify variables multivariately associated with TA. Results: Eighty-nine (14.8 %) of 596 patients developed TA. Atrial fibrillation was most frequent (60.7 %). Presence of SIRS or sepsis (adj. OR = 36.45; 95 % CI: 11.5–115.5), high admission SAPS (adj. OR = 1.25/point; 95 % CI: 1.08–1.44), high CVP (adj. OR = 1.27/mmHg; 95 % CI: 1.09–1.48), and low arterial oxygen tension (adj. OR = 0.97/mmHg); 95 % CI: 0.95–0.99) were found to be significant predictors for development of TA. Conclusions: In surgical patients hypoxia, high cardiac filling pressures, a greater degree of physiologic derangement at admission, and the presence of SIRS and sepsis are independent risk factors for the development of TA.

Management of Vasodilatory Shock Defining the Role of Arginine Vasopressin

The rationale for an arginine vasopressin (argipressin) infusion was put forward after it was discovered that patients in shock states might have an endogenous arginine vasopressin deficiency. Subsequently, several investigations impressively demonstrated that arginine vasopressin can successfully stabilise haemodynamics even in advanced vasodilatory shock. We report on physiological and pharmacological aspects of arginine vasopressin, and summarise current clinical knowledge on employing a continuous arginine vasopressin infusion in critically ill patients with catecholamine-resistant vasodilatory shock of different aetiologies. In view of presented experimental evidence and current clinical experience, a continuous arginine vasopressin infusion of ∼2 to ∼6 IU/h can be considered as a supplemental strategy to vasopressor catecholamines in order to preserve cardiocirculatory homeostasis in patients with advanced vasodilatory shock. Because data on adverse effects are still limited, arginine vasopressin should be reserved for patients in whom adequate haemodynamic stabilisation cannot be achieved with conventional vasopressor therapy or who have obvious adverse effects of catecholamines that result in further significant haemodynamic deterioration. For the same reasons, arginine vasopressin should not be used as a single, alternative vasopressor agent instead of catecholamine vasopressors. Future prospective studies will be necessary to define the exact role of arginine vasopressin in the therapy of vasodilatory shock.

Antifactor Xa activity in intensive care patients receiving thromboembolic prophylaxis with standard doses of enoxaparin

BACKGROUND Low-molecular-weight heparins (LMWHs) have become increasingly used to prevent thromboembolic complications in intensive care patients. Unlike in medical and surgical patients, no data on the anticoagulant effectiveness of standard LMWH dosages exist in intensive care patients. Therefore, we prospectively investigated antifactor Xa (aFXa) levels after subcutaneous administration of 40 mg of enoxaparin in 89 intensive care patients over a 24-h period. METHODS AFXa levels were measured before, 4, 12 and 24 h after subcutaneous administration of enoxaparin. Laboratory parameters including prothrombin time, activated partial thromboplastin time, antithrombin III, fibrinogen as well as platelet count were collected at same intervals. Demographics included age, sex, height, weight, body mass index, admission diagnosis, a thromboembolic risk score and a modified Goris multiple organ dysfunction score. RESULTS At 4, 12 and 24 h, 56.5%, 39.3% and 12.6% of the study patients were within recommended antithrombotic aFXa levels (0.1-0.3 U ml(-1)). Presence of multiple organ dysfunction as well as high body weight were significantly correlated with low aFXa levels. CONCLUSION European standard dosages of 40 mg of enoxaparin once daily proved to be ineffective in achieving recommended antithrombotic aFXa levels in intensive care patients. This was most pronounced in patients with high body weight and presence of multiple organ dysfunction.