Early experience with critically ill patients with COVID-19 in Montreal.

PURPOSE: Montreal has been the epicentre of the coronavirus disease (COVID-19) pandemic in Canada. Given the regional disparities in incidence and mortality in the general population, we aimed to describe local characteristics, treatments, and outcomes of critically ill COVID-19 patients in Montreal. METHODS: A single-centre retrospective cohort of consecutive adult patients admitted to the intensive care unit (ICU) of Hôpital du Sacré-Coeur de Montréal with confirmed COVID-19 were included. RESULTS: Between 20 March and 13 May 2020, 75 patients were admitted, with a median [interquartile range (IQR)] age of 62 [53-72] yr and high rates of obesity (47%), hypertension (67%), and diabetes (37%). Healthcare-related infections were responsible for 35% of cases. The median [IQR] day 1 sequential organ failure assessment score was 6 [3-7]. Invasive mechanical ventilation (IMV) was used in 57% of patients for a median [IQR] of 11 [5-22] days. Patients receiving IMV were characterized by a moderately decreased median [IQR] partial pressure of oxygen:fraction of inspired oxygen (day 1 PaO2:FiO2 = 177 [138-276]; day 10 = 173 [147-227]) and compliance (day 1 = 48 [38-58] mL/cmH2O; day 10 = 34 [28-42] mL/cmH2O) and very elevated estimated dead space fraction (day 1 = 0.60 [0.53-0.67]; day 10 = 0.72 [0.69-0.79]). Overall hospital mortality was 25%, and 21% in the IMV patients. Mortality was 82% in patients ≥ 80 yr old. CONCLUSIONS: Characteristics and outcomes of critically ill patients with COVID-19 in Montreal were similar to those reported in the existing literature. We found an increased physiologic dead space, supporting the hypothesis that pulmonary vascular injury may be central to COVID-19-induced lung damage.

RéSUMé: OBJECTIF: Montréal a été l'épicentre de la pandémie du coronavirus (COVID-19) au Canada. Étant donné les disparités régionales dans l'incidence et la mortalité dans la population générale, nous avons tenté de décrire les caractéristiques locales, les traitements et le devenir des patients atteints de la COVID-19 en état critique à Montréal. MéTHODE: Notre étude de cohorte rétrospective monocentrique a inclus tous les patients adultes admis consécutivement à l'unité de soins intensifs de l'Hôpital du Sacré-Cœur de Montréal avec un diagnostic confirmé de COVID-19. RéSULTATS: Soixante-quinze patients ont été admis entre le 20 mars et le 13 mai 2020. Ceux-ci avaient un âge médian [écart interquartile (ÉIQ)] de 62 [53­72] ans et présentaient une incidence élevée d'obésité (47 %), d'hypertension (67 %) et de diabète (37 %). Les transmissions associées aux soins de santé étaient responsables de 35 % des cas. Au jour 1, le score SOFA (Sequential Organ Failure Assessment ­ évaluation séquentielle de défaillance des organes) médian [ÉIQ] était de 6 [3­7]. La ventilation mécanique invasive (VMI) a été utilisée chez 57 % des patients, pour une durée médiane [ÉIQ] de 11 [5­22] jours. Les patients ayant reçu une VMI étaient caractérisés par une médiane [ÉIQ] modérément réduite de la pression partielle de la fraction d'oxygène inspiré (jour 1 PaO2:FiO2 = 177 [138­276]; jour 10 = 173 [147­227]), de la compliance (jour 1 = 48 [38­58] mL/cmH2O; jour 10 = 34 [28­42] mL/cmH2O), ainsi que par une fraction d'espace mort estimé très élevée (jour 1 = 0,60 [0,53-0,67]; jour 10 = 0,72 [0,69-0,79]). La mortalité hospitalière était de 25 % globalement, et de 21 % chez les patients avec VMI. La mortalité a atteint 82 % chez les patients agés de ≥ 80 ans. CONCLUSION: Les caractéristiques et le devenir des patients en état critique atteints de la COVID-19 à Montréal étaient semblables à ceux rapportés dans la littérature existante. Nous avons observé un espace mort physiologique augmenté, ce qui appuie l'hypothèse que des lésions vasculaires pulmonaires seraient primordiales dans les lésions pulmonaires induites par la COVID-19.

