The current treatment regimen of patients with septic shock includes a targeted antimicrobial/anti-inflammatory therapy and a sufficient hemodynamic support aiming to preserve tissue oxygen requirements and perfusion (1-4). For the latter condition, aggressive fluid challenge and vasopressor agents play a pivotal role (5). To increase total peripheral resistance and preserve organ perfusion, a continuous infusion of catecholamines with predominantly α-adrenergic properties is often needed.
In contrast to norepinephrine (NE), which stimulates α-1, β-1, and β-2 receptors, phenylephrine is a selective α-1 receptor agonist mainly constricting larger arterioles and having virtually no effects on terminal arterioles (6). Despite widespread use of phenylephrine to treat arterial hypotension in different clinical settings (7, 8), its effects on global and regional hemodynamics in patients with septic shock are not well described and remain to be further investigated. Reinelt et al. (9) demonstrated in six septic shock patients that phenylephrine decreases hepatosplanchnic blood flow.
Recently, Krejci et al. (10) compared the effects of NE and phenylephrine on microcirculatory blood flow in multiple abdominal organs in a porcine model of sepsis. Whereas the NE-induced increase in perfusion pressure was associated with blood flow distribution away from the mesenteric circulation, phenylephrine did not impair mesenterial blood flow distribution, suggesting possible beneficial properties of phenylephrine on hepatosplanchnic perfusion in septic shock.
On this basis, we hypothesized that phenylephrine may likewise better preserve hepatosplanchnic perfusion versus NE in patients suffering from septic shock. Therefore, the present study was conducted as a prospective, open-labeled crossover pilot study to compare the effects of NE and phenylephrine on systemic and regional hemodynamics in patients with catecholamine-dependent septic shock.
MATERIALS AND METHODS
The study was approved by the local institutional ethics committee, and informed consent was obtained from the patients' next of kin. We enrolled 15 patients who fulfilled the criteria of septic shock (4) requiring NE to maintain MAP between 65 and 75 mmHg despite adequate volume resuscitation (pulmonary artery occlusion pressure [PAOP], 12-15 mmHg; central venous pressure (CVP), 8-12 mmHg). Exclusion criteria of the study were age younger than 18 years, pregnancy, present or suspected acute coronary artery disease, and present or suspected acute mesenteric ischemia.
All patients received mechanical ventilation using a volume-controlled mode. The ventilatory settings remained unchanged throughout the study. All patients were appropriately analgosedated using sufentanil and midazolam. The doses of these drugs were not modified during the study. As a standard treatment of catecholamine-dependent septic shock, all patients received hydrocortisone (50 mg every 6 h; i.v.). No adrenocortical stimulation tests were performed.
Systemic hemodynamic monitoring of the patients (Vigilance II; Edwards Lifesciences, Irvine, Calif) included a pulmonary artery catheter (7.5-F; Edwards Lifesciences) and a radial artery catheter (20 G; Arrow International, Inc., Reading, Pa). MAP, right atrial pressure, mean pulmonary arterial pressure, and PAOP were measured at end-expiration. Heart rate (HR) was analyzed from a continuous recording of electrocardiogram with ST segments monitored. Cardiac index (CI) was measured using the continuous thermodilution technique (Vigilance II; Edwards Lifesciences). Systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), left ventricular stroke work index (LVSWI), right ventricular stroke work index (RVSWI), oxygen delivery index (DO2I), oxygen consumption index (VO2I), and oxygen extraction ratio (O2-ER) were calculated using standard formulae. Arterial and mixed venous blood samples were taken for measuring oxygen tensions and saturations, as well as carbon dioxide tensions, standard bicarbonate, base excess (BE), pH, and arterial lactate concentrations.
Regional hemodynamic monitoring of the patients was performed with a 4-F oximetry thermo-dye dilution catheter (PV2024L; Pulsion Medical System AG, Munich, Germany) inserted through the femoral artery for the determination of plasma disappearance rate of indocyanine green (PDR) and blood clearance of indocyanine green related to body surface area (CBI). Moreover, an air tonometer (Tonocap; Datex-Ohmeda, Helsinki, Finland) was inserted via the nasogastric route for gastric mucosal carbon dioxide tension measurement.
