Cheryl L. Holmes

Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock

BACKGROUND Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors. METHODS In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 microg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 microg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions. RESULTS A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P=1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P=0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P=0.76). A test for heterogeneity between these two study strata was not significant (P=0.10). CONCLUSIONS Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors. (Current Controlled Trials number, ISRCTN94845869 [controlled-trials.com].).

Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock

Objective:Vasopressin and corticosteroids are often added to support cardiovascular dysfunction in patients who have septic shock that is nonresponsive to fluid resuscitation and norepinephrine infusion. However, it is unknown whether vasopressin treatment interacts with corticosteroid treatment. Design:Post hoc substudy of a multicenter randomized blinded controlled trial of vasopressin vs. norepinephrine in septic shock. Setting:Twenty-seven Intensive Care Units in Canada, Australia, and the United States. Patients:Seven hundred and seventy-nine patients who had septic shock and were ongoing hypotension requiring at least 5 &mgr;g/min of norepinephrine infusion for 6 hours. Interventions:Patients were randomized to blinded vasopressin (0.01–0.03 units/min) or norepinephrine (5–15 &mgr;g/min) infusion added to open-label vasopressors. Corticosteroids were given according to clinical judgment at any time in the 28-day postrandomization period. Measurements:The primary end point was 28-day mortality. We tested for interaction between vasopressin treatment and corticosteroid treatment using logistic regression. Secondary end points were organ dysfunction, use of open-label vasopressors and vasopressin levels. Main Results:There was a statistically significant interaction between vasopressin infusion and corticosteroid treatment (p = 0.008). In patients who had septic shock and were also treated with corticosteroids, vasopressin, compared to norepinephrine, was associated with significantly decreased mortality (35.9% vs. 44.7%, respectively, p = 0.03). In contrast, in patients who did not receive corticosteroids, vasopressin was associated with increased mortality compared with norepinephrine (33.7% vs. 21.3%, respectively, p = 0.06). In patients who received vasopressin infusion, use of corticosteroids significantly increased plasma vasopressin levels by 33% at 6 hours (p = 0.006) to 67% at 24 hours (p = 0.025) compared with patients who did not receive corticosteroids. Conclusions:There is a statistically significant interaction between vasopressin and corticosteroids. The combination of low-dose vasopressin and corticosteroids was associated with decreased mortality and organ dysfunction compared with norepinephrine and corticosteroids.

Vasoactive drugs in the intensive care unit.

Purpose of the reviewVasoactive drugs are the mainstay of hemodynamic management of vasodilatory shock when fluids fail to restore tissue perfusion. In this review, studies published during the past year that increase our understanding of the use of vasoactive drugs in the intensive care unit are discussed. Recent findingsIn septic shock, there is no benefit in increasing mean arterial pressure from 65 to 85 mmHg. Norepinephrine did not worsen renal function. Epinephrine induced visceral hypoperfusion and hyperlactatemia, and worsened organ function and survival compared with norepinephrine and vasopressin. There are a number of reports of the safety and efficacy of vasopressin but it is not currently recommended as first line therapy, and if used, should be given as a continuous low dose infusion. Terlipressin is showing promise but decreases cardiac output. Metaraminol is being investigated as an alternative to norepinephrine. Dopamine may improve splanchnic flow mainly by increasing cardiac output. Dobutamine improves oxygen delivery and may improve mesenteric blood flow. SummaryOver the last 40 years, there have been few controlled clinical trials to guide clinicians on the use of vasoactive drugs of treating shock states. It is not known whether the currently favored combination of norepinephrine and dobutamine is superior to traditional therapy with dopamine. Epinephrine is not recommended as the first-line therapy. The role of vasopressin and terlipressin remains unknown. Three large ongoing clinical trials will be completed soon and the results should clarify the role of these various agents.

Attenuation of lung inflammation by adrenergic agonists in murine acute lung injury.

