Inpatient palliative care referral and 9-month hospital readmission in patients with congestive heart failure: a linked nationwide analysis.

OBJECTIVE: End-stage heart failure (HF) is characterized by high symptom burden and frequent hospitalization. Palliative care (PC) is recommended for advanced HF, and there is some evidence in other diseases that this may reduce readmission rates. We attempted examine the association of an inpatient PC visit on hospital readmission for patients admitted with HF. METHODS: Retrospective linked nationwide analysis from 2013 with 9-month follow-up for all hospital readmissions for patients admitted with HF exacerbations using the Nationwide Readmission Database (NRD). The NRD gathers all hospital admissions for patients from 22 states and tracks patients throughout the year, allowing for examination of readmission statistics. A propensity score model for PC visit was made, and patients were matched in a 1 : 1 fashion. RESULTS: There were 102 746 patients who survived an admission for HF in the first 3 months of 2013. Of these, 2287 (2.2%) patients had a PC visit as inpatients. After matching based on propensity for a PC visit during the index hospitalization, 2282 patients who received a PC visit were matched to 2282 patients who did not. Those receiving a PC visit were less likely to be readmitted for HF (9.3% vs. 22.4%, P < 0.01) or for any cause (29.0% vs. 63.2%, P < 0.01) during the 9-month follow-up period. The average hospital charges during the follow-up period for the non-PC cohort were $77 643 per patient. The average charges for PC patients were $23 200 (P < 0.01). CONCLUSIONS: Patients with HF who received an inpatient PC visit had significantly lower rates of all-cause and HF-specific readmission in the subsequent 9 months. Total 9-month hospital charges were also significantly lower for patients who received an inpatient PC visit.

Two-year follow-up of patients with septic shock presenting with low HDL: the effect upon acute kidney injury, death and estimated glomerular filtration rate.

BACKGROUND: Sepsis is associated with decreased levels of high-density lipoprotein (HDL) cholesterol. HDL has anti-inflammatory properties, and the use of Apo A-I mimetic peptides is associated with renal function improvement in animal models of sepsis. However, it is not known whether decreased HDL level results in impaired renal function in human sepsis. We investigated whether low levels of HDL conferred an increased risk of sepsis-associated acute kidney injury (AKI) or long-term decreased estimated glomerular filtration rate (eGFR) after sepsis. METHODS: HDL concentration (mg dL-1 ) was measured in plasma samples from 180 patients with septic shock at admission to the Emergency Department (ED). We divided the patients using median HDL as a cut-off value and assessed the frequency of sepsis-associated AKI and long-term decreased eGFR after sepsis. Univariate and multivariate analyses were performed. RESULTS: Patients with low HDL had a significantly greater frequency of KDIGO 2 or 3 sepsis-associated AKI [39/90 (43.3%) vs. 12/90 (13.3%), P < 0.001] and decreased long-term eGFR [24/58 (41.4%) vs. 11/57 (19.3%), P = 0.018] compared to those with high HDL. The adjusted OR for sepsis-associated AKI and decreased eGFR after sepsis in the lower HDL group was 2.80 (95% CI 1.08-7.25, P = 0.033) and 5.45 (95% CI 1.57-18.93, P = 0.008), respectively. CONCLUSION: Low HDL levels during sepsis are associated with increased risk of sepsis-associated AKI, and/or subsequent decreased eGFR. These results suggest that HDL may be involved and/or may be a marker of kidney injury during and after sepsis.

PIERS proteinuria: relationship with adverse maternal and perinatal outcome.

OBJECTIVE: To examine the ability of three different proteinuria assessment methods (urinary dipstick, spot urine protein:creatinine ratio [Pr/Cr], and 24-hour urine collection) to predict adverse pregnancy outcomes. METHODS: We performed a prospective multicentre cohort study, PIERS (Preeclampsia Integrated Estimate of RiSk), in seven academic tertiary maternity centres practising expectant management of preeclampsia remote from term in Canada, New Zealand, and Australia. Eligible women were those admitted with preeclampsia who had at least one antenatal proteinuria assessment by urinary dipstick, spot urine Pr/Cr ratio, and/or 24-hour urine collection. Proteinuria assessment was done either visually at the bedside (by dipstick) or by hospital clinical laboratories for spot urine Pr/Cr and 24-hour urine collection. We calculated receiver operating characteristic area under the curve (95% CI) for each proteinuria method and each of the combined adverse maternal outcomes (within 48 hours) or adverse perinatal outcomes (at any time). Models with AUC ≥ 0.70 were considered of interest. Analyses were run for all women who had each type of proteinuria assessment and for a cohort of women ("ALL measures") who had all three proteinuria assessments. RESULTS: More women were proteinuric by urinary dipstick (≥ 2+, 61.4%) than by spot urine Pr/Cr (≥ 30 g/mol, 50.4%) or 24-hour urine collection (≥ 0.3g/d, 34.7%). Each proteinuria measure evaluated had some discriminative power, and dipstick proteinuria (categorical) performed as well as other methods. No single method was predictive of adverse perinatal outcome. CONCLUSION: The measured amount of proteinuria should not be used in isolation for decision-making in women with preeclampsia. Dipstick proteinuria performs as well as other methods of assessing proteinuria for prediction of adverse events.