PDR and CBI were determined with the thermal-dye dilution method as assessed by a Cold Z-021 (Pulsion Medical System AG) using an established protocol (11, 12). Every value was calculated as a mean of three measurements, each consisting of a bolus of 0.3 mg·kg−1 indocyanine green at 2 mg·mL−1 (Pulsion Medical Systems) in ice-cold 5% glucose solution injected into the right atrium. In addition, the gradient between gastric mucosal and arterial PCO2 (Pg-aCO2) was calculated, which has been shown to be more appropriate for the detection of regional ischemia than the calculation of mucosal pH (13). Enteral feeding and histamine (H2) receptor antagonists were discontinued 8 h before and during the 24-h study period. Urine samples were collected to assess urinary output and creatinine clearance.
The present study was designed as a prospective, open-labeled crossover pilot study. All patients enrolled in the study required NE to maintain MAP between 65 and 75 mmHg despite adequate volume resuscitation. An initial set of measurements was obtained and considered as baseline. After 8 h had elapsed during stable hemodynamic conditions, a second set of data was obtained (NE I). Norepinephrine infusion was then replaced by continuous intravenous infusion of phenylephrine, and the dosage rate was adjusted to maintain the same threshold MAP as before (65-75 mmHg). After another 8 h had elapsed during stable conditions, a third set of data was obtained (phenylephrine). Then, the treatment was switched back to NE again to maintain MAP between 65 and 75 mmHg, and after another 8-h period in stable conditions, a final set of data was obtained (NE II).
Fluid challenge (hydroxyethyl starch 6%) was performed to maintain PAOP and CVP at baseline ± 3 mmHg during the 24-h study period. Packed red blood cells were transfused when hemoglobin concentrations decreased to less than 8 g·dL−1. All other medications were held constant.
Statistical analysis was performed using Sigma Stat 3.10 software (SPSS, Chicago, Ill). After confirming normal distribution of all variables (Kolmogorov-Smirnov test), paired data obtained before and phenylephrine infusion were compared using Student t test. Statistical significance was assumed when P was less than 0.05. Values are presented as mean ± SD. Because this study was designed as a pilot study and due to the lack of clinical data, no ex ante power analysis was performed.
Demographic and baseline characteristics of the enrolled patients, origins of septic shock, and mortality rates are summarized in Table 1.
Variables of systemic hemodynamics, global oxygen transport, and acid-base balance remained unchanged after replacing NE (0.82 ± 0.69 μg·kg−1·min−1) by phenylephrine (4.39 ± 5.23 μg·kg−1·min−1), except for a significant decrease in HR (89 ± 18 vs. 93 ± 18 bpm; P < 0.05; Table 2).
Both PDR (13.5 ± 7.1 vs. 16.4 ± 8.7%·min−1) and CBI (330 ± 197 vs. 380 ± 227 mL·min−1·m2), surrogates of hepatosplanchnic perfusion and function, decreased significantly by phenylephrine infusion (both P < 0.05 phenylephrine vs. NE I). At the same time, arterial lactate concentrations increased significantly (1.7 ± 1.0 vs. 1.4 ± 1.1; P < 0.05 phenylephrine vs. NE I; Table 3). Whereas phenylephrine infusion did not affect gastric mucosal perfusion, it decreased creatinine clearance as compared with NE (81.3 ± 78.4 vs. 94.3 ± 93.5 mL·min−1; P < 0.05; phenylephrine vs. NE I). However, returning back to NE infusion, gastric mucosal perfusion increased, as indicated by a decrease in the Pg-aCO2 gradient (25.8 ± 9.3 vs. 21.5 ± 7.3; P < 0.05 phenylephrine vs. NE II; Figs. 1-4).
Eight hours after the treatment had been switched back to NE (NE II), all variables returned back to values obtained before phenylephrine infusion except creatinine clearance and gastric mucosal perfusion (Figs. 1-4).