BackgroundAcute lung injury leading to a systemic inflammatory response greatly increases mortality in critically ill patients. Cardiovascular management of these patients frequently involves &bgr;-adrenergic agonists. These agents may alter the inflammatory response. Therefore, the authors tested the hypothesis that &bgr;-adrenergic agonists alter the pulmonary inflammatory response during acute lung injury in mice. MethodsFive-week-old CD-1 mice received continuous infusions of 10 &mgr;g · kg−1 · min−1 dobutamine, 6 &mgr;g · kg−1 · min−1 dopexamine, or vehicle via intraperitoneal mini osmotic pumps, followed immediately by intratracheal instillation of approximately 2 &mgr;g/kg endotoxin (or phosphate-buffered saline control). Six hours later the mice were killed, and lung lavage was performed. Interleukin-6 and -10 concentrations in lung homogenates were measured using enzyme-linked immunosorbent assay. Interleukin-6 and macrophage inflammatory protein-2 mRNA was measured using reverse-transcription polymerase chain reaction. ResultsInterleukin-6 protein and mRNA significantly increased after intratracheal endotoxin (P < 0.001), and the fraction of neutrophils in lung lavage fluid increased in endotoxin-treated (41 ± 25%) versus control mice (2 ± 4%, P < 0.05). Treatment of endotoxic mice with dobutamine significantly decreased interleukin-6 protein (P < 0.05) and mRNA (P < 0.05) expression. Dopexamine had similar but less pronounced effects. Dobutamine decreased interleukin-10 expression, whereas dopexamine did not. In endotoxemic mice, both dobutamine and dopexamine decreased induction of macrophage inflammatory protein-2 mRNA (P < 0.05) and reduced the fraction of neutrophils in lung lavage fluid (P < 0.05). ConclusionsIn endotoxin-induced acute lung injury, &bgr;-adrenergic agonists can significantly decrease proinflammatory cytokine expression, decrease induction of chemokine mRNA, and decrease the resultant neutrophil infiltrate in the lung.

Vasopressin in the ICU.

Purpose of the reviewVasopressin is one of the most important endogenously released stress hormones during shock. In this review, studies published in the past year that add to our understanding of the use of vasopressin in the ICU are discussed. Recent findingsEndogenous vasopressin levels are inappropriately low in adults with severe sepsis but not in children with meningococcal septic shock. Vasopressin but not norepinephrine improved renal blood flow and oxygen delivery and prolonged survival in animal models of septic shock. In human vasodilatory shock, the combination of low-dose vasopressin and norepinephrine was found to be safe and effective. In humans, vasopressin can cause gastrointestinal hypoperfusion and ischemic skin lesions. In hypodynamic animal models of sepsis vasopressin compromised oxygen delivery and decreased systemic and gut blood flow. High-dose bolus vasopressin appeared promising in animal studies of hemorrhagic shock and cardiopulmonary arrest and in a large, randomized clinical trial of vasopressin versus epinephrine in human cardiopulmonary arrest with asystole. However, poor neurologic outcomes raised controversy in introducing vasopressin into CPR guidelines. SummaryThere is growing evidence that vasopressin infusion in septic shock is safe and effective. Several studies published this year support the hypothesis that vasopressin should be used as a continuous low-dose infusion (between 0.01 and 0.04 U/min in adults) and not titrated as a single vasopressor agent. However, multiple studies highlight the clinical equipoise that exists regarding the use of vasopressin in vasodilatory shock. Guidelines on management of septic shock recommend “cautious use of vasopressin pending further studies.”

Vasoactive drugs for vasodilatory shock in ICU.