Acute Kidney Injury and Renal Replacement Therapy in COVID-19 Versus Other Respiratory Viruses: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-2019 (COVID-19). Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, to its viral receptor, angiotensin converting enzyme 2 (ACE2), results in viral entry and may cause AKI. OBJECTIVES: We performed a systematic review and meta-analysis of the frequencies of AKI and renal replacement therapy (RRT) in critically ill COVID-19 patients and compared those frequencies with patients who were infected by respiratory viruses that bind or downregulate ACE2 (ACE2-associated viruses) and viruses that do not bind nor downregulate ACE2 (non-ACE2-associated viruses). DESIGN: Systematic review and meta-analysis. SETTING: Observational studies on COVID-19 and other respiratory viral infections reporting AKI and RRT were included. The exclusion criteria were non-English articles, non-peer-reviewed articles, review articles, studies that included patients under the age of 18, studies including fewer than 10 patients, and studies not reporting AKI and RRT rates. PATIENTS: Adult COVID-19, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and influenza patients. MEASUREMENTS: We extracted the following data from the included studies: author, year, study location, age, sex, race, diabetes mellitus, hypertension, chronic kidney disease, shock, vasopressor use, mortality, intensive care unit (ICU) admission, ICU mortality, AKI, and RRT. METHODS: We systematically searched PubMed and EMBASE for articles reporting AKI or RRT. AKI was defined by authors of included studies. Critical illness was defined by ICU admission. We performed a random effects meta-analysis to calculate pooled estimates for the AKI and RRT rate within each virus group using a random intercept logistic regression model. RESULTS: Of 23 655 hospitalized, critically ill COVID-19 patients, AKI frequencies were not significantly different between COVID-19 patients (51%, 95% confidence interval [CI]: 44%-57%) and critically ill patients infected with ACE2-associated (56%, 95% CI: 37%-74%, P = .610) or non-ACE2-associated viruses (63%, 95% CI: 43%-79%, P = .255). Pooled RRT rates were also not significantly different between critically ill, hospitalized patients with COVID-19 (20%, 95% CI: 16%-24%) and ACE2-associated viruses (18%, 95% CI: 8%-33%, P = .747). RRT rates for both COVID-19 and ACE2-associated viruses were significantly different (P < .001 for both) from non-ACE2-associated viruses (49%, 95% CI: 44%-54%). After adjusting for shock or vasopressor use, AKI and RRT rates were not significantly different between groups. LIMITATIONS: Limitations of this study include the heterogeneity of definitions of AKI that were used across different virus studies. We could not match severity of infection or do propensity matching across studies. Most of the included studies were conducted in retrospective fashion. Last, we did not include non-English publications. CONCLUSIONS: Our findings suggest that viral ACE2 association does not significantly alter the rates of AKI and RRT among critically ill patients admitted to the ICU. However, the rate of RRT is lower in patients with COVID-19 or ACE2-associated viruses when compared with patients infected with non-ACE2-binding viruses, which might partly be due to the lower frequencies of shock and use of vasopressors in these two virus groups. Prospective studies are necessary to demonstrate whether modulation of the ACE2 axis with Renin-Angiotensin System inhibitors impacts the rates of AKI and whether they are beneficial or harmful in COVID-19 patients.

