Co-morbidity associated with development of severe COVID-19 before vaccine availability: a retrospective cohort study in the first pandemic year among the middle-aged and elderly in Jönköping county, Sweden.

BACKGROUND: In preparation of future pandemics, it is important to recognise population-level determinants associated with development of severe illness before efficient vaccines and evidence-based therapeutic measures are available. The aim of this study was to identify pre-pandemic diagnoses recorded in a middle-aged and elderly population that were associated with development of severe COVID-19 during the first pandemic year. METHODS: A cohort study design was used. Severe COVID-19 was defined as a course of illness that resulted in hospital admission or death. A retrospective analysis was performed that comprised all individuals aged 39 years and older (N = 189,951) living in Jönköping County, Sweden. All diagnosed morbidity recorded in contacts with health care during the pre-pandemic year 2019 was used to identify which diagnoses that were associated with development of severe COVID-19 in the first pandemic year 2020. The analyses were performed separately for each diagnosis using binary logistic regression with adjustment for sex and age. RESULTS: Severe COVID-19 was suffered by 0.67% (N = 1,280) of the middle-aged and elderly population in the first pandemic year. Individuals previously diagnosed with dementia, cerebral palsy, kidney failure, type 2 diabetes mellitus, hypertension, and obesity were at higher risk of developing severe COVID-19. For patients with Type 2 diabetes mellitus, the odds ratio (OR) was 2.18 (95% confidence interval, 1.92-2.48). Type 1 diabetes mellitus was not associated with increased risk. CONCLUSION: Diagnoses suggesting service provision at long-term healthcare facilities and co-morbidity with components of the metabolic syndrome were associated with an increased risk of developing severe COVID-19 in a middle-aged and elderly population before vaccines were available.

Model-predicted capillary leakage in graded hypotension: Extended analysis of experimental spinal anesthesia.

BACKGROUND: Crystalloid fluid infused during the induction of spinal anesthesia is involved in a complex set of physiological responses, including vasodilatation, reactive vasoconstriction, and changes in mean arterial pressure (MAP). The present evaluation compares the modeled capillary leakage in anesthetized versus nonanesthetized body regions. METHODS: Ten female volunteers (mean age, 29 years) received 25 ml/kg of Ringer's acetate over 60 min during experimental spinal anesthesia. Blood hemoglobin was measured repeatedly in the radial artery (reference), arm (cubital) vein, and leg (femoral) vein for 240 min. Each pattern of data served as a dependent variable in volume kinetic analyses that used mixed models software and MAP as covariate. RESULTS: The capillary leakage of fluid from the plasma to the extravascular space peaked at 17 ml/min when MAP was 100 mmHg, and the two venous curves were virtually identical. At MAP 60 mmHg, the rate was reduced to 10-12 ml/min when assessed in arterial blood and leg vein blood, but only 5 mmHg in blood collected from the arm vein. The distribution half-life of infused fluid was then 40 min in the leg and 80 min in the arm. These results suggest that vasoconstriction in nonanesthetized body regions halves the capillary leakage that is observed in vasodilated, anesthetized body regions. CONCLUSION: Graded hypotension during spinal anesthesia reduced the capillary filtration of fluid as determined by volume kinetic analysis. The effect was twice as great when venous blood was sampled from a nonanesthetized body region than from an anesthetized body region.

Kinetics of Ringer's Solution in Extracellular Dehydration and Hemorrhage.

