Leena Mildh

Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study

IntroductionPositive fluid balance has been associated with an increased risk for mortality in critically ill patients with acute kidney injury with or without renal replacement therapy (RRT). Data on fluid accumulation prior to RRT initiation and mortality are limited. We aimed to study the association between fluid accumulation at RRT initiation and 90-day mortality.MethodsWe conducted a prospective, multicenter, observational cohort study in 17 Finnish intensive care units (ICUs) during a five-month period. We collected data on patient characteristics, RRT timing, and parameters at RRT initiation. We studied the association of parameters at RRT initiation, including fluid overload (defined as cumulative fluid accumulation > 10% of baseline weight) with 90-day mortality.ResultsWe included 296 RRT-treated critically ill patients. Of 283 patients with complete data on fluid balance, 76 (26.9%) patients had fluid overload. The median (interquartile range) time from ICU admission to RRT initiation was 14 (3.3 to 41.5) hours. The 90-day mortality rate of the whole cohort was 116 of 296 (39.2%; 95% confidence interval 38.6 to 39.8%). The crude 90-day mortality of patients with or without fluid overload was 45 of 76 (59.2%) vs. 65 of 207 (31.4%), P < 0.001. In logistic regression, fluid overload was associated with an increased risk for 90-day mortality (odds ratio 2.6) after adjusting for disease severity, time of RRT initiation, initial RRT modality, and sepsis. Of the 168 survivors with data on RRT use at 90 days, 34 (18.9%, 95% CI 13.2 to 24.6%) were still dependent on RRT.ConclusionsPatients with fluid overload at RRT initiation had twice as high crude 90-day mortality compared to those without. Fluid overload was associated with increased risk for 90-day mortality even after adjustments.

Junctional ectopic tachycardia after surgery for congenital heart disease: incidence, risk factors and outcome

OBJECTIVES Junctional ectopic tachycardia (JET) is a serious, haemodynamically compromising tachyarrhythmia associated with paediatric cardiac surgery, with a reported mortality up to 14%. The incidence, risk factors and outcome of this tachyarrhythmia were evaluated in this population-based, case-control patient cohort. METHODS A total of 1001 children, who underwent open-heart surgery during a 5-year period, were retrospectively analysed. The patients with haemodynamically significant tachycardia were identified, and their postoperative electrocardiograms were analysed. Three controls matched with the same type of surgery were selected for each patient with JET. RESULTS JET was diagnosed in 51 patients (5.0%). These patients had longer cardiopulmonary bypass time (138 vs 119 min, p=0.002), higher body temperature (38.0 vs 37.4 °C, p=0.013) and higher level of postoperative troponin-T (3.7 vs 2.1 μg l(-1), p<0.001) compared with controls. They also needed longer ventilatory support (3 vs 2 days, p=0.004) and intensive care stay (7 vs 5 days, p<0.001) as well as use of noradrenaline (23/51 vs 35/130, p=0.019). Ventricular septal defect (VSD) closure was part of the surgery in 33/51 (64.7%) of these patients. The mortality was 8% in the JET group and 5% in the controls (p=0.066). In the logistic regression model, JET was not an independent risk factor for death (p=0.557). CONCLUSIONS The incidence of JET was 5.0% in this large paediatric open-heart surgery patient group. Compared with controls, these patients had longer cardiopulmonary bypass time and higher level of troponin-T, possibly reflecting the extent of surgical trauma. However, the tachycardia was not an independent risk factor for death.

Time course of changes in breathing pattern in morphine- and oxycodone-induced respiratory depression

The time course of changes in breathing pattern in opioid‐induced respiratory depression was characterised for two opioids. Intravenous morphine (0.039 mg.kg−1 bolus + 0.215 mg.kg−1.h−1 infusion) and oxycodone (0.05 mg.kg−1 bolus + 0.275 mg.kg−1.h−1 infusion) were administered to six healthy male volunteers for 2 h in a random, double‐blind and cross‐over fashion. Monitoring included pulse oximetry and noninvasive respiratory‐inductive plethysmography for the measurement of breathing pattern. The total amounts of drugs given were 35.1 (0.0) mg [mean (SD)] morphine and 41.3 (8.0) mg oxycodone. Four of the six oxycodone infusions had to be stopped at 99 (14) min because of respiratory depression as judged by pulse oximetry. No morphine infusions were stopped. The first changes in breathing pattern were a decrease in respiratory rate and an increase in the contribution of the rib cage to tidal volume, while the compensatory increase in tidal volume became evident later. A decrease in minute ventilation and inspiratory duty cycle were also found.