MISE EN CONTEXTE: L'insuffisance rénale aiguë (IRA) est une complication potentiellement mortelle de la maladie à coronavirus-2019 (COVID-19). Obligatoire du Coronavirus 2 du Syndrome Respiratoire Aigu Sévère (SARS-CoV-2), le virus responsable du COVID-19, à son récepteur, l'enzyme de conversion de l'angiotensine 2 (ACE2), entraîne une entrée virale et peut provoquer une IRA. OBJECTIFS DE L'ÉTUDE: Nous avons effectué une revue systématique et une méta-analyse des fréquences de l'IRA et de la thérapie de remplacement renal (RRT) chez les patients COVID-19 gravement malades et a comparé ces fréquences avec les patients qui ont été infectés par des voies respiratoires virus qui lient ou régulent négativement l'ACE2 (virus associés à l'ACE2) et les virus qui ne régulent pas négativement ni ne lient l'ACE2 (virus non associés à l'ACE2). CADRE ET TYPE D'ÉTUDE: Revue systématique et méta-analyse. Des études d'observation sur le COVID-19 et d'autres infections virales respiratoires signalant une AKI et une RRT ont été incluses. Les critères d'exclusion étaient des articles non anglophones, des articles non évalués par des pairs, des articles de revue, des études incluant des patients moins de 18 ans, les études incluant moins de 10 patients et les études ne rapportant pas les taux d'IRA et de RRT. PATIENTS: Adultes COVID-19, syndrome respiratoire aigu sévère (SRAS), syndrome respiratoire du Moyen-Orient (MERS) et malades de la grippe. MESURES: Nous avons extrait les données suivantes des études incluses : auteur, année, lieu de l'étude, âge, sexe, race, diabète sucré, hypertension, maladie rénale chronique, état de choc, utilisation de vasopresseurs, mortalité, admission en unité de soins intensifs (USI), Mortalité en soins intensifs, AKI et RRT. MÉTHODOLOGIE: Nous avons systématiquement recherché dans PubMed et EMBASE les articles rapportant AKI ou RRT. AKI a été défini par les auteurs des études incluses. La maladie grave a été définie par l'admission aux soins intensifs. Nous avons effectué une méta-analyse à effets aléatoires pour calculer estimations regroupées pour le taux d'IRA et de RRT au sein de chaque groupe de virus à l'aide d'un modèle de régression logistique d'interception aléatoire. RÉSULTATS: Sur 23 655 patients hospitalisés et gravement malades COVID-19, les fréquences AKI n'étaient pas significativement différentes entre patients COVID-19 (51 %, intervalle de confiance à 95 % [IC] : 44 %-57 %) et patients gravement malades infectés par l'ACE2 associé (56 %, IC à 95 % : 37 % à 74 %, P = 0,610) ou des virus non associés à l'ACE2 (63 %, IC à 95 % : 43 % à 79 %, P = 0,255). Tarifs RRT groupés n'étaient pas non plus significativement différents entre les patients hospitalisés gravement malades atteints de COVID-19 (20 %, IC à 95 % : 16 % à 24 %) et virus associés à l'ACE2 (18 %, IC à 95 % : 8 % à 33 %, P = 0,747). Taux de RRT pour les virus associés au COVID-19 et à l'ACE2 étaient significativement différents (P < 0,001 pour les deux) des virus non associés à l'ACE2 (49 %, IC à 95 % : 44 % à 54 %). Après ajustement pour le choc ou l'utilisation de vasopresseurs, les taux d'IRA et de RRT n'étaient pas significativement différents entre les groupes. LIMITES DE L'ÉTUDE: Les limites de cette étude incluent l'hétérogénéité des définitions de l'IRA qui ont été utilisées pour différents virus études. Nous n'avons pas pu faire correspondre la gravité de l'infection ou faire une correspondance de propension entre les études. La plupart des études incluses ont été menées de manière rétrospective. Enfin, nous n'avons pas inclus les publications non anglophones. CONCLUSIONS: Nos résultats suggèrent que l'association virale ACE2 ne modifie pas de manière significative les taux d'IRA et de RRT parmi les patients gravement malades admis aux soins intensifs. Cependant, le taux de RRT est plus faible chez les patients atteints de COVID-19 ou associés à l'ACE2 virus par rapport aux patients infectés par des virus ne se liant pas à l'ACE2, ce qui pourrait être dû en partie à la plus faible fréquences de choc et utilisation de vasopresseurs dans ces deux groupes de virus. Des études prospectives sont nécessaires pour démontrer si la modulation de l'axe ACE2 avec les inhibiteurs du système rénine-angiotensine a un impact sur les taux d'IRA et si ells sont bénéfiques ou nocifs chez les patients COVID-19.