BACKGROUND: Ringer's solution might be used to treat volume depletion (extracellular dehydration) and hemorrhage, but there is no integrated view of how these fluid balance disorders influence the kinetics of the infused volume. METHODS: Acute dehydration (mean 1.7 L) was induced by repeated doses of furosemide (5 mg) in 10 healthy male volunteers, and 0.5 L and 0.9 L of blood was withdrawn in random order on different occasions in another 10 male volunteers, just before administration of Ringer's acetate solution. Infusions performed in the normovolemic state served as controls. Measurements of blood hemoglobin and urinary excretion were used to create volume kinetic profiles that were analyzed using mixed-effects modeling software. RESULTS: Infusions over 15 to 30 min showed a marked distribution phase during which the plasma volume transiently increased by 50% to 75% of the administered volume. Dehydration and hemorrhage accelerated redistribution but retarded the elimination; the half-life of the infused fluid increased from 36 to 51 min (mean) from 1 L of dehydration and to 95 min from 1 L of hemorrhage. Extravascular accumulation decreased with the dehydration volume and increased with the hemorrhage volume.Simulations show that 60% as much Ringer is needed to replace volume depletion amounting to 1 L as compared with hemorrhage over a 2-h period. A continued but slower drip after the initial fluid resuscitation prevents rebound hypovolemia. CONCLUSIONS: Furosemide-induced dehydration and blood withdrawal in normotensive volunteers had modest effects on the Ringer's acetate kinetics. Urinary excretion was inhibited more by hemorrhage than by dehydration.

Effects of fluid resuscitation with hypertonic saline dextrane or Ringer's acetate after nonhemorrhagic shock caused by pulmonary contusion.

BACKGROUND: Injured lungs are sensitive to fluid resuscitation after trauma. Such treatment can increase lung water content and lead to desaturation. Hypertonic saline with dextran (HSD) has hyperosmotic properties that promote plasma volume expansion, thus potentially reducing these side effects. The aim of this study was to (1) evaluate whether fluid treatment counteracts hypotension and improves survival after nonhemorrhagic shock caused by lung contusion and (2) analyze whether resuscitation with HSD is more efficient than treatment with Ringer's acetate (RA) in terms of blood oxygenation, the amount of lung water, circulatory effects, and inflammatory response. METHODS: Twenty-nine pigs, all wearing body armor, were shot with a 7.62-mm assault rifle to produce a standardized pulmonary contusion. These animals were allocated into three groups: HSD, RA, and an untreated shot control group. Exposed animals were compared with animals not treated with fluid and shot with blank ammunition. For 2 hours after the shot, the inflammatory response and physiologic parameters were monitored. RESULTS: The impact induced pulmonary contusion, desaturation, hypotension, increased heart rate, and led to an inflammatory response. No change in blood pressure was observed after fluid treatment. HSD treatment resulted in significantly less lung water (p < 0.05) and tended to give better Pao2 (p = 0.09) than RA treatment. Tumor necrosis factor-α release and heart rate were significantly lower in animals given fluids. CONCLUSION: Fluid treatment does not affect blood pressure or mortality in this model of nonhemorrhagic shock caused by lung contusion. However, our data indicate that HSD, when compared with RA, has advantages for the injured lung.

Modelling of peripheral fluid accumulation after a crystalloid bolus in female volunteers - a mathematical study.

OBJECTIVE: To simultaneously model plasma dilution and urinary output in female volunteers. METHODS: Ten healthy female non-pregnant volunteers, aged 21-39 years (mean 29), with a bodyweight of 58-67 kg (mean 62.5 kg) participated. No oral fluid or food was allowed between midnight and completion of the experiment. The protocol included an infusion of acetated Ringer's solution, 25 ml/kg over 30 min. Blood samples (4 ml) were taken every 5 min during the first 120 min, and thereafter the sampling rate was every 10 min until the end of the experiment at 240 min. A standard bladder catheter connected to a drip counter to monitor urine excretion continuously was used. The data were analysed by empirical calculations as well as by a mathematical model. RESULTS: Maximum urinary output rate was found to be 19 (13-31) ml/min. The subjects were likely to accumulate three times as much of the infused fluid peripherally as centrally; 1/µ = 2.7 (2.0-5.7). Elimination efficacy, E(eff), was 24 (5-35), and the basal elimination k(b) was 1.11 (0.28-2.90). The total time delay T(tot) of urinary output was estimated as 17 (11-31) min. CONCLUSION: The experimental results showed a large variability in spite of a homogenous volunteer group. It was possible to compute the infusion amount, plasma dilution and simultaneous urinary output for each consecutive time point and thereby the empirical peripheral fluid accumulation. The variability between individuals may be explained by differences in tissue and hormonal responses to fluid boluses, which needs to be further explored.

