Esko Ruokonen

Increased Mortality Associated with Growth Hormone Treatment in Critically Ill Adults

BACKGROUND The administration of growth hormone can attenuate the catabolic response to injury, surgery, and sepsis. However, the effect of high doses of growth hormone on the length of stay in intensive care and in the hospital, the duration of mechanical ventilation, and the outcome in critically ill adults who are hospitalized for long periods is not known. METHODS We carried out two prospective, multicenter, double-blind, randomized, placebo-controlled trials in parallel involving 247 Finnish patients and 285 patients in other European countries who had been in an intensive care unit for 5 to 7 days and who were expected to require intensive care for at least 10 days. The patients had had cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. The patients received either growth hormone (mean [+/-SD] daily dose, 0.10 +/- 0.02 mg per kilogram of body weight) or placebo until discharge from intensive care or for a maximum of 21 days. RESULTS The in-hospital mortality rate was higher in the patients who received growth hormone than in those who did not (P<0.001 for both studies). In the Finnish study, the mortality rate was 39 percent in the growth hormone group, as compared with 20 percent in the placebo group. The respective rates in the multinational study were 44 percent and 18 percent. The relative risk of death for patients receiving growth hormone was 1.9 (95 percent confidence interval, 1.3 to 2.9) in the Finnish study and 2.4 (95 percent confidence interval, 1.6 to 3.5) in the multinational study. Among the survivors, the length of stay in intensive care and in the hospital and the duration of mechanical ventilation were prolonged in the growth hormone group. CONCLUSIONS In patients with prolonged critical illness, high doses of growth hormone are associated with increased morbidity and mortality.

A prospective, randomized study of goal-oriented hemodynamic therapy in cardiac surgical patients

Organ dysfunction and multiple organ failure are the main causes of prolonged hospital stay after cardiac surgery, which increases resource use and health care costs. Increased levels of oxygen delivery and consumption are associated with improved outcome in different groups of postoperative patients. Cardiac surgical patients are at risk of inadequate perioperative oxygen delivery caused by extracorporeal circulation and limited cardiovascular reserves. The purpose of our study was to test whether increasing oxygen delivery immediately after cardiac surgery would shorten hospital and intensive care unit (ICU) stay. Four hundred three elective cardiac surgical patients were enrolled in the study and randomly assigned to either the control or the protocol group. Goals of the protocol group were to maintain Svo2 >70% and lactate concentration ≤2.0 mmol/L from admission to the ICU and up to 8 h thereafter. Hemodynamics, oxygen transport data, and organ dysfunctions were recorded. The median hos-pital stay was shorter in the protocol group (6 vs 7 days, P < 0.05), and patients were discharged faster from the hospital than those in the control group (P < 0.05). Discharge from the ICU was similar between groups (P = 0.8). Morbidity was less frequent at the time of hospital discharge in the protocol group (1.1% vs 6.1%, P < 0.01). Increasing oxygen delivery to achieve normal Svo2 values and lactate concentration during the immediate postoperative period after cardiac surgery can shorten the length of hospital stay. Implications Health care economics has challenged clinicians to reduce costs and improve resource use in cardiac surgery and anesthesia in a patient population increasing in age and in severity of disease. Optimizing cardiovascular function to maintain adequate oxygen delivery during the immediate postoperative period after cardiac surgery can decrease morbidity and reduce length of hospital stay.

Regional blood flow and oxygen transport in septic shock

ObjectiveTo measure the blood flow distribution and regional oxygen transport in hyperdynamic septic shock during hypotension and after correction by vasopressor doses of dopamine or norepinephrine. DesignProspective, randomized, controlled trial. SettingTertiary care center. PatientsTen patients with hyperdynamic septic shock (ages ranging from 45.1 ± 16.6 yrs) and a control group of 11 postoperative cardiac surgery patients (ages ranging from 54.8 ± 7.9 yrs). InterventionsSystemic and regional hemodynamics and oxygen transport were measured in ten patients with hyperdynamic septic shock during hypotension and after vasopressor therapy (norepinephrine or dopamine). Oxygen consumption (Vo2) was measured by indirect calorimetry and splanchnic and leg blood flow with indocyanine green infusion. Measurements and Main ResultsSplanchnic blood flow and (Vo2 (p<.05) were increased in septic shock during hypotension and during vasopressor therapy. Both dopamine and norepinephrine increased systemic blood flow and Vo2 independently of the arterial lactate level. Despite the relatively small changes in systemic oxygen transport, major regional changes occurred in oxygen delivery and Vo2, and these changes were unpredictable from systemic changes. ConclusionsRegional changes in oxygen transport in septic shock cannot be predicted from the changes in the whole body. The increased oxygen demand in the splanchnic region is the main risk factor for splanchnic tissue hypoxia in speptic shock. (Crit Care Med 1993; 21:1296–1303)