Sepsis in pregnancy and the puerperium.

Sepsis remains a leading cause of maternal morbidity and mortality. Recognition and treatment of maternal sepsis are often delayed due to the physiological adaptations of pregnancy and vague or absent signs and symptoms during its initial presentation. Over the past decade, our understanding of sepsis has evolved and maternal early warning systems have been developed in an effort to help providers promptly identify and stratify parturients who are at risk. In addition, new consensus definitions and care bundles have recently been published by the World Health Organization and the Surviving Sepsis Campaign to facilitate earlier recognition and timely management of sepsis. In this narrative review, we summarize the available evidence about sepsis and provide an overview of the research efforts focused on maternal sepsis to date. Controversies and challenges surrounding the anesthetic management of parturients with sepsis or at risk of developing sepsis during pregnancy or the puerperium will be highlighted.

Current CHS and NHBPEP criteria for severe preeclampsia do not uniformly predict adverse maternal or perinatal outcomes.

OBJECTIVE: To determine the association between adverse maternal/perinatal outcomes and Canadian and U.S. preeclampsia severity criteria. METHODS: Using PIERS data (Preeclampsia Integrated Estimate of RiSk), an international continuous quality improvement project for women hospitalized with preeclampsia, we examined the association between preeclampsia severity criteria and adverse maternal and perinatal outcomes (univariable analysis, Fisher's exact test). Not evaluated were variables performed in <80% of pregnancies (e.g., 24-hour proteinuria). RESULTS: Few of the evaluated variables were associated with adverse maternal (chest pain/dyspnea, thrombocytopenia, 'elevated liver enzymes', HELLP syndrome, and creatinine >110 microM) or perinatal outcomes (dBP >110 mm Hg and suspected abruption) (at p < 0.01). CONCLUSIONS: In the PIERS cohort, most factors used in the Canadian or American classifications of severe preeclampsia do not predict adverse maternal and/or perinatal outcomes. Future classification systems should take this into account.

Gastric-arterial PCO2 gradient does not reflect systemic and splanchnic hemodynamics or oxygen transport after cardiac surgery.

Gastric mucosal-arterial PCO2 gradient (P(g-a)CO2) is used to assess splanchnic perfusion and oxygenation. We evaluated whether P(g-a)CO2 reflects whole body (Q) and splanchnic (Qsp) blood flow, oxygen delivery (DO2) and consumption (VO2) after coronary artery by pass graft (CABG) operation. Thirty patients received dobutamine or dopexamine to increase cardiac index, 15 patients enalapril or sodium nitroprusside to lower blood pressure, and 30 patients were controls. We measured Q, Qsp (hepatic vein catheter and indocyanine green), and gastric mucosal PCO2 (nasogastric tonometer) before and after interventions. Multiple linear regression model showed that none of the changes in Q, Qsp, and splanchnic or systemic DO2 and VO2 significantly explained changes in P(g-a)CO2 (deltaP(g-a)CO2). All independent variables together explained only 7% of deltaP(g-a)CO2. Increased splanchnic blood flow (0.65 +/- .19 vs. 0.94 +/- .31 L/min/m2, P < 0.001) and increased splanchnic DO2 (101 +/- 28 vs. 143 +/- 42 mL/min/m2, P < 0.001) during catecholamine infusions were associated with increased P(g-a)CO2 (8 +/- 8 vs. 11 +/- 7 mmHg, P = 0.003). P(g-a)CO2 does not reflect whole body or splanchnic blood flow, DO2 or VO2 after CABG operations. The physiology of P(g-a)CO2 is complex and therefore it is difficult for clinicians to interpret changes in gastric mucosal-arterial PCO2 gradient in individual patients after cardiac surgery.

Assessment of three methods to reduce the influence of mathematical coupling on oxygen consumption and delivery relationships.

