Dobutamine in Severe Scorpion Envenomation

Dobutamine in Severe Scorpion Envenomation* Effects on Standard Hemodynamics, Right Ventricular Performance, and Tissue Oxygenation Souheil Elatrous, MD; Semir Nouira, MD; Lamia Besbes-Ouanes, MD; Mohamed Boussarsar, MD; Riadh Boukef, MD; Soudani Marghli, MD; and Fekri Abroug, MD

Objectives: To document the effects of dobutamine on standard hemodynamics and right ventricular (RV) performance in patients exhibiting pulmonary edema following severe scorpion envenomation, and to characterize the tissue oxygenation profile in patients sustaining scorpion envenomation-related shock. Design: Prospective cohort study. Setting: An ICU in a university hospital. Patients: Nineteen consecutive patients were admitted to the ICU for severe scorpion envenomation; all 19 patients exhibited hemodynamic pulmonary edema, and 10 patients had peripheral shock. Interventions: All patients underwent a hemodynamic study with a Swan-Ganz catheter. In 8 of 19 patients, the thermodilution catheter was equipped with a fast-response thermistor. Measurements and results: Standard hemodynamic parameters were recorded on admission and following the infusion of dobutamine in all patients at a dosage, from 7 to 20 mg/kg/min, intended to achieve the best hemodynamic and tissue oxygenation compromise. RV ejection fraction (RVEF) and RV volumes were simultaneously recorded in 8 patients, and tissue oxygenation parameters were assessed in the 10 patients with peripheral shock. The clinical signs of tissue hypoperfusion improved, and optimal hemodynamic parameters were achieved at a mean 6 SD dobutamine dosage of 17 6 7 mg/kg/min. Dobutamine infusion evoked statistically significant increases in cardiac index, from 2.3 6 0.6 to 3.6 6 0.7 L/min/m2; stroke volume index, from 18 6 5 to 31 6 10 mL/m2; and systemic arterial pressure, from 64 6 12 to 78 6 14 mm Hg. Pulmonary artery occlusion pressure (PAOP) and venous admixture decreased significantly: from 23 6 4 to 15 6 6 mm Hg and from 29 6 7% to 20 6 5%, respectively. With respect to RV function, dobutamine infusion significantly increased the RVEF, from 24 6 7% to 42 6 9%, without significantly changing the RV end-diastolic volume index, reflecting an enhanced RV contractility. In patients with peripheral circulatory failure, the baseline tissue oxygenation profile was consistent with cardiogenic shock, showing increased oxygen extraction as a consequence of a striking depression in oxygen delivery (DO2). After dobutamine infusion, DO2 improved significantly, from 386 6 104 to 676 6 156 mL/min/m2, with a significant decrease in oxygen extraction, from 34 6 8% to 24 6 6%. Conclusions: In severe scorpion envenomation, dobutamine infusion improves impaired heart function. The effects involve both left ventricular and RV dysfunction. Impaired tissue oxygenation is also improved. (CHEST 1999; 116:748–753) Key words: dobutamine; heart failure; scorpion envenomation Abbreviations: CI 5 cardiac index; Do2 5 oxygen delivery; HR 5 heart rate; LV 5 left ventricular; PAOP 5 pulmonary artery occlusion pressure; PAP 5 pulmonary artery pressure; RV 5 right ventricular; RVEDVI 5 RV end-diastolic volume index; RVEF 5 RV ejection fraction; RVESVI 5 RV end-systolic volume index; SAP systemic arterial pressure; SVI 5 stroke volume index; V˙o2 5 oxygen consumption

sting, a dreaded accident in tropical and S corpion subtropical countries, usually results in localized manifestations. Nevertheless, systemic reactions in*From the Intensive Care Unit, CHU F. Bourguiba, Monastir, Tunisia. Manuscript received September 10, 1998; revision accepted March 17, 1999. Correspondence to: Fekri Abroug, MD, Intensive Care Unit, CHU F. Bourguiba, Monastir 5000, Tunisia; e-mail: [email protected] 748