Purpose of reviewVasoactive drugs are the mainstay of hemodynamic management of vasodilatory shock when fluids fail to restore adequate tissue perfusion. In this review, studies published during the past year that increase our understanding of the use of vasoactive drugs in the ICU are discussed. Recent findingsThe Vasopressin and Septic Shock Trial did not find a difference between low-dose vasopressin and norepinephrine vs. norepinephrine alone in the hemodynamic support of septic shock, suggesting that either approach is reasonable. However, vasopressin may be beneficial in the less severe septic shock subgroup. In this study, patients who were also treated with corticosteroids, vasopressin, compared with norepinephrine, were associated with significantly decreased mortality. Epinephrine, phenylephrine and terlipressin can be used safely in the ICU setting as first-line therapy for septic shock. The incidence of global left ventricular hypokinesia in patients with septic shock is 60%, much higher than previously described. Although dobutamine remains the gold standard therapy for septic myocardial depression, combined milrinone and metoprolol therapy may be an effective alternative therapy. SummaryCurrent evidence does not support a clear recommendation of one vasopressor over another; indeed norepinephrine, vasopressin, terlipressin, phenylephrine and epinephrine may be used safely with similar survival outcomes.

Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine.

IntroductionCardiac troponins are sensitive and specific biomarkers of myocardial necrosis. We evaluated troponin, CK, and ECG abnormalities in patients with septic shock and compared the effect of vasopressin (VP) versus norepinephrine (NE) on troponin, CK, and ECGs.MethodsThis was a prospective substudy of a randomized trial. Adults with septic shock randomly received, blinded, a low-dose infusion of VP (0.01 to 0.03 U/min) or NE (5 to 15 μg/min) in addition to open-label vasopressors, titrated to maintain a mean blood pressure of 65 to 75 mm Hg. Troponin I/T, CK, and CK-MB were measured, and 12-lead ECGs were recorded before study drug, and 6 hours, 2 days, and 4 days after study-drug initiation. Two physician readers, blinded to patient data and drug, independently interpreted ECGs.ResultsWe enrolled 121 patients (median age, 63.9 years (interquartile range (IQR), 51.1 to 75.3), mean APACHE II 28.6 (SD 7.7)): 65 in the VP group and 56 in the NE group. At the four time points, 26%, 36%, 32%, and 21% of patients had troponin elevations, respectively. Baseline characteristics and outcomes were similar between patients with positive versus negative troponin levels. Troponin and CK levels and rates of ischemic ECG changes were similar in the VP and the NE groups. In multivariable analysis, only APACHE II was associated with 28-day mortality (OR, 1.07; 95% CI, 1.01 to 1.14; P = 0.033).ConclusionsTroponin elevation is common in adults with septic shock. We observed no significant differences in troponin, CK, and ECGs in patients treated with vasopressin and norepinephrine. Troponin elevation was not an independent predictor of mortality.Trial registrationControlled-trials.com ISRCTN94845869

Vasopressin decreases sepsis-induced pulmonary inflammation through the V2R☆

UNLABELLED The early use of vasopressors in sepsis has been associated with a decrease in immune activation independent of hemodynamic effects, although the mechanism behind this remains unclear. We hypothesize that low dose vasopressin will reduce the pulmonary inflammation associated with sepsis. Our aims were to (1) determine whether vasopressin reduces lipopolysaccharide (LPS)-induced pulmonary inflammation and (2) determine which vasopressin receptor is responsible for pulmonary immune modulation. Mice were treated with intraperitoneal LPS to induce both systemic and pulmonary inflammation. Vasopressin or saline was infused via peritoneal pump and interleukin 6 (IL-6) in lung and serum was measured at 6h. NF-kappaB activation as was determined in the lung through immunoblotting total and phospho-IkappaB. Hemodynamic data was also obtained at the 6h mark. In a separate series of experiments mice received both LPS and vasopressin infusion following pretreatment with vasopressin receptor antagonists to V1R, V2R and OTR. Low dose LPS dramatically raises both serum IL-6 and pulmonary levels of IL-6 and phospho-IkappaB despite no significant changes in mean arterial pressure at 6h. Compared to saline, vasopressin infusion significantly decreases both the pulmonary IL-6 levels and phospho-IkappaB in LPS treated mice without raising arterial pressure. Pretreatment with V2R antagonist results in complete attenuation of vasopressins immunosuppressive effects, with restoration of pulmonary IL-6 and phospho-IkappaB levels to those seen with LPS alone. CONCLUSIONS Vasopressin exerts a local anti-inflammatory effect on the lung through the V2R in a model of sepsis.