Bilateral vagotomy inhibits apnea and attenuates other physiological responses after blunt chest trauma.

BACKGROUND: Behind armor blunt trauma (BABT) is defined as the nonpenetrating injury resulting from a ballistic impact on body armor. Some of the kinetic energy is transferred to the body, causing internal injuries and, occasionally, death. The aim of this study was to investigate if apnea and other pathophysiological effects after BABT is a vagally mediated reflex. METHODS: Sixteen anesthetized pigs wearing body armor, of which five were vagotomized, were shot with a standard 7.62 mm assault rifle. These animals were compared with control animals (n = 8), shot with blank ammunition. We performed bilateral vagotomy before the shot and assessed the outcome on the apnea period, respiration, circulation, and brain function. Animals were monitored during a 2-hour period after the shot. RESULTS: Nonvagotomized animals had a mean apnea period of 22 (6-44) seconds. This group also showed a significant decrease in oxygen saturation compared with control animals. Furthermore, electroencephalogram-changes were more pronounced in nonvagotomized animals. In contrast, vagotomized animals were protected from apnea and showed only a minor decrease in oxygen saturation. All exposed animals showed impaired circulation, and postmortem examination revealed a pulmonary contusion. CONCLUSION: This study shows that apnea after BABT is a vagally mediated reflex that can be inhibited by bilateral vagotomy. Our results indicate that the initial apnea period is an important factor for hypoxia after BABT. Supported ventilation should begin immediately if the affected person is unconscious and suffers from apnea. It should continue until the neurologic paralysis disappears and sufficient spontaneous breathing begins.

A volume loading test for the detection of hypovolemia and dehydration.

BACKGROUND AND OBJECTIVES: There is a need for simple method allowing detection of dehydration and hypovolemia. Based on a new theory of homeostatic blood states, we hypothesized that hemodilution following standardized crystalloid fluid bolus can be used to discriminate between baseline normohydration and dehydration, also normovolemia and hypovolemia. METHODS: Computer simulations based on previously published kinetic data were used to define the best time points for discrimination between baseline normohydration and dehydration, also normovolemia and hypovolemia. Hemodilution was compared at the proposed timing in 20 volunteers who received 40 infusions of Ringer's solution of 25 mL/kg during 30 minutes. RESULTS: Simulations indicated that preexisting hypovolemia could be best detected at the end of infusion, while dehydration 20-30 min later. In baseline hypovolemia, the peak reduction of hemoglobin concentration was 16.0% at the end of infusion, while it was only 11.8%, when participants were normovolemic (P<0.004). In baseline dehydration, the residual hemodilution was 8.6%, when measured 30 min after the end of infusion. It was only 3.1% in baseline normohydration (P<0.006). CONCLUSIONS: In response to fluid load, the baseline dehydration exaggerates the lowering of residual hemoglobin in respect to baseline. Meanwhile, baseline hypovolemia exaggerates the lowering of peak hemoglobin concentration. The volume loading test that deploys interpretation of hemoglobin dynamics in response to the test volume load could possibly serve as an easily available guide to indicate an individual patient's baseline hydration state and volemia. The introduction of continuous noninvasive monitoring of hemoglobin concentration would expand the applicability of the new method.

Severe lung contusion and death after high-velocity behind-armor blunt trauma: relation to protection level.

The most-used safety recommendation for protective vests is that the impact should not cause more than a 44-mm impression in plasticine. The aim of this study was to investigate whether this criterion was sufficient if the vest was exposed to a high-velocity projectile. We tested the hypothesis with pigs divided into a 40-mm group (n = 10) and a 34-mm group (n = 8) protected by a vest allowing a 40-mm or 34-mm impression in plasticine, respectively. Five (50%) of 10 animals in the 40-mm group and 2 (25%) of 8 in the 34-mm group died due to the trauma. We observed severe lung hematoma, impaired circulation, desaturation, and electroencephalogram changes. These effects were more aggravated in the 40-mm group compared to the 34-mm group. Based on our results, the overall judgment is that the safety criterion of 44-mm impression is insufficient when a vest is exposed to a high-velocity projectile.