STUDY OBJECTIVES: To determine if oxygen consumption/oxygen delivery (VO2/DO2) relationships derived using calorimetry (which are not influenced by shared measurement error) agreed with those obtained using the pulmonary artery (PA) catheter alone. To evaluate three strategies to reduce the influence of shared measurement error to determine if agreement between the two methods could be improved. METHODS: Twenty-seven patients were studied following coronary artery bypass surgery. Calorimetric VO2, six thermodilution cardiac outputs (COs), and arterial and mixed venous oxygen content measurements were made at baseline and were repeated 30 min following dobutamine administrations of 3 microg/kg/min and 5 microg/kg/min. RESULTS: Dobutamine produced a dose-dependent increase in DO2, from 378+/-65 mL/min/m2 to 446+/-78 mL/min/m2 (p<0.01) and in both PA catheter and calorimetric-derived VO2, from 104+/-18 mL/min/Mi2 to 114+/-22 mL/min/m2 (p<0.05) and from 117+/-15 mL/min/m2 to 126+/-19 mL/min/m2 (p<0.01), respectively. Agreement was poor (bias=12%, SD=21%) between the calorimetric and PA catheter methods of determining VO2/DO2 slope. When three CO measurements were used to calculate VO2, and three separate CO measurements were used to calculate DO2, the level of agreement between the two methods improved (bias=2%, SD=15%). Increasing the number of COs resulted in a similar improvement in the level of agreement between the two methods. Weighting the slope to the observed change in DO2 was the best method to improve the level of agreement (bias=2%, SD=6% for three COs). CONCLUSIONS: To reduce the influence of shared measurement error, the best strategy to improve the measurement of VO2/DO2 slope is to maximize the change in DO2 (optimally over 100 mL/min/m2).

Physiology of vasopressin relevant to management of septic shock.

Vasopressin is emerging as a rational therapy for the hemodynamic support of septic shock and vasodilatory shock due to systemic inflammatory response syndrome. The goal of this review is to understand the physiology of vasopressin relevant to septic shock in order to maximize its safety and efficacy in clinical trials and in subsequent therapeutic use. Vasopressin is both a vasopressor and an antidiuretic hormone. It also has hemostatic, GI, and thermoregulatory effects, and is an adrenocorticotropic hormone secretagogue. Vasopressin is released from the axonal terminals of magnocellular neurons in the hypothalamus. Vasopressin mediates vasoconstriction via V1-receptor activation on vascular smooth muscle and mediates its antidiuretic effect via V2-receptor activation in the renal collecting duct system. In addition, vasopressin, at low plasma concentrations, mediates vasodilation in coronary, cerebral, and pulmonary arterial circulations. Septic shock causes first a transient early increase in blood vasopressin concentrations that decrease later in septic shock to very low levels compared to other causes of hypotension. Vasopressin infusion of 0.01 to 0.04 U/min in patients with septic shock increases plasma vasopressin levels to those observed in patients with hypotension from other causes, such as cardiogenic shock. Increased vasopressin levels are associated with a lesser need for other vasopressors. Urinary output may increase, and pulmonary vascular resistance may decrease. Infusions of > 0.04 U/min may lead to adverse, likely vasoconstriction-mediated events. Because clinical studies have been relatively small, focused on physiologic end points, and because of potential adverse effects of vasopressin, clinical use of vasopressin should await a randomized controlled trial of its effects on clinical outcomes such as organ failure and mortality.

Plasma ionized calcium and blood lactate concentrations are inversely associated in human lactic acidosis.

Plasma ionized calcium [Ca++] concentrations are decreased in patients having lactic acidosis. To further investigate this observation, we prospectively studied nine critically ill patients who had lactic acidosis and measured arterial pH, PCO2, [Ca++], lactate, and albumin concentrations. We found a strong association between decreased [Ca++] and increased plasma lactate concentrations (r2 = 0.78, p less than or equal to 0.001). This unexpected association--[Ca++] usually increases with increasing acidosis--might be clinically important and the mechanism deserves further investigation.

The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series.

OBJECTIVE: To review all cases of septic shock treated with vasopressin to determine the effects on hemodynamic and renal function and to document any adverse effects. SETTING: A 14-bed mixed medical-surgical ICU of St. Paul's Hospital, a 450-bed tertiary referral hospital affiliated with the University of British Columbia. PATIENTS: All ICU patients who received vasopressin for treatment of severe septic shock between August 5, 1997, and March 21, 1999. RESULTS: We identified 50 patients: age 60 (+/-14); APACHE II score 27 (+/-7). Baseline data (T0) was compared to data at T4, T24 and T48 (4, 24 and 48 h) on infusion. Mean arterial pressure (MAP) increased by 18% from T0 to T4 and remained stable at T24 (p=0.006) and T48 (p=0.008). Systolic pulmonary artery pressure (PAP) was unchanged at 45+/-13 mmHg. Mean cardiac index (CI) decreased by 11% at T4 (p=0.03). Urine output increased 79% at T4 (p=0.005) and further increases were not significant at T24 and T48. Mean pressor dosage decreased by 33% at T4 (p=0.001), by 53% at T24 (p=0.002) and by 48% at T48 (p=0.01). Hospital mortality was 85%. There were six cardiac arrests; all but one occurred at a vasopressin dose of 0.05 U/min or more. CONCLUSIONS: In this group of patients with severe septic shock, vasopressin infusion increased MAP and urine output and decreased catecholamine requirements. Doses higher than 0.04 U/min were not associated with increased effectiveness and may have been associated with higher adverse effects.