From bench to bedside.

Because the microcirculation has emerged as an important reanimation target, appropriate methods to monitor the microcirculatory function are crucial. Several teams have now succeeded in crossing this bridge from bench to bedside, but the choice of the tissues of interest remains a debate. The potential accessible vascular beds that doctors could use in reanimation strategies and the relationship of these beds to more relevant microcirculatory ones are important issues to address.

Refractory Hyperlactatemia After a Septic Shock in a Patient With Carnitine Deficiency: A Case Report.

A 56-year-old woman with septic shock presented with persistent hyperlactatemia, despite an adequate clinical response to treatment. Carnitine deficiency was suspected, as the patient was malnourished and chronically taking valproic acid. No other plausible cause of hyperlactatemia was found. Carnitine supplementation resulted in rapid normalization of lactatemia.

Pentastarch 10% (250 kDa/0.45) is an independent risk factor of acute kidney injury following cardiac surgery.

UNLABELLED: OBJECTIVE, DESIGN AND PATIENTS: The risk of acute kidney injury (AKI) associated with hydroxyethyl starch may be limited to higher molecular weight agents. We retrospectively evaluated the risk of AKI using pentastarch 10% (250 kDa, 0.45) in a random cohort of 563 patients operated for a cardiac surgery at a university hospital. MEASURES: We assessed previously identified preoperative, perioperative, and postoperative risk factors, and the volume of pentastarch given until the end of the first postoperative day. We defined AKI by a 50% rise in serum creatinine within 4 days after surgery. Different propensity adjustment methods were used to further assess the selection bias. RESULTS: Fifty-four (10%) patients developed AKI. Risk factors of AKI were age, female gender, preoperative creatinine clearance, hypertension, diuretic use, left ventricular ejection fraction, valvular surgery, duration of extracorporeal circulation, duration and dose of postoperative vasopressor support, and the number of red blood cells and fresh frozen plasma transfusions. Patients with AKI received 16 +/- 9 mL/kg of pentastarch as opposed to 10 +/- 7 mL/kg in controls (p < 0.001). Pentastarch remained independently predictive of AKI, with an adjusted odds ratio per mL/kg of 1.08 (95% confidence interval 1.04-1.12, p = 0.001). This risk was dose-dependent, and the optimal cutoff volume predicting AKI was 14 mL/kg. Different propensity adjustment methods were tested, and pentastarch as a risk factor of AKI was identified. CONCLUSIONS: This study identified a dose-dependent risk of AKI with pentastarch following cardiac surgery, given until the end of the first postoperative day.

Evaluation of sublingual and gut mucosal microcirculation in sepsis: a quantitative analysis.

OBJECTIVE: To determine the relationship between sublingual and intestinal mucosal microcirculatory perfusion. DESIGN: Observational, experimental study. SETTING: University-affiliated large animal laboratory. SUBJECTS: Ten fasted, anesthetized, mechanically ventilated, male pigs randomized to a sham group (n = 3) or to a hyperdynamic septic shock group (n = 7) in which cholangitis was induced by direct infusion of Escherichia coli into the common bile duct. This model was developed because it is not accompanied by changes in intra-abdominal pressure. MEASUREMENTS AND MAIN RESULTS: The sublingual and intestinal microcirculations were simultaneously assessed at 4-hr intervals for up to 12 hrs with a modified orthogonal polarization spectral device and functional microvessel density and erythrocyte velocity were measured quantitatively. In sham animals, both regions maintained a stable functional microvessel density and erythrocyte velocity throughout the study period. In contrast, in septic animals, already after 4 hrs of sepsis, functional microvessel density was markedly decreased (>50%) in the sublingual and gut regions; mean erythrocyte velocity decreased dramatically and similarly in both regions, from 1022 +/- 80 to 265 +/- 43 mum/sec in the sublingual region and from 1068 +/- 45 to 243 +/- 115 mum/sec in the gut (p < 0.001, at T12). There was a significant correlation between the sublingual and gut microcirculations in septic animals (r = 0.92, p < 0.0001). CONCLUSIONS: The severity and the time course of microcirculatory changes were similar in the sublingual and in the gut region in this clinically relevant model of severe sepsis. These findings support the sublingual region as an appropriate region to monitor the microcirculation in sepsis.