Electroencephalogram, circulation, and lung function after high-velocity behind armor blunt trauma.

BACKGROUND: Behind armor blunt trauma (BABT) is defined as the nonpenetrating injury resulting from a ballistic impact on personal body armor. The protective vest may impede the projectile, but some of the kinetic energy is transferred to the body, causing internal injuries and occasionally death. The aim in this study was to investigate changes in electroencephalogram (EEG) and physiologic parameters after high-velocity BABT. METHODS: Eight anesthetized pigs, wearing body armor (including a ceramic plate) on the right side of their thorax, were shot with a 7.62-mm assault rifle (velocity approximately 800 m/s). The shots did not penetrate the armor and these animals were compared with control animals (n = 4), shot with blank ammunition. EEG and several physiologic parameters were thereafter monitored during a 2-hour period after the shot. RESULTS: All animals survived during the experimental period. Five of the exposed animals showed a temporary effect on EEG. Furthermore, exposed animals displayed decreased cardiac capacity and an impaired oxygenation of the blood. Postmortem examination revealed subcutaneous hematomas and crush injuries to the right lung. CONCLUSION: The results in our animal model indicate that high-velocity BABT induce circulatory and respiratory dysfunction, and in some cases even transient cerebral functional disturbances.

Tranexamic acid does not prevent rebleeding in an uncontrolled hemorrhage porcine model.

BACKGROUND: Fluid resuscitation after uncontrolled hemorrhage might promote rebleeding and irreversible shock. Tranexamic acid is a procoagulant drug that limits blood loss after surgery of the hip, knee, and heart. We hypothesized that pretreatment with tranexamic acid reduces the rebleeding in uncontrolled hemorrhage and thereby allows safe administration of crystalloid fluid resuscitation. METHODS: A 120-minute intravenous infusion of 100 mL/kg of Ringer's solution was given to 24 pigs (mean weight, 20 kg) 10 minutes after lacerating the infrarenal aorta. The animals were randomized to receive an intravenous injection of 15 mg/kg of tranexamic acid or placebo just before starting the resuscitation. Rebleeding events were monitored by two ultrasonic probes positioned proximal and distal to the laceration. RESULTS: Tranexamic acid had no effect on the number of rebleeding events, bled volume, or mortality. The initial bleeding stopped within 4 minutes after the injury. The five animals that died suffered from 4.4 rebleeding events on average, which tripled the total blood loss, whereas the survivors had only 1.3 such events during fluid resuscitation (p < 0.02). At autopsy, death was associated with a larger total hemorrhage; the blood recovered from the abdomen weighed 1.4 kg (median) in nonsurvivors and 0.6 kg in survivors (p < 0.001), with the difference being attributable to rebleeding. CONCLUSION: Rebleeding events increased the amount of blood lost and the mortality in uncontrolled aortic hemorrhage. Tranexamic acid offered no benefit.

Hemodynamic response and oxygen transport in pigs resuscitated with maleimide-polyethylene glycol-modified hemoglobin (MP4).