Heterogeneity of oxygen delivery impairs oxygen extraction by peripheral tissues: theory.

The hypothesis that the distribution of oxygen demand in relation to oxygen supply (dO2/qO2) effects oxygen extraction in peripheral tissues was tested. By using a simple theoretical model, realistic biphasic oxygen consumption-delivery relationships were predicted from dO2/qO2 distributions. Increasing width (relative dispersion) of the dO2/qO2 distribution, indicating mismatch between oxygen demand and supply, nonlinearly decreased the critical oxygen extraction ratio (calculated by using dual-line regression). Skewed dO2/qO2 distributions had a lesser effect. Incomplete oxygen uptake, due to diffusion limitation or other causes of physiological arteriovenous shunt, linearly decreased the critical oxygen extraction ratio. Approximate dO2/qO2 distributions were then estimated from previously reported capillary transit-time distributions. Critical oxygen extraction ratios predicted from these estimated dO2/qO2 distributions match reported values. This theoretical approach also predicts the decrease in the critical oxygen extraction ratio in porcine gut after endotoxin infusion in the companion paper (M. F. Humer, P. T. Phang, B. P. Friesen, M. F. Allard, C. M. Goddard, and K. R. Walley. J. Appl. Physiol. 81: 895-904, 1996). Much as pulmonary ventilation-perfusion relationships account for pulmonary gas exchange, dO2/qO2 distributions quantitatively account for measured tissue oxygen extraction and predict novel features of the relationship between heterogeneity and oxygen extraction.

Low-dose dopamine hastens onset of gut ischemia in a porcine model of hemorrhagic shock.

Gut metabolism may become anaerobic before the whole body during progressive phlebotomy in dogs. Because dopamine has selective mesenteric vasodilator effects, we asked whether dopamine could delay onset of bowel ischemia during hemorrhagic shock. We studied whole body and gut O2 consumption (VO2) and O2 delivery (QO2) using progressive phlebotomy in anesthetized pigs. Nine pigs received a dopamine infusion of 2 micrograms.kg-1.min-1, whereas a control group of seven pigs received equivalent saline infusion. Onset of ischemia in whole body and gut was determined as critical O2 delivery (QO2c), the intersection point of biphasic regression on plots of VO2-QO2 relationships. Blood flow and O2 extraction were measured as mechanisms of gut ischemia for entire in situ small and large gut using a superior mesenteric venous fistula. Dopamine hastened onset of gut ischemia relative to onset of whole body ischemia (gut critical point in terms of whole body QO2 9.9 +/- 2.1 ml O2.kg-1.min-1, whole body QO2c 7.8 +/- 0.7 ml O2.kg-1.min-1, P less than 0.01). In contrast, onset of gut ischemia in control animals occurred at same time as onset of whole body ischemia (gut critical point in terms of whole body QO2 7.4 +/- 2.3 ml O2.kg-1.min-1, whole body QO2c 7.1 +/- 2.7 ml O2.kg-1.min-1, P = not significant). Hastening of onset of gut ischemia in dopamine-treated animals was associated with decreased ability of gut to extract O2. Low-dose dopamine was not protective against gut ischemia during shock but rather caused earlier onset of gut ischemia during hemorrhagic shock.

Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs.

Why the myocardial oxygen extraction ratio (ERm) is decreased during septic shock in humans is unknown. Therefore, we calculated ERm in 15 anesthetized pigs by measuring arterial and coronary venous oxygen content. We measured myocardial lactate flux, myocardial contractility, and global myocardial blood flow and its distribution. After baseline measurements, animals received either saline (n = 6) or 50 micrograms/kg of endotoxin (n = 9). Measurements were repeated for 4 h. After endotoxin, ERm decreased from 67 +/- 12% at baseline to 36 +/- 10% (P < 0.01) at 1 h and 54 +/- 10% (P < 0.05) at 4 h, associated with an increased myocardial blood flow that was heterogeneous. Neither myocardial oxygen nor lactate consumption decreased in the endotoxin group, and changes in left ventricular contractility were not correlated with changes in ERm. We conclude that the decrease in ERm after endotoxin infusion is due to both increased blood flow and mismatching between myocardial oxygen delivery and demand. Impaired myocardial oxygen extraction capacity during sepsis did not cause global myocardial tissue hypoxia.