volving GI symptoms, hyperthermia, diaphoresis, or cardiopulmonary abnormalities may occur in up to 3% of stung patients.1 Despite their scarcity, cardiac dysfunction and pulmonary edema are the leading causes of death related to scorpion envenomation.2 Cardiogenic pulmonary edema and/or acute circulatory failure are the clinical features of acute congestive heart failure complicating severe scorpion envenomation.3–10 Right ventricular (RV) assessment Clinical Investigations in Critical Care

by means of angioscintigraphy or thermodilution techniques have shown that RV function is impaired to the same extent as left ventricular (LV) function.9,11 Whether scorpion-related cardiomyopathy is of an ischemic, catecholaminergic, or toxic type is currently the subject of speculation.12 To date, no medication has achieved acceptance as the gold standard; even serotherapy, the only specific treatment of scorpion envenomation, is currently the focus of a wide debate regarding its actual efficacy.12–18 Hence, alternative approaches, especially symptomatic treatments, are warranted. Based on recent insights into the pathophysiology of the cardiopulmonary consequences of severe scorpion envenomation, it could be speculated that dobutamine, an inotropic agent widely prescribed in the treatment of acute myocardial failure of various origins, might be useful in the setting of severe scorpion envenomation. However, data reporting the effects of dobutamine on the hemodynamic disturbances induced by scorpion envenomation are lacking. Accordingly, we report herein the effects of dobutamine infusion on hemodynamic parameters pertaining to LV and RV function in patients who were victims of severe scorpion envenomation. The baseline tissue oxygenation profile and the effects of dobutamine infusion on said profile are also emphasized. Materials and Methods This prospective cohort study included 19 consecutive patients admitted between July 1992 and September 1995 to the medical ICU of Monastir University Hospital in Tunisia because of severe scorpion envenomation. The study was approved by the human research committee of our institution, and informed consent was obtained from all patients or their relatives. The diagnosis of scorpion envenomation was based on a positive history of scorpion sting, with the scorpion being seen or captured by the patient or bystander. The scorpions from 14 patients were examined and identified as Androctonus australis, the most common scorpion species in Tunisia. All patients (12 men and 7 women; age, 14 to 68 years old) sustained severe scorpion envenomation, as defined by the occurrence of acute pulmonary edema. Acute circulatory failure was diagnosed in 10 patients who had a mean arterial pressure # 60 mm Hg and peripheral signs of tissue hypoperfusion (peripheral cyanosis and urine output , 20 mL/h). All patients were previously free from cardiorespiratory disease. The elapsed time between the occurrence of scorpion envenomation and ICU admission ranged from 1 to 24 h. Prior to ICU admission, all but two patients received 10 to 20 mL of scorpion antivenin (10 DL50/mL; Institut Pasteur; Tunis, Tunisia) and/or IV hydrocortisone hemisuccinate, 200 mg, as part of their first-line treatment. Interventions Within the first 3 h, a Swan-Ganz pulmonary artery catheter was inserted percutaneously in all participating patients via the

right internal jugular vein. The position of the catheter in the pulmonary artery was confirmed by waveform analysis of the pressure recorded from the distal end of the catheter with and without balloon inflation. A 20-gauge radial arterial catheter was inserted percutaneously to monitor arterial pressure and blood gases. In the first eight patients, who were admitted between July 1992 and July 1993, the hemodynamic study was performed with a modified quadruple-lumen pulmonary arterial catheter equipped with a fast-response thermistor (7.5F; Baxter Healthcare, Edwards Critical Care; Irvine, CA) allowing RV ejection fraction (RVEF) measurement. A baseline set of measurements in the latter subset of patients were previously published.9 Mechanical ventilation, when indicated, was started before insertion of the pulmonary artery catheter. A Doppler echocardiographic study was performed in 13 of 19 patients upon ICU admission. Moderate mitral regurgitation was detected in five patients, and tricuspid insufficiency was not detected in any participating patients. Hemodynamic Measurement Protocol Hemodynamic measurements were performed at baseline prior to any inotropic or vasoactive support and after dobutamine infusion (mean dosage, 17 6 7 mg/kg/min). The range of dobutamine dosage, from 7 to 20 mg/kg/min, was tailored so that the clinical signs of tissue hypoperfusion regressed completely in the 10 patients with peripheral shock, and so that the best hemodynamic parameters (mean systemic arterial pressure [SAP] and cardiac index [CI]) could be achieved in the other patients. In the 10 patients with peripheral shock, tissue oxygenation parameters were simultaneously calculated and were considered when defining the hemodynamic goal. When the optimal dose of dobutamine was achieved, it was not changed; the second set of hemodynamic measurements was performed within 20 min. During each set of hemodynamic measurements, the following data were recorded: mean pulmonary artery pressure (PAP), right atrial pressure, and pulmonary artery occlusion pressure (PAOP). Cardiac output was measured by the thermodilution technique. In patients whose RV function was assessed, RVEF, RV end-diastolic volume index (RVEDVI), and RV end-systolic volume index (RVESVI) were calculated. Arterial and mixed venous blood samples were simultaneously obtained and analyzed to determine arterial and mixed venous oxygen contents. Oxygen delivery (Do2), oxygen consumption (V˙o2), oxygen extraction ratio, and other derived variables were calculated using standard formulas. Statistical Analysis Data are expressed as mean 6 SD. A Wilcoxon signed rank test was applied to compare data at baseline and after dobutamine infusion. A p value , 0.05 was considered significant.