The concentration-effect relationship of the respiratory depressant effects of alfentanil and fentanyl

The relative potencies of fentanyl and alfentanil for respiratory depression were determined in eight healthy male volunteers in a double-blinded, randomized study with a cross-over design. The drugs were delivered by computer-driven infusion with logarithmically ascending plasma concentrations until the respiratory rate reached 2/min and/or oxygen saturation decreased below 85% with subjects breathing room air. Ventilation was measured with respiratory inductive plethysmography, indirect calorimetry, and arterial blood gas analysis, and plasma drug concentrations were determined. Pharmacodynamic modeling was performed using a fractional Emax model for minute volume and respiratory rate and the concentrations producing 50% depression (i.e., apparent 50% effective concentration [EC50] values) were determined. Both drugs decreased ventilation in a similar manner, and drug infusions were terminated at mean ± sd measured plasma concentrations of 254 ± 88 ng/mL and 5.1 ± 1.7 ng/mL for alfentanil and fentanyl, respectively. Alfentanil decreased minute volume from baseline by 54% ± 19% and respiratory rate by 40% ± 11% with EC50 values of 234 ± 57 ng/mL and 195 ± 101 ng/mL. The respective decreases for fentanyl were 50% ± 11%, 41% ± 15%, and the estimated EC50 values were 6.1 ± 1.4 ng/mL and 3.5 ± 1.4 ng/mL, respectively. Using the apparent EC50 values, the calculated potency ratio for alfentanil:fentanyl was (mean and 95% confidence interval) 1:39 (1:31–1:46) for minute volume and 1:51 (1:34–1:68) for respiratory rate. This is analogous to the analgesic effect studied earlier. The findings support the notion of parallel analgesic and respiratory depressant effects of alfentanil and fentanyl. Therefore equianalgesic concentrations of both drugs will lead to equally pronounced respiratory depression.

Effects of tramadol and meperidine on respiration, plasma catecholamine concentrations, and hemodynamics

STUDY OBJECTIVE To evaluate the effects of high analgesic doses of tramadol and meperidine on respiration, plasma catecholamine concentrations, and hemodynamic parameters. STUDY DESIGN Randomized, double-blind, cross-over, controlled volunteer study. SETTING Laboratory at a university hospital. SUBJECTS 8 healthy male volunteers. INTERVENTIONS Tramadol was given as a 150 mg bolus plus a succeeding 3-hour steady infusion of 250 mg (83.3 mg/hr). Meperidine was given in a similar manner as a bolus dose of 112.5 mg plus 187.5 mg in a 3-hour steady infusion (62.5 mg/hr). Experimental pain was induced using a tourniquet. MEASUREMENTS AND MAIN RESULTS Respiration was studied noninvasively with respiratory inductive plethysmography and pulse oximetry. Arterial line was used for measurement of hemodynamics and blood sampling. Tramadol did not have any clinically significant effects on respiration, breathing pattern, or hemodynamics, but an increase in plasma epinephrine levels was noted. Meperidine bolus decreased tidal volume (p < 0.05, difference from baseline) and pulse oxygen saturation (from 97% to 94%, p < 0.05), but during the succeeding infusion, the respiratory drive, measured as mean inspiratory flow, was enhanced (p < 0.05 difference from baseline), and the respiratory parameters returned to baseline level. No change in hemodynamics was noted, but a significant increase in plasma norepinephrine and epinephrine levels (from 0.9 to 1.6 nmol/L and from 0.3 to 0.8 nmol/L, respectively; p < 0.05) was observed after meperidine administration. Tramadol caused nausea more often than meperidine (p < 0.05, between treatments). CONCLUSIONS Tramadol exhibited a minimal effect on respiration and breathing pattern in healthy volunteers. The respiratory effects of meperidine bolus were predictable with decreasing tidal volume and pulse oxygen saturation. In contrast, during meperidine infusion, adequate respiration was preserved despite the large amount of meperidine infused.