Effects of dexamethasone on macrophage migration inhibitory factor production in sepsis.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a major role in the pathogenesis of sepsis. Some studies have indicated that glucocorticoids increase MIF production in physiological conditions. The goal of this study was to determine whether glucocorticoid treatment also upregulates MIF production in sepsis. Male NMRI mice (6-10 weeks old) underwent laparotomy, proximal ligation of the cecum, and double perforation with a 19-gauge needle (cecal ligation and puncture). Mice were randomly treated with saline (control) or dexamethasone at doses of 0.1, 1, or 10 mg/kg ip. At 6 or 18 h postoperatively, 10 mice per group were euthanized; and blood, peritoneal fluid, liver, lung, kidney, and heart tissue samples were retrieved. MIF, IL-6, TNF-alpha, and IL-10 were measured by enzyme-linked immunosorbent assay. Sepsis induced by cecal ligation and puncture produced a marked increase in MIF and cytokine levels in plasma and peritoneal fluid. Treatment with dexamethasone 10 mg/kg decreased MIF levels in plasma after 18 h, but there was no effect of dexamethasone on MIF production locally in the peritoneal cavity or in the liver, lungs, heart, or kidneys. We conclude that glucocorticoid treatment does not upregulate MIF production in sepsis.

Skin microcirculation and vasopressin infusion: a laser Doppler study.

Use of arginine vasopressin in the management of refractory vasodilatory shock has been associated with development of ischaemic skin lesions. Because of the increasing popularity of arginine vasopressin, it is important to evaluate its effects on microcirculatory blood flow. Such studies are crucial if we are to appreciate the microcirculatory consequences of our various resuscitation strategies. However, methodological issues must always be considered because they can significantly influence interpretation of the results. Some aspects of use of laser Doppler to evaluate the microcirculation are reviewed within the context of recent findings presented by Luckner and coworkers in this issue of Critical Care.

The following is the abstract of the article discussed in the subsequent letter:.

Sublingual and intestinal mucosal blood flow and Pco(2) were studied in a canine model of endotoxin-induced circulatory shock and resuscitation. Sublingual Pco(2) (Ps(CO(2))) was measured by using a novel fluorescent optrode-based technique and compared with lingual measurements obtained by using a Stowe-Severinghaus electrode [lingual Pco(2) (Pl(CO(2)))]. Endotoxin caused parallel changes in cardiac output, and in portal, intestinal mucosal, and sublingual blood flow (Q(s)). Different blood flow patterns were observed during resuscitation: intestinal mucosal blood flow returned to near baseline levels postfluid resuscitation and decreased by 21% after vasopressor resuscitation, whereas Q(s) rose to twice that of the preshock level and was maintained throughout the resuscitation period. Electrochemical and fluorescent Pco(2) measurements showed similar changes throughout the experiments. The shock-induced increases in Ps(CO(2)) and Pl(CO(2)) were nearly reversed after fluid resuscitation, despite persistent systemic arterial hypotension. Vasopressor administration induced a rebound of Ps(CO(2)) and Pl(CO(2)) to shock levels, despite higher cardiac output and Q(s), possibly due to blood flow redistribution and shunting. Changes in Pl(CO(2)) and Ps(CO(2)) paralleled gastric and intestinal Pco(2) changes during shock but not during resuscitation. We found that the lingual, splanchnic, and systemic circulations follow a similar pattern of blood flow variations in response to endotoxin shock, although discrepancies were observed during resuscitation. Restoration of systemic, splanchnic, and lingual perfusion can be accompanied by persistent tissue hypercarbia, mainly lingual and intestinal, more so when a vasopressor agent is used to normalize systemic hemodynamic variables.

Undiagnosed Chronic Granulomatous Disease, Burkholderia cepacia complex Pneumonia, and Acquired Hemophagocytic Lymphohistiocytosis: A Deadly Association.