Packed red blood cells were infused in two patients during the study period. Transfusion had no statistically significant effect on any of the investigated variables.
The major finding of the present study was that for the same MAP, phenylephrine decreased hepatosplanchnic perfusion as indicated by a decrease in PDR and CBI of indocyanine green as compared with NE. In addition, as suggested by a decrease in creatinine clearance, phenylephrine impaired renal function.
Although the effects of NE and phenylephrine on systemic hemodynamics have been studied in the setting of arterial hypotension, there are no comparative studies in patients with septic shock. In fluid-resuscitated patients, NE has been reported to stimulate α-1, β-1, and β-2 receptors, thereby counteracting arterial hypotension by simultaneously increasing systemic vascular resistance and cardiac output (14-16). Phenylephrine is a selective α-1 receptor agonist that increases systemic vascular resistance without elevating cardiac output (16, 17). The lack of β-1 stimulation by phenylephrine can be an advantage over NE because β-1 stimulation increases HR and myocardial oxygen demand. Therefore, the observation of a decrease in HR in the present study may be considered as a positive effect because prolonged tachycardia may increase the incidence of major cardiac events in critically ill patients (18).
Several trials have evaluated the effects of NE on splanchnic perfusion in patients who have septic shock. Most of these studies reported increased or preserved splanchnic and gastric blood flow, suggesting that infusion of moderate NE doses does not worsen splanchnic perfusion in the presence of septic shock (19-23). However, recently, Krejci et al. (10) reported that NE decreases regional mesenteric and microcirculatory blood flow in the intestine despite a significant increase in MAP and systemic oxygen delivery in a porcine model of septic shock. More importantly, the same authors reported for the first time that NE distributes blood flow away from the splanchnic circulation (i.e., small intestine) (10).
The effects of phenylephrine on regional blood flow are still not fully understood, and the results of comparative animal studies are controversial. In this regard, O'Dwyer et al (24) reported a decrease in splanchnic blood flow in pigs treated with phenylephrine during cardiopulmonary bypass grafting. Conversely, Breslow et al. (25) showed that phenylephrine has similar effects as NE on splanchnic oxygen supply. These findings were confirmed by Schwarz et al. (26), reporting that despite major differences in systemic hemodynamics, phenylephrine does not decrease jejunal tissue oxygen supply as compared with NE. In a study by Zhang et al. (27), phenylephrine neither influenced hepatosplanchnic blood flow, nor global and liver oxygen extraction capabilities in the presence of endotoxemia in dogs. However, phenylephrine administration was linked to an increase in tumor necrosis factor-α. Whereas NE reduced blood flow in both the jejunal mucosa and in the jejunal muscularis, phenylephrine did not affect blood flow in the jejunal mucosa but even increased blood flow in the jejunal muscularis (10). Taken together, the above referenced studies suggest that in endotoxin shock models, phenylephrine induces no adverse effects on gastrointestinal mucosal perfusion when used to maintain or increase MAP. In accordance with these previous findings, in the present study, phenylephrine did not impair gastrointestinal mucosal perfusion, as indicated by the lack of changes in gastric tonometry. Nevertheless, returning to NE, gastric mucosal perfusion improved, as reflected by a decrease in the Pg-aCO2 gradient.
In contrast to the findings of preserved gastrointestinal mucosal perfusion reported in our protocol and in the above-cited experimental studies, the present trial clearly shows that phenylephrine may impair hepatosplanchnic blood flow, as reflected by decreases in PDR and CBI. Notably, our findings are in harmony with the results from the study of Reinelt et al. (9). The latter authors demonstrated in six septic shock patients that hepatosplanchnic oxygen delivery and blood flow decreases when NE is gradually replaced by phenylephrine doses suitable to maintain MAP and CI.