Neurodevelopmental Burden at Age 5 Years in Patients With Univentricular Heart

BACKGROUND: Despite increasing survival, patients with hypoplastic left heart syndrome (HLHS) and other forms of functionally univentricular heart defects (UVHs) remain at increased risk of long-term neurodevelopmental deficits. METHODS: A nationwide sample of 23 patients with HLHS, 13 with UVH, and 40 controls were followed prospectively until the age of 5 years, when neurologic, neuropsychological, and motor examinations and brain MRI were performed. RESULTS: The median full-scale IQ was significantly lower in patients with HLHS (97, P < .001) and patients with UVH (112, P = .024) compared with controls (121). Major neurodevelopmental impairment was found in 26% of the patients with HLHS and 23% of those with UVH, and minor neurologic dysfunction was found in 43% and 46%, respectively. MRI revealed abnormalities, mostly ischemic changes of different degrees, in 82% of the patients with HLHS and in 56% of those with UVH. Prominent changes were significantly associated with neurodevelopmental findings and parental reports of adaptive behavior. In linear regression, significant risk factors for a worse outcome were a history of clinical seizures in connection with the primary operation, a lower diameter of the neonatal ascending aorta, and several pre-, peri-, and postoperative factors related to the primary and bidirectional Glenn operations. CONCLUSIONS: Although median cognitive performance was within the normal range, neurodevelopmental and brain MRI abnormalities were found in the majority of the patients with UVH, and especially in those with HLHS, at preschool age. Both a narrowed ascending aorta and operation-related factors contributed to these findings.

Neurodevelopment in children with hypoplastic left heart syndrome.

OBJECTIVE To assess neurodevelopment in children with hypoplastic left heart syndrome (HLHS) or other types of functionally single ventricle (univentricular heart, UVH) and to estimate the effect of possible clinical predictors on outcome. STUDY DESIGN A total of 22 patients with HLHS and 14 with UVH, surviving after palliative surgery performed in the same center, and 42 healthy control subjects were examined at a median age of 30.2 months neurologically and according to the Bayley Scales of Infant Development in a population based prospective neurodevelopmental follow-up study. RESULTS The mean Mental Developmental Index was significantly lower (89.9) in patients with HLHS than in control subjects (105.5, P<.001), whereas there was no difference between patients with UVH (98.5) and control subjects. The mean Psychomotor Developmental Index in patients with HLHS (80.7, P<.001) as well as in those with UVH (94.5, P=.016) was significantly inferior to that in control subjects (105.3). CONCLUSIONS In patients with HLHS, mean Mental Developmental Index lags behind control subjects. Psychomotor Developmental Index is impaired in patients with both HLHS and UVH. Routine neurodevelopmental follow-up is recommended for this seriously ill patient group.

Association of oliguria with the development of acute kidney injury in the critically ill

Urine output (UO) criterion may increase the sensitivity of the definition of acute kidney injury (AKI). We determined whether the empirically derived definition for oliguria (<0.5 ml/kg/h) is independently associated with adverse outcome. Data analysis included hourly recorded UO from the prospective, multicenter FINNAKI study conducted in 16 Finnish intensive care units. Confounder-adjusted association of oliguria of different severity and duration primarily with the development of AKI defined by creatinine criterion (Cr-AKI) or renal replacement therapy (RRT) was assessed. Secondarily, we determined the association of oliguria with 90-day mortality. Of the 1966 patients analyzed for the development of AKI, 454 (23.1%) reached this endpoint. Within this AKI cohort, 312 (68.7%) developed Cr-AKI, 21 (4.6%) commenced RRT without Cr-AKI, and 121 (26.7%) commenced RRT with Cr-AKI. Episodes of severe oliguria (<0.1 ml/kg/h) for more than 3 h were independently associated with the development of Cr-AKI or RRT. The shortest periods of consecutive oliguria independently associated with an increased risk for 90-day mortality were 6-12 h of oliguria from 0.3 to <0.5 ml/kg/h, over 6 h of oliguria from 0.1 to <0.3 ml/kg/h, and severe oliguria lasting over 3 h. Thus, our findings underlie the importance of hourly UO measurements.Kidney International advance online publication, 9 September 2015; doi:10.1038/ki.2015.269.