Background. Chronic granulomatous disease is a rare inherited disorder of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The clinical course of the disease is marked by recurrent infections, including Burkholderia cepacia complex infection. Case Report. Here we report the case of a 21-year-old male hospitalized for a Burkholderia cepacia complex pneumonia. Despite the broad spectrum antibiotic treatment, fever continued and patient's condition worsened. Anemia and thrombocytopenia developed together with hypofibrinogenemia. The patient died of multiple organ dysfunction 17 days after his admission. Autopsy revealed hemophagocytosis, suggesting the diagnosis of acquired hemophagocytic lymphohistiocytosis. DNA analysis showed a deletion in the p47phox gene, confirming the diagnosis of autosomal recessive chronic granulomatous disease. Discussion. In addition to chronic granulomatous disease, recent findings have demonstrated that Burkholderia cepacia complex can decrease activity of the NADPH oxidase. Interestingly, hemophagocytic lymphohistiocytosis is characterized by an impaired function of the T-cell mediated inflammation which is partly regulated by the NADPH oxidase. Physicians should therefore pay particular attention to this deadly association.

Microvascular response to red blood cell transfusion in patients with severe sepsis.

OBJECTIVES: Microvascular alterations may play a role in the development of multiple organ failure in severe sepsis. The effects of red blood cell transfusions on microvascular perfusion are not well defined. We investigated the effects of red blood cell transfusion on sublingual microvascular perfusion in patients with sepsis. DESIGN: Prospective, observational study. SETTING: A 31-bed, medical-surgical intensive care unit of a university hospital. PATIENTS: Thirty-five patients with severe sepsis requiring red blood cell transfusions. INTERVENTIONS: Transfusion of one to two units of leukocyte-reduced red blood cells. MEASUREMENTS AND MAIN RESULTS: The sublingual microcirculation was assessed with an Orthogonal Polarization Spectral device before and 1 hr after red blood cell transfusion. Red blood cell transfusions increased hemoglobin concentration from 7.1 (25th-75th percentile, 6.7-7.6) to 8.1 (7.5-8.6) g/dL (p < .01), mean arterial pressure from 75 (69-89) to 82 (75-90) mm Hg (p < .01), and oxygen delivery from 349 (278-392) to 391 (273-473) mL/min.M (p < .001). Microvascular perfusion was not significantly altered by transfusion, but there was considerable interindividual variation. The change in capillary perfusion after transfusion correlated with baseline capillary perfusion (Spearman-rho = -.49; p = .003). Capillary perfusion was significantly lower at baseline in patients who increased their capillary perfusion by >8% compared with those who did not (57 [52-64] vs. 75 [70-79]; p < .01), while hemodynamic and global oxygen transport variables were similar in the two groups. Red blood cell storage time had no influence on the microvascular response to red blood cell transfusion. CONCLUSIONS: The sublingual microcirculation is globally unaltered by red blood cell transfusion in septic patients; however, it can improve in patients with altered capillary perfusion at baseline.

Euglycemic hyperinsulinemia in severe sepsis and septic shock.

BACKGROUND: Recent studies have suggested that strict glucose control with intensive insulin therapy in critically ill patients may result in better outcomes. Whether this is also true in septic shock has not been determined. In addition, whether it is the insulin administration per se or the glucose control that contributes to the beneficial effects is unclear. We raised the hypothesis that euglycemic hyperinsulinemia (EH) might improve the outcome from septic shock due to peritonitis. MATERIALS AND METHODS: Fourteen anesthetized, mechanically ventilated, and hemodynamically monitored sheep received 1.5 g/kg body weight i.p. feces to induce sepsis. Ringer's lactate and 6% hydroxyethyl starch solutions were infused throughout the experiment to prevent hypovolemia. Two hours after feces injection, the animals were randomized to either an EH group (n = 7) receiving insulin 0.25 U/ kg/h, 20% glucose (to maintain blood glucose at 40-90 mg/dl), and potassium (to maintain the potassium level at 4.0- 5.5 mmol/l) or a control group (n = 7) with no intervention. All animals were studied until their spontaneous death or for 30 h. RESULTS: The EH group received a greater volume of 20% glucose, but blood glucose and potassium concentrations were similar in the two groups. No significant differences were found in hemodynamic variables. The circulating interleukin-6 levels increased in both groups after feces injection, but tended to be lower in the EH group (p < 0.05). The survival times were similar in the two groups (median 20.0 h in the EH group vs. 17.0 h in the control group; p = 0.73). CONCLUSIONS: In this clinically relevant sheep septic shock model, EH decreased blood interleukin-6 concentrations but did not change hemodynamics or improve the outcome.