Harnessing the Hidden Curriculum: A Four-Step Approach to Developing and Reinforcing Reflective Competencies in Medical Clinical Clerkship.

Changing the culture of medicine through the education of medical students has been proposed as a solution to the intractable problems of our profession. Yet few have explored the issues associated with making students partners in this change. There is a powerful hidden curriculum that perpetuates not only desired attitudes and behaviors but also those that are less than desirable. So, how do we educate medical students to resist adopting unprofessional practices they see modeled by supervisors and mentors in the clinical environment? This paper explores these issues and, informed by the literature, we propose a specific set of reflective competencies for medical students as they transition from classroom curricula to clinical practice in a four-step approach: (1) Priming—students about hidden curriculum in their clinical environment and their motivations to conform or comply with external pressures; (2) Noticing—educating students to be aware of their motivations and actions in situations where they experience pressures to conform to practices that they may view as unprofessional; (3) Processing—guiding students to analyze their experiences in collaborative reflective exercises and finally; (4) Choosing—supporting students in selecting behaviors that validate and reinforce their aspirations to develop their best professional identity.

Agreement in electrocardiogram interpretation in patients with septic shock.

Objective:The reliability of electrocardiogram interpretation to diagnose myocardial ischemia in critically ill patients is unclear. In adults with septic shock, we assessed intra- and inter-rater agreement of electrocardiogram interpretation, and the effect of knowledge of troponin values on these interpretations. Design:Prospective substudy of a randomized trial of vasopressin vs. norepinephrine in septic shock. Setting:Nine Canadian intensive care units. Patients:Adults with septic shock requiring at least 5 &mgr;g/min of norepinephrine for 6 hrs. Interventions:Twelve-lead electrocardiograms were recorded before study drug, and 6 hrs, 2 days, and 4 days after study drug initiation. Measurements:Two physician readers, blinded to patient data and group, independently interpreted electrocardiograms on three occasions (first two readings were blinded to patient data; third reading was unblinded to troponin). To calibrate and refine definitions, both readers initially reviewed 25 trial electrocardiograms representing normal to abnormal. Cohens Kappa and the &phgr; statistic were used to analyze intra- and inter-rater agreement. Results:One hundred twenty-one patients (62.2 ± 16.5 yrs, Acute Physiology and Chronic Health Evaluation II 28.6 ± 7.7) had 373 electrocardiograms. Blinded to troponin, readers 1 and 2 interpreted 46.4% and 30.0% of electrocardiograms as normal, and 15.3% and 12.3% as ischemic, respectively. Intrarater agreement was moderate for overall ischemia (&kgr; 0.54 and 0.58), moderate/good for “normal” (&kgr; 0.69 and 0.55), fair to good for specific signs of ischemia (ST elevation, T inversion, and Q waves, reader 1 &kgr; 0.40 to 0.69; reader 2 &kgr; 0.56 to 0.70); and good/very good for atrial arrhythmias (&kgr; 0.84 and 0.79) and bundle branch block (&kgr; 0.88 and 0.79). Inter-rater agreement was fair for ischemia (&kgr; 0.29), moderate for ST elevation (&kgr; 0.48), T inversion (&kgr; 0.52), and Q waves (&kgr; 0.44), good for bundle branch block (&kgr; 0.78), and very good for atrial arrhythmias (&kgr; 0.83). Inter-rater agreement for ischemia improved from fair to moderate (&kgr; 0.52, p = .028) when unblinded to troponin. Conclusions:In patients with septic shock, inter-rater agreement of electrocardiogram interpretation for myocardial ischemia was fair, and improved with troponin knowledge.