Quality of life after prolonged intensive care

OBJECTIVE To assess the subjective health status, quality of life, and functional ability of patients whose intensive care stay was prolonged and to compare their quality of life with that of the general population. DESIGN Inception cohort study. SETTING Twenty-three-bed multidisciplinary intensive care unit (ICU) in a tertiary care center. PATIENTS A consecutive sample of 718 patients aged > or = 18 yrs who required intensive care > or = 4 days. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The Nottingham Health Profile was used to compare the ICU patients with a random sample (n = 2,595) of the general population. The quality of life and functional ability of 368 respondents (78.3% of 470 survivors) were assessed at 6 months after ICU admission. The length of the ICU stay was 13.6+/-11.8 (median, 9; maximum, 81) days. The quality of life and its various dimensions were influenced by the diagnosis for ICU admission and age. Although problems in physical mobility and energy were prevalent among all patient groups, only a small proportion was dependent on others for the management of daily activities. Patients with trauma or respiratory failure experienced the most limitations. The quality of life of elderly patients and patients who had undergone cardiac surgery was comparable with the general population regarding emotional reactions, social isolation, and pain. CONCLUSIONS The quality of life of survivors after a prolonged intensive care stay is fairly good, although not comparable with that of the general population. The psychosocial aspects of the quality of life are restored more rapidly than physical performance.

Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial

IntroductionIt is unclear to which level mean arterial blood pressure (MAP) should be increased during septic shock in order to improve outcome. In this study we investigated the association between MAP values of 70 mmHg or higher, vasopressor load, 28-day mortality and disease-related events in septic shock.MethodsThis is a post hoc analysis of data of the control group of a multicenter trial and includes 290 septic shock patients in whom a mean MAP ≥ 70 mmHg could be maintained during shock. Demographic and clinical data, MAP, vasopressor requirements during the shock period, disease-related events and 28-day mortality were documented. Logistic regression models adjusted for the geographic region of the study center, age, presence of chronic arterial hypertension, simplified acute physiology score (SAPS) II and the mean vasopressor load during the shock period was calculated to investigate the association between MAP or MAP quartiles ≥ 70 mmHg and mortality or the frequency and occurrence of disease-related events.ResultsThere was no association between MAP or MAP quartiles and mortality or the occurrence of disease-related events. These associations were not influenced by age or pre-existent arterial hypertension (all P > 0.05). The mean vasopressor load was associated with mortality (relative risk (RR), 1.83; confidence interval (CI) 95%, 1.4-2.38; P < 0.001), the number of disease-related events (P < 0.001) and the occurrence of acute circulatory failure (RR, 1.64; CI 95%, 1.28-2.11; P < 0.001), metabolic acidosis (RR, 1.79; CI 95%, 1.38-2.32; P < 0.001), renal failure (RR, 1.49; CI 95%, 1.17-1.89; P = 0.001) and thrombocytopenia (RR, 1.33; CI 95%, 1.06-1.68; P = 0.01).ConclusionsMAP levels of 70 mmHg or higher do not appear to be associated with improved survival in septic shock. Elevating MAP >70 mmHg by augmenting vasopressor dosages may increase mortality. Future trials are needed to identify the lowest acceptable MAP level to ensure tissue perfusion and avoid unnecessary high catecholamine infusions.