Small bowel tonometry is more accurate than gastric tonometry in detecting gut ischemia.

Gastric tonometer PCO2 measurement may help identify gut ischemia in critically ill patients but is frequently associated with large measurement errors. We tested the hypothesis that small bowel tonometer PCO2 measurement yields more accurate information. In 10 anesthetized, mechanically ventilated pigs subject to progressive hemorrhage, we measured gut oxygen delivery and consumption. We also measured tonometer PCO2 minus arterial PCO2 (DeltaPCO2) and calculated the corresponding intracellular pH from tonometers placed in the stomach and jejunum. We found that the correlation coefficient (r2) for biphasic gut oxygen delivery-DeltaPCO2 relationships was 0.29 +/- 0.52 for the gastric tonometer vs. 0.76 +/- 0.25 for the small bowel tonometer (P < 0.05). In addition, the critical gastric tonometer DeltaPCO2 was excessively high and variable (62.9 +/- 39.6) compared with the critical small bowel tonometer DeltaPCO2 (17.0 +/- 15.0, P < 0.01). Small bowel tonometer PCO2 was closely correlated with superior mesenteric vein PCO2 (r2 = 0.81, P < 0.001), whereas gastric tonometer PCO2 was not (r2 = -0.13, P = not significant). We conclude that measurement of gastric tonometer PCO2 yields excessively noisy and inaccurate data on the onset of gut anaerobic metabolism in hemorrhagic shock. Small bowel tonometer PCO2 is less noisy and, as a result, is superior in detecting gut hypoperfusion and the onset of anaerobic metabolism.

Decrease in left ventricular contractility after tumor necrosis factor-alpha infusion in dogs.

Whether systolic contractility or diastolic compliance changes soon after tumor necrosis factor-alpha (TNF-alpha) exposure is not known. Accordingly, we measured hemodynamics, left ventricular contractility using the slope of the end-systolic pressure-volume relationship, and diastolic pressure-volume relationships in six control dogs and in six dogs receiving 60 micrograms.kg-1.h-1 i.v. of TNF-alpha. Mean aortic pressure decreased by 22% 1 h after TNF-alpha infusion and remained decreased (P < 0.05). Cardiac output increased by 19% 1 h after TNF-alpha infusion and remained significantly greater than control values (P < 0.05). Left ventricular contractility decreased by 23% (P < 0.05) 1 h after TNF-alpha infusion and decreased by 52% (P < 0.01) 5 h after TNF-alpha infusion. The diastolic pressure-volume relationship did not change in the TNF-alpha group or the control group. Ejection fraction did not change after TNF-alpha infusion despite the decrease in contractility because afterload decreased. We conclude that TNF-alpha is important in causing the hypotensive, hyperdynamic circulation of sepsis. The new finding that left ventricular contractility is decreased shortly after TNF-alpha infusion suggests that TNF-alpha, or another mediator released very soon after TNF-alpha, is an important myocardial depressant factor.

Histamine decreases left ventricular contractility in normal human subjects.

To determine whether histamine alters human left ventricular contractility we measured heart rate, calibrated carotid arterial pressure, and left ventricular dimensions (echocardiogram) in nine healthy volunteers. We assessed baseline contractility using the end-systolic pressure-dimension relationship and the end-systolic meridional wall stress-rate-corrected velocity of circumferential fiber shortening relationship determined over a wide range of afterloads using phenylephrine and nitroprusside infusions. We then infused histamine for 3-5 min at a dose predetermined to decrease mean arterial pressure by 20%, both before and after H1 receptor antagonist pretreatment (diphenhydramine 50 mg i.v.). Histamine decreased end-systolic pressure but, unlike an equally hypotensive infusion of nitroprusside, did not decrease end-systolic dimension or increase fractional shortening. Histamine also decreased velocity of circumferential fiber shortening at the same end-systolic meridional wall stress as controls (P < 0.05). These effects of histamine were inhibited by H1 antagonist pretreatment. We conclude that the dominant effect of histamine on the human heart is to decrease left ventricular contractility and that this decrease in contractility is dependent, at least partially, on H1-receptor activation.