Cell-free Hb increases systemic and pulmonary pressure and resistance and reduces cardiac output and heart rate in animals and humans, effects that have limited their clinical development as "blood substitutes." The primary aim of this study was to evaluate the hemodynamic response to infusion of several formulations of a new polyethylene glycol (PEG)-modified human Hb [maleimide PEG Hb (MalPEGHb)] in swine, an animal known to be sensitive to Hb-induced vasoconstriction. Anesthetized animals underwent controlled hemorrhage (50% of blood volume), followed by resuscitation (70% of shed volume) with 10% pentastarch (PS), 4% MalPEG-Hb in lactated Ringer (MP4), 4% MalPEG-Hb in pentastarch (HS4), 2% MalPEG-Hb in pentastarch (HS2), or 4% stroma-free Hb in lactated Ringer solution (SFH). Compared with baseline, restoration of blood volume after resuscitation was similar and not significantly different for the PS (103%), HS2 (99%), HS4 (106%), and MP4 (87%) animals but significantly less for the SFH animals (66%) (P < 0.05). All solutions that contained MalPEG-Hb restored mean arterial and pulmonary pressure and cardiac output. Systemic vascular resistance was unchanged, and pulmonary arterial pressure and resistance were increased slightly. Both systemic and pulmonary vascular resistance increased significantly in animals that received SFH, despite less adequate blood volume restoration. Oxygen consumption was maintained in all animals that received MalPEG-Hb, but not PS. Base excess improved only with MalPEG-Hb and PS, but not SFH. Red blood cell O2 extraction was significantly increased in animals that received Hb, regardless of formulation. These data demonstrate resuscitation with MalPEG-human Hb without increasing systemic vascular resistance and support our previous observations in animals suggesting that the efficacy of low concentrations of PEG-Hb in the plasma results from reduced vasoconstriction.

Distribution and elimination of crystalloid fluid in pre-eclampsia.

Pre-eclampsia (PE) is a disease of pregnancy associated with peripheral oedema and hypovolaemia, but few details are known about how women with PE handle a volume load of crystalloid fluid compared with healthy pregnant women. To study this issue, Ringer's acetate solution (12.5 ml/kg of body weight) was given by intravenous infusion over 30 min to eight women with PE and to eight healthy pregnant women matched with respect to gestational week (mean, 34 weeks). Venous blood was sampled and excreted urine was collected over 90 min to study the time course of the volume expansion by means of volume kinetic analysis. The results show that the size of the central body fluid space expanded by the infused fluid was smaller in PE (mean, 2940 ml compared with 4240 ml respectively; P<0.04), and the clearance constants for distribution (100 ml/min compared with 43 ml/min; P<0.04) and elimination (125 ml/min compared with 36 ml/min; P<0.02) were higher in the women with PE than in the controls. Less excess volume accumulated in the central body fluid space in the presence of PE, whereas the rates of distribution and elimination were higher during and for 15 min after the infusion. It is concluded that Ringer's acetate solution fluid is both distributed and eliminated faster in women with PE than in matched pregnant controls.

Rapid water and slow sodium excretion of acetated Ringer's solution dehydrates cells.

UNLABELLED: Acetated Ringer's solution is a slightly hypotonic infusion fluid (osmolality 270 mosmol/kg) that has inspired the belief that the fluid causes a shift of water volume to the intracellular space. We assessed the role of the kidney in modifying this volume shift by infusing 25 mL/kg of Ringer's acetate solution (mean, 1565 mL) over a time period of 15, 30, 45, and 80 min on different occasions in 5 healthy female volunteers. Regardless of the rate of administration, the excreted urine contained only half as much sodium (mean, 67 mmol/L) as the infused fluid. As there was only a slight increase of 0.9 mmol/L in the serum sodium level, mass balance calculations indicated that 274 mL of water had shifted from the intracellular to the extracellular space 30 min after the infusions ended (P < 0.001). This fluid shift was also maintained over the subsequent 90 min. In conclusion, infusion of Ringer's acetate solution does not promote cellular swelling as a result of the excretion of urine that is low in sodium. A slight dehydration of fluid from the intracellular space still persisted when our measurements ended 2 h after completing the infusion. IMPLICATIONS: The kidney promotes slight cellular dehydration after infusion of Ringer's acetate solution by rapid excretion of water, whereas natriuresis occurs more slowly. In volunteers, this translocation amounted to 18% of the infused fluid volume and persisted for at least 2 h.

Kinetics of isotonic and hypertonic plasma volume expanders.