In parallel with the decrease in hepatosplanchnic perfusion, we noticed a slight increase in arterial lactate concentrations, suggesting some degree of splanchnic ischemia. The fact that we did not find differences in terms of acid-base balance or pH, however, suggests that the degree of hepatosplanchnic ischemia was not severe. In addition, we would like to emphasize that our protocol does not allow distinguishing between possible phenylephrine-induced elevations in arterial lactate concentrations from an increased splanchnic lactate production versus decreased hepatic, renal, or myocardial lactate clearance. Conversely, the finding that the reduction of splanchnic blood flow occurred in parallel with a decrease in creatinine clearance strengthens the hypothesis of a reduced lactate clearance. The effects of phenylephrine on splanchnic perfusion observed in our protocol are in harmony with the results of a recent study of Nygren et al. (28), who reported in postcardiac surgery patients that for the same MAP and CI, phenylephrine induced a more pronounced splanchnic vasoconstriction compared with NE.
In harmony with the findings of Reinelt et al. (9), switching back to NE restored values obtained before phenylephrine infusion. Despite the distinct pharmacological characteristics (16), NE and phenylephrine did not exert different effects on systemic hemodynamics except for the phenylephrine-linked reduction in HR. This in turn suggests that the reduction of hepatosplachnic blood flow after phenylephrine infusion was not due to a decrease in cardiac output and systemic oxygen delivery. Thus, it is most likely that the modifications of PDR, CBI, and Pg-aCO2 gradient resulted from different effects of α- and β-adrenergic stimulation on hepatosplanchnic perfusion.
Our data are in agreement with the experimental studies of Zhang et al. (14, 27), who reported that the increases in global and hepatic arterial blood flow after NE infusion are the result of its β-1 and β-2 adrenergic stimulation, rather than its effects on α-1 receptors. The findings of the present study confirm the importance of β-adrenergic stimulation in preserving hepatosplanchnic perfusion in catecholamine-dependent septic shock (27, 29-31).
Nevertheless, in the light of these results, pathophysiological differences between experimental endotoxemia and human septic shock have to be taken into account. Differences in the species, comorbidity, and the difficulty in determining the exact onset of septic shock in clinical practice, and, thus, any duration-related alteration in splanchnic perfusion, may possibly explain the discrepancy between the results obtained from experimental and clinical studies.
Another interesting finding of the present study is that phenylephrine decreased creatinine clearance. This observation supports the notion that mixed α- and β-adrenergic agents, when given to increase or maintain MAP, may improve renal blood flow (14, 32-35).
Our study has some limitations that we want to acknowledge. First, direct measurements of regional and local splanchnic blood flow in septic shock patients are invasive and require special skills and instruments that are not readily available at bedside. Thus, in the present study, hepatosplanchnic perfusion was assessed using PDR, CBI, and gastric tonometry as surrogates of hepatosplanchnic perfusion and function. Second, for safety reasons, we chose an open-label crossover design not including a time-control group, and, thus, the patients have been enrolled in the study at different times during the evolution of septic shock. Although the study design may limit this bias (each patient serves as his own control), it is possible that the different severity of cardiovascular dysfunction among the study patients could have affected the results. In such study design, carryover effects cannot be ruled out despite the 8-h study period for each drug. Moreover, the design of our pilot study required a relative long time interval (24 h) between baseline and final evaluations. In addition, the lack of randomization in the assignment of interventions does not allow excluding a direct time-dependent effect unrelated to the specific agent. Thus, we cannot guarantee that the observed effects are only the consequence of the administered study drugs. Finally, because the present trial was designed as a pilot study, we investigated only a small number of septic shock patients to compare the effects of NE and phenylephrine on systemic and regional hemodynamics. Because of the limitation of the study design, caution is required when interpreting the data. A larger, randomized controlled study is now needed to confirm these results.
In summary, this is the first study evaluating the use of phenylephrine versus NE on systemic and hepatosplanchnic perfusion in patients with septic shock. Despite some limitations, our results suggest that phenylephrine causes a more pronounced hepatosplanchnic vasoconstriction and an impairment of renal function as compared with NE. Because adrenergic agents with β-adrenergic properties may better preserve hepatosplanchnic perfusion and renal function than selective α-adrenergic receptor agents, phenylephrine should be used with caution in the clinical setting of catecholamine-dependent septic shock.
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