Heterogeneity of gut capillary transit times and impaired gut oxygen extraction in endotoxemic pigs.

We tested the hypothesis that endotoxin increases the heterogeneity of gut capillary transit times and impairs oxygen extraction. The gut critical oxygen extraction ratio was determined by measuring multiple oxygen delivery-consumption points during progressive phlebotomy in eight control and eight endotoxin-infused anesthetized pigs. In multiple 1- to 2-g samples of small bowel, we measured blood volume (radiolabeled red blood cells) and flow (radiolabeled 15-microns microspheres) before and after critical oxygen extraction. Red blood cell transit time (= volume/flow) multiplied by morphologically determined capillary/total blood volume gave capillary transit time. During hemorrhage, capillary/total blood volume did not change in the endotoxin group (0.5 +/- 4.5%) but increased in the control group (17.6 +/- 2.5%; P < 0.05) due to a decrease in total gut blood volume. Flow decreased significantly in the endotoxin group (36 +/- 10%; P < 0.05) but not in the control group (12 +/- 10%). Capillary transit-time heterogeneity increased in the endotoxin group (12.3 +/- 4.9%) compared with the control group (-5.8 +/- 7.4%; P < 0.05), predicting a critical oxygen extraction ratio 0.14 lower in the endotoxin group than in the control group (K. R. Walley. J. Appl. Physiol. 81: 885-894, 1996). This matches the measured difference (endotoxin group, 0.60 +/- 0.04; control group, 0.74 +/- 0.03; P < 0.05). Increased heterogeneity of capillary transit times may be an important cause of impaired oxygen extraction.

Effect of crystalloid administration on oxygen extraction in endotoxemic pigs.

We asked whether crystalloid administration improves tissue oxygen extraction in endotoxicosis. Four groups of anesthetized pigs (n = 8/group) received either normal saline infusion or no saline and either endotoxin or no endotoxin. We measured whole body (WB) and gut oxygen delivery and consumption during hemorrhage to determine the critical oxygen extraction ratio (ERO2 crit). Just after onset of ischemia (critical oxygen delivery rate), gut was removed for determination of area fraction of interstitial edema and capillary hematocrit. Radiolabeled microspheres were used to determine erythrocyte transit time for the gut. Endotoxin decreased WB ERO2 crit (0.82 +/- 0.06 to 0.55 +/- 0.08, P < 0.05) and gut ERO2 crit (0.77 +/- 0.07 to 0.52 +/- 0.06, P < 0.05). Unexpectedly, saline administration also decreased WB ERO2 crit (0.82 +/- 0.06 to 0.62 +/- 0.08, P < 0.05) and gut ERO2 crit (0.77 +/- 0.07 to 0.67 +/- 0.06, P < 0.05) in nonendotoxin pigs. Saline administration increased the area fraction of interstitial space (P < 0.05) and resulted in arterial hemodilution (P < 0.05) but not capillary hemodilution (P > 0.05). Saline increased the relative dispersion of erythrocyte transit times from 0.33 +/- 0.08 to 0.72 +/- 0.53 (P < 0.05). Thus saline administration impairs tissue oxygen extraction possibly by increasing interstitial edema or increasing heterogeneity of microvascular erythrocyte transit times.

Acute hypervolemia lengthens red cell pulmonary transit time during exercise in endurance athletes.

The purpose was to determine if acute plasma volume expansion (PVE) changed red-cell pulmonary transit time (PTT) during severe exercise. Twelve endurance athletes performed 6.5 min of severe cycling exercise on different days. Pentaspan [(500 ml, infusion condition, I] or placebo [(60 ml saline), non-infusion condition, N] were infused prior to exercise. Blood gas tensions, PTT, multigated acquisition (MUGA) derived cardiac output, and oxygen uptake were measured during exercise. PTT was measured during minute 3 of exercise by radionuclide cardiography. Arterial P(O(2)) (Pa(O(2))), and alveolar-arterial oxygen pressure difference (AaD(O(2))) at minute 3 of exercise did not differ between conditions. Mean PTT at minute 3 of exercise was 0.3 sec longer in the I condition (P=0.002). However, the change in PTT between conditions was not correlated to the change in either Pa(O(2)) or AaD(O(2)). We conclude that PVE slows (lengthens) PTT without affecting pulmonary gas exchange. Therefore, rapid PTT may not be related to hypoxemia during exercise.