BACKGROUND: Major differences in plasma volume expansion between infusion fluids are fairly well known, but there is a lack of methods that express their dynamic properties. Therefore, a closer description enabled by kinetic modeling is presented. METHODS: Ten healthy male volunteers received, on different occasions, a constant-rate intravenous infusion over 30 min consisting of 25 ml/kg of 0.9% saline, lactated Ringer's solution, acetated Ringer's solution, 5 ml/kg of 7.5% saline, or 3 ml/kg of 7.5% saline in 6% dextran. One-, two-, and three-volume kinetic models were fitted to the dilution of the total venous hemoglobin concentration over 240 min. Osmotic fluid shifts were considered when hypertonic fluid was infused. RESULTS: All fluids induced plasma dilution, which decreased exponentially after the infusions. The ratio of the area under the dilution-time curve and the infused fluid volume showed the following average plasma-dilution dose-effect (efficiency), using 0.9% saline as the reference (= 1): lactated Ringer's solution, 0.88; acetated Ringer's solution, 0.91; hypertonic saline, 3.97; and hypertonic saline in dextran, 7.22 ("area approach"). Another comparison, based on kinetic analysis and simulation, showed that the strength of the respective fluids to dilute the plasma by 20% within 30 min was 0.94, 0.97, 4.44, and 6.15 ("target dilution approach"). Between-subject variability was approximately half as high for the latter approach. CONCLUSIONS: The relative efficiency of crystalloid infusion fluids differs depending on whether the entire dilution-time profile or only the maximum dilution is compared. Kinetic analysis and simulation is a useful tool for the study of such differences.

Lower dose of hypertonic saline dextran reduces the risk of lethal rebleeding in uncontrolled hemorrhage.

To challenge whether the recommended dose of 4 mL/kg of 7.5% sodium chloride in 6% Dextran (HSD) is optimal for fluid resuscitation in uncontrolled hemorrhage, 30 anesthetized pigs were randomized to receive a 5-min intravenous infusion of either 1, 2, or 4 mL/kg of HSD beginning 10 min after inducing a 5-mm laceration in the infrarenal aorta. In addition to conventional hemodynamic monitoring, the blood loss was calculated as the difference in blood flow rates between flow probes placed proximal and distal to the injury. The results show that the bleeding stopped between 3 and 4 min after the injury and amounted to 338+/-92 mL (mean +/- SEM), which corresponds to 28.5%+/-6.6% of the estimated blood volume. After treatment with HSD was started, six rebleeding events occurred in the 1-mL group, 11 in the 2-mL group, and 16 in the 4-mL group. The amount of blood lost due to rebleeding increased significantly with the dose of HSD and was also associated with a fatal outcome. The total blood loss was 408 mL in the survivors and 630 mL in the nonsurvivors (median, P < 0.007). The mortality in the three groups was 20%, 50%, and 50%, respectively. In conclusion, infusing 4 mL/kg of HSD after uncontrolled aortic hemorrhage promoted rebleeding and increased the mortality, while a dose of 1 mL/kg appeared to be more suitable.

Leukocytosis after fluid loading and induction of epidural anesthesia.

The present study shows that leukocytosis occurs from fluid loading and from the small amounts of adrenaline given epidurally. Five healthy volunteers received an intravenous infusion of 25 ml·kg-1 b.w. of Ringer's acetate solution over 15, 30, 45, and 80 min, and epidural anesthesia (EDA) was induced in 25 urology patients using mepivacaine 2% with or without adrenaline 1∶200 000. In the volunteers, we found that the total leukocyte count increased by up to 33% within 1 h after rapid volume loading. This increase was accounted for by neutrophils and lymphocytes. In the patients, the leukocyte count increased by 32% during the onset of EDA when mepivacaine with adrenaline was used. This increase was accounted for by lymphocytes. Our results suggest that caution is needed when interpreting the importance of a raised leukocyte count in samples taken in association with fluid loading and also when EDA is induced by a local anesthestic solution that contains adrenaline.