SALINE PCO2 IS AN IMPORTANT SOURCE OF ERROR IN THE ASSESSMENT OF GASTRIC INTRAMUCOSAL PH

Objective: To determine whether the measurement error of saline Pco2, using blood gas analyzers, is relevant for the interpretation and clinical use of the gastric intramucosal pH measurement. Design: A comparison of four different blood gas analyzers (ABL‐520, Ciba Corning, IL‐1302, and Nova), using tonometered saline as the reference. Setting: Clinical laboratory of a university hospital intensive care unit. Interventions: None. Measurements and Main Results: The bias and the precision of each blood gas analyzer was determined for measurements of Pco2 in saline samples. These samples had been balanced to Pco2 levels of 30, 45, and 68 torr (4, 6, and 9 kPa, respectively). In addition, the effect of buffering the saline was evaluated. The bias of the Pco2 measurement increased (p < .001) at the higher Pco2 levels. The bias ranged from ‐5.2 to ‐25.9 torr (‐0.69 to ‐3.45 kPa) at a Pco2 of 45 torr (6 kPa) and from ‐5.2 to ‐33.1 torr (‐0.69 to ‐4.41 kPa) at a Pco2 of 68 torr (9 kPa), and there was a significant ( p < .001) analyzer‐Pco2 level interaction. The type of the analyzer also influenced the bias ( p < .001). The Nova analyzer underestimated the Pco2 by 50% to 60%. The other analyzers underestimated the Pco2 by 5% to 19%. The use of the buffer reduced the bias of all analyzers ( p < .001). Based on the precision of the saline Pco2 measurement, a difference in gastric intramucosal pH of 0.06 pH units can be reliably detected at a Pco2 of 45 torr (6 kPa) by all analyzers, with the exception of the Nova analyzer. Conclusions: Measurement of saline Pco2 is an important source of error in the assessment of gastric intramucosal pH, and the error depends on both the analyzer used and the actual Pco2 level. Direct comparison of pH values obtained by different analyzers is not valid. Changes in gastric intramucosal pH of 0.06 pH units can be detected by most analyzers in the clinically relevant Pco2 level. (Crit Care Med 1994; 22:1877–1879)

Long-term outcome and quality-adjusted life years after severe sepsis

Objective: To study long-term mortality, quality of life (QOL), quality-adjusted life years (QALYs), and costs per QALY in an unselected intensive care unit (ICU) patient population with severe sepsis. Design: Prospective observational cohort study. Setting: Twenty-four ICUs in Finland. Patients: A total of 470 adult patients with severe sepsis who were treated in ICUs between November 1, 2004 and February 28, 2005. The QOL before critical illness was assessed in 252 patients and QOL after severe sepsis in 156 patients (58% of the patients surviving in April 30, 2006). Ninety-eight patients responded to both questionnaires. QOL was assessed by a generic EuroQol-5D (EQ-5D) measurement with summary index (EQsum) and visual analogue scale (VAS). Measurements and Main Results: The 2-year mortality after severe sepsis was 44.9% (211 of 470). The median response time for QOL assessment after severe sepsis was 17 months (interquartile range [IQR] 16–18). The median EQsum (75, IQR 56–92) and EQ VAS (66, IQR 50–80) were lower after severe sepsis than age- and sex-adjusted reference values (p < 0.001 and p < 0.001). The decrease between the mean EQsum reference value and that of severe sepsis patients was 12 (95% confidence interval [CI], 9–16). The difference between the mean EQ VAS reference values and the mean EQ VAS was 8 (95% CI, 5–11). The mean calculated QALYs after severe sepsis were 10.9 (95% CI, 9.7–12.1) and the calculated cost for one QALY was only 2139 &OV0556; for all survivors and nonsurvivors. Conclusions: Two-year mortality after severe sepsis was high (44.9%) and the QOL was lower after severe sepsis than before critical illness as assessed by EQ-5D. However, the mean QALYs for the surviving patients were reasonable and the cost for one QALY was reasonably low, which makes intensive care in patients with severe sepsis cost effective.