Morphine-induced cardiovascular stimulation : The effects of two doses on healthy subjects

UNLABELLED In humans, morphine induces hypotension, probably because of histamine liberation. Earlier animal studies have, however, suggested that morphine can induce immediate cardiovascular stimulation when given as a sole medication. The aim of this study was to evaluate the initial effects of morphine on circulation, oxygen consumption, and plasma histamine and catecholamine concentrations. Oxycodone was used as a reference drug. Eight healthy volunteers received, in a random, cross-over, double-blinded fashion: 0.07 mg/kg morphine (M1); 0.14 mg/kg morphine (M2); 0.14 mg/kg oxycodone (O); and placebo (P) as a 2-min IV injection for pain. Mean arterial blood pressure (MAP), heart rate (HR), and oxygen consumption (VO(2)) were recorded. Plasma histamine and catecholamine concentrations were determined. Both M1 and M2 elicited an initial, but transient, increase in MAP from 84 +/- 5 to 96 +/- 9 mm Hg (P < 0.05) and from 83 +/- 8 to 100 +/- 10 mm Hg (P < 0.05), respectively. A parallel increase in HR was also seen after M1 (from 62 +/- 12 to 70 +/- 10 bpm, P < 0.05) and M2 (from 67 +/- 9 to 78 +/- 8 bpm, P < 0.05). After M2, this was accompanied by a simultaneous increase in VO(2) from 295 +/- 39 mL/min to 322 +/- 61 mL/min (P < 0.05). After O, as well as P, no increase in MAP or HR was detected. Plasma histamine and catecholamine concentrations were not clearly affected by any of the treatments. We conclude that the immediate effect of morphine on the hemodynamics of healthy volunteers was stimulation, not hypotension. This effect was not seen in conjunction with oxycodone, a morphine-like mu-receptor agonist. IMPLICATIONS In this double-blinded, randomized study, we evaluated whether morphine could induce immediate cardiovascular stimulation, as seen previously in animal studies. In healthy volunteers, during a painful stimulus, morphine caused an initial, transient hemodynamic stimulation, accompanied by increased oxygen consumption, without detectable release of histamine or catecholamines into the plasma. Oxycodone caused only minor hemodynamic alterations.

The effect of low‐dose ketamine on fentanyl‐induced respiratory depression

This study evaluated if adding low‐dose ketamine to fentanyl could offer a haemodynamically stable drug combination with little respiratory side‐effects. Eight healthy, consenting male volunteers received in a random, cross‐over and double‐blind fashion both fentanyl 2 μgkg−1 + ketamine 0.25 mgkg−1 and fentanyl 2 μgkg−1 + placebo. The fentanyl and placebo reduced minute ventilation, alveolar ventilation and oxygen consumption ( p < 0.05), with little effect on haemodynamics. After fentanyl and ketamine, the decrease in minute ventilation and alveolar ventilation was attenuated compared to the placebo‐containing combination ( p < 0.05), but with a simultaneous increase in oxygen consumption ( p < 0.05) and stimulation of haemodynamics ( p < 0.05). Both treatments decreased oxygen saturation and arterial oxygen pressure similarly. Ketamine thus attenuated the fentanyl‐induced reduction in ventilation without preventing the decrease in blood oxygenation. In conclusion, combining low‐dose ketamine to fentanyl offers no benefits in terms of preventing respiratory depression.