Effects of drotrecogin alfa activated on microcirculatory alterations in patients with severe sepsis.

OBJECTIVE: Microvascular alterations may play an important role in the development of sepsis-induced organ dysfunction. Drotrecogin alfa activated (DAA) improves outcome in patients with severe sepsis, but its precise mechanism of action is not entirely defined. We investigated whether DAA can influence microcirculatory alterations in patients with severe sepsis. DESIGN: Prospective, nonrandomized study. SETTING: A 31-bed, medico-surgical intensive care unit of a university hospital. PATIENTS: Forty adult patients with severe sepsis who met the EU criteria for DAA administration. INTERVENTIONS: Twenty patients received the drug (DAA) and 20 had a contraindication to DAA administration (control). MEASUREMENTS AND MAIN RESULTS: An orthogonal polarization spectral imaging technique was used to visualize the sublingual microcirculation. In all patients, measurements were obtained at baseline, 4 hrs later, and then every 24 hrs for up to 7 days. In patients receiving DAA, measurements were also obtained just before and 4 hrs after the end of DAA infusion. The two groups were well matched for severity of disease, number of failing organs, and the degree of microvascular alterations at baseline. The proportion of perfused capillaries increased in the DAA treated patients already at 4 hrs (from 64% [51-80%] to 84% [71-88%], p < .01) but not in the control group (from 67% [59-76%] to 68% [61-71%], p = not significant). Microvascular perfusion decreased transiently at the end of DAA infusion. The improvement in microvascular blood flow was associated with a more rapid resolution of hyperlactatemia. CONCLUSIONS: DAA administration rapidly improves sepsis-induced microvascular alterations, whereas its cessation is associated with a transient deterioration.

The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects.

OBJECTIVE: To evaluate the effects of dobutamine on microcirculatory blood flow alterations in patients with septic shock. DESIGN: Prospective, open-label study. SETTING: A 31-bed, medico-surgical intensive care unit of a university hospital. PATIENTS: Twenty-two patients with septic shock. INTERVENTIONS: Intravenous administration of dobutamine (5 mug/kg.min) for 2 hrs (n = 22) followed by the addition of 10 M acetylcholine (topically applied, n = 10). MEASUREMENTS AND MAIN RESULTS: Complete hemodynamic measurements were obtained before and after dobutamine administration. In addition, the sublingual microcirculation was investigated with an orthogonal polarization spectral imaging technique before and after dobutamine administration and after topical application of acetylcholine. Dobutamine significantly improved capillary perfusion (from 48 +/- 15 to 67 +/- 11%, p = .001), but with large individual variation, whereas capillary density remained stable. The addition of topical acetylcholine completely restored capillary perfusion (98 +/- 1%, p = .001) and capillary density. The changes in capillary perfusion during dobutamine administration were not related to changes in cardiac index (p = .45) or arterial pressure (p = .29). Interestingly, the decrease in lactate levels was proportional to the improvement in capillary perfusion (y = 0.07 - 0.02x, r = .46, p = .005) but not to changes in cardiac index (p = .55). CONCLUSIONS: The administration of 5 mug/kg.min dobutamine can improve but not restore capillary perfusion in patients with septic shock. These changes are independent of changes in systemic hemodynamic variables.

Beneficial effects of alkaline phosphatase in septic shock.