Results The clinical and demographic characteristics of the 19 patients included in the study are presented in Table 1. Pulmonary edema, which was required for inclusion in the study, was associated with peripheral circulatory failure in 10 patients. Eleven patients required mechanical ventilation for a mean duration of 2.4 6 1.1 days (range, 1 to 4 days). Standard hemodynamic data, RV volumes, RVEF, CHEST / 116 / 3 / SEPTEMBER, 1999

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Table 1—Clinical Characteristics of Study Patients* Patient No.

Age, yr

Gender

Time Lapse, h

Treatment

SAPS

Pao2/Fio2, mm Hg

MV

Duration of Stay, d

Outcome

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Mean 6 SD

68 28 14 18 17 28 25 26 23 19 12 34 20 20 24 18 15 18 17 23 6 12

M M F F F F M F F F F M F F M M M F F —

12 18 24 24 18 10 6 18 2 8 10 18 10 10 12 1 11 12 5 12 6 6

H SAV 1 H SAV 1 H SAV 1 H SAV 1 H SAV 1 H H H SAV 1 H SAV 1 H — SAV 1 H SAV 1 H SAV 1 H H SAV 1 H SAV 1 H — SAV 1 H —

11 17 8 11 11 11 9 14 16 6 15 5 6 8 7 14 11 10 11 11 6 3

297 291 357 178 277 216 286 315 285 268 214 204 319 270 192 184 297 210 322 262 6 54

2 1 2 1 1 2 2 2 1 1 1 1 2 2 1 1 2 1 1 —

7 1 7 9 6 7 11 7 10 8 3 3 11 10 2 9 8 7 12 763

S D S S S S S S S S S D S S S S S S S —

*SAV 5 scorpion antivenin; H 5 hydrocortisone hemisuccinate; SAPS 5 Simplified Acute Physiology score19; Fio2 5 fraction of inspired oxygen; MV 5 mechanical ventilation; S 5 survived; D 5 died; M 5 male; F 5 female.

and parameters of tissue oxygenation at baseline and after dobutamine infusion are shown in Tables 2– 4. Baseline hemodynamics are characterized by the standard profile of acute cardiac failure previously described in severe scorpion envenomation.3,4 PAOP was increased, while CI and stroke volume index (SVI) were decreased and heart rate (HR) accelerated. Do2 was markedly reduced and V˙o2 was low, despite an increase in oxygen extraction. There was an elevated venous admixture. RVEF was markedly depressed, RVEDVI was within the normal range, and RVESVI was increased.

Table 2—Hemodynamic Data at Baseline and After Dobutamine Infusion* Data

Baseline

After Dobutamine Infusion†

HR, beats/min RAP, mm Hg PAOP, mm Hg Mean PAP, mm Hg Mean SAP, mm Hg PVRI, IU SVRI, IU CI, L/min/m2 SVI, mL/m2 Qva/Qt, %

122 (23) 6 (4) 23 (4) 27 (4) 64 (12) 1.9 (1.4) 25.3 (7.2) 2.3 (0.6) 18 (5) 29 (7)

124 (31) 4 (3) 15 (6)