The effects of ICU admission and discharge times on mortality in Finland

ObjectiveHospital mortality increases if acutely ill patients are admitted to hospitals on weekends as compared with weekdays. Night discharges may increase mortality in intensive care unit (ICU) patients but the effect of ICU admission time on mortality is not known. We studied the effects of ICU admission and discharge times on mortality and the time of death in critically ill patients.DesignCohort study using a national ICU database.SettingEighteen ICUs in university and central hospitals in Finland.PatientsConsecutive series of all 23,134 emergency admissions in January 1998–June 2001.InterventionsNone.Measurements and main resultsWe defined weekend (as opposed to weekday) from 1600 hours Friday to 2400 hours Sunday and “out-of-office” hours (as opposed to “office hours”) from 1600 hours to 0800 hours. Mortality was adjusted for disease severity, intensity of care, and whether restrictions for future care were set. ICU-mortality was 10.9% and hospital mortality 20.7%. Adjusted ICU-mortality was higher for weekend as compared with weekday admissions [odds ratio (OR 1.20) 95% CI 1.01–1.43], but similar for “out-of-office” and “office hour” admissions (OR 0.98, 0.85–1.13). Adjusted risk of ICU death was higher during “out-of-office” hours as compared with office hours (OR 6.89, 5.96–7.96). The time of discharge from ICU to wards was not associated with further hospital mortality.ConclusionsWeekend ICU admissions are associated with increased mortality, and patients in the ICU are at increased risk of dying in evenings and during nighttime. Our findings may have important implications for organization of ICU services.

Predictive value of procalcitonin decrease in patients with severe sepsis: a prospective observational study

IntroductionThis prospective study investigated the predictive value of procalcitonin (PCT) for survival in 242 adult patients with severe sepsis and septic shock treated in intensive care.MethodsPCT was analyzed from blood samples of all patients at baseline, and 155 patients 72 hours later.ResultsThe median PCT serum concentration on day 0 was 5.0 ng/ml (interquartile range (IQR) 1.0 and 20.1 ng/ml) and 1.3 ng/ml (IQR 0.5 and 5.8 ng/ml) 72 hours later. Hospital mortality was 25.6% (62/242). Median PCT concentrations in patients with community-acquired infections were higher than with nosocomial infections (P = 0.001). Blood cultures were positive in 28.5% of patients (n = 69), and severe sepsis with positive blood cultures was associated with higher PCT levels than with negative cultures (P = < 0.001). Patients with septic shock had higher PCT concentrations than patients without (P = 0.02). PCT concentrations did not differ between hospital survivors and nonsurvivors (P = 0.64 and P = 0.99, respectively), but mortality was lower in patients whose PCT concentration decreased > 50% (by 72 hours) compared to those with a < 50% decrease (12.2% vs. 29.8%, P = 0.007).ConclusionsPCT concentrations were higher in more severe forms of severe sepsis, but a substantial concentration decrease was more important for survival than absolute values.

Septic shock and multiple organ failure

ObjectiveTo assess the frequency and mortality rates of septic shock in ICU patients and the clinical course of multiple organ failure associated with septic shock. DesignRetrospective case survey. SettingTertiary care center. PatientsDuring a 2-yr period, 2,469 consecutive intensive care patients were studied regarding the frequency and hospital mortality rates of septic shock. A subset of 1,311 patients was further analyzed for the occurrence of organ system failures within 48 hrs of the onset of septic shock and again 4 to 7 days later. Measurements and Main ResultsThe frequency rate of septic shock was 1.9% (n = 48), with a mortality rate of 72.9% (n = 35) in patients with septic shock. Deaths due to septic shock represented 14.6% of all deaths in the ICU during the study period. Eighteen patients died within 72 hrs of the onset of septic shock. Refractory hypotension was the cause of death in 15 of these 18 patients. Beyond 72 hrs, multiple organ failure accounted for eight of 17 deaths. The mean ± SD number of organ systems failing at 48 hrs was 3.3 ± 1.3 in survivors and 4.0 ± 1.1 in nonsurvivors, and at 4 to 7 days was 2.1 ± 1.5 in survivors and 4.0 ± 1.5 in nonsurvivors (p < .05). None of the specific organ system failures had prognostic value. The number of organ system failures was not related to the duration of hypotension, but had a weak correlation (r2 = .26, p < .05) with the duration of vasoactive treatment at 4 to 7 days. The prolonged need for norepinephrine therapy was associated with an increased occurrence of renal failure. Thirty (62.5%) patients had positive blood cultures and a mortality rate similar to the mortality rate of patients with negative blood cultures. Patients with negative blood cultures died more often with hypotension (p < .02). ConclusionsSeptic shock is a major cause of death in intensive care patients. Refractory hypotension is a main cause of early deaths. Later on, multiple organ failure becomes the primary clinical problem and cause of mortality.