OBJECTIVE: Alkaline phosphatase may decrease the harmful effects of lipopolysaccharide by detoxifying lipid A. The aim of this study was to investigate whether administration of alkaline phosphatase is beneficial in a clinically relevant septic shock model. DESIGN: Interventional laboratory study. SETTING: University hospital animal research laboratory. SUBJECTS: Fourteen fasted, anesthetized, invasively monitored, mechanically ventilated, female sheep (27.6 +/- 3.9 kg). INTERVENTIONS: Each animal received 1.5 g/kg body weight of feces intraperitoneally to induce sepsis. Ringer's lactate and a 6% hydroxyethyl starch solution were infused throughout the experiment to prevent hypovolemia. Two hours after feces injection, animals were randomized to alkaline phosphatase (60 units/kg intravenous bolus followed by a continuous infusion of 20 units/kg/hr for a total of 15 hrs) or no alkaline phosphatase (control group). MEASUREMENTS AND MAIN RESULTS: All animals were studied until their spontaneous death or for a maximum of 30 hrs. Plasma alkaline phosphatase concentrations decreased in the control group but increased in the treatment group following alkaline phosphatase administration. In the treatment group, the Pao2/Fio2 ratio was higher (p < .05), blood interleukin-6 concentrations were lower (p < .05), and the survival time was longer (median time 23.8 vs. 17 .0 hrs, p < 0.05) than in the control group. There were no significant differences in systemic hemodynamics or diuresis. CONCLUSIONS: In this clinically relevant septic shock model, alkaline phosphatase administration improved gas exchange, decreased interleukin-6 concentrations, and prolonged survival time.

Prediction of postoperative complications after urgent laparotomy by intraperitoneal microdialysis: A pilot study.

OBJECTIVE: The aim of the present study was to investigate the role of intraperitoneal microdialysis (IPM) techniques in monitoring the evolution of postoperative critically ill patients requiring urgent laparotomy. SUMMARY BACKGROUND DATA: Postoperative intraabdominal sepsis is associated with an important degree of morbidity and mortality in acutely ill patients. Early diagnosis is critical to improve outcomes. METHODS: : The study included 25 consecutive patients admitted to the intensive care unit (ICU) after urgent laparotomy. Measurements of microdialysate fluid were performed through a microdialysis catheter, positioned intraperitoneally, during the first 5 postoperative days and lactate/pyruvate (L/P) ratios calculated. Patients were followed until hospital discharge. RESULTS: Ten patients had a complicated postoperative course, including 4 deaths (3 refractory shock, 1 mesenteric ischemia), 3 reinterventions (1 necrotic collection, 1 mesenteric ischemia, 1 biliary leak), 2 secondary peritonitis, and 1 intraabdominal collection. The IPM L/P ratio in these patients was already significantly higher during the first 24 postoperative hours compared with patients who had no complications (35 +/- 21 vs. 18 +/- 6, P < 0.01). An IPM L/P ratio above 22 on postoperative day 1 had a sensitivity of 0.64 and a specificity of 0.79 for complications. There were no significant differences between the two groups in pH, lactate, white blood cell count, or subcutaneous L/P ratio. No complication was associated with the technique. CONCLUSIONS: IPM is safe and reliable and provides valuable information after urgent laparotomy. Persistently high L/P values should raise the possibility of serious postoperative complications.

How monitoring of the microcirculation may help us at the bedside.

PURPOSE OF REVIEW: Recent technologic developments have allowed the direct visualization of the microcirculation at the bedside. The present review explores how the monitoring of microcirculation can help in clinical practice. RECENT FINDINGS: Using orthogonal polarization spectral (OPS) imaging techniques, various investigators have reported microcirculatory alterations in critically ill patients and especially in patients with severe sepsis and septic shock. These alterations include a decrease in vessel density and an increased proportion of nonperfused or intermittently perfused capillaries. The persistence of these alterations is associated with the development of organ failure and death. Several therapeutic interventions, including vasoactive agents, fluid resuscitation, and activated protein C, can affect the microcirculation. Vasoactive agents have variable effects but vasodilatory agents seem very promising. Unfortunately, although many animal studies have investigated the effects of many of these interventions, human data are limited. SUMMARY: Microcirculation plays an important role in the pathogenesis of shock and organ dysfunction, especially in sepsis. Monitoring microcirculation at the bedside may be used to assess severity of the disease and to predict outcome, but in the absence of sufficient data regarding the effects of therapeutic interventions it cannot yet be used to guide therapy, even though this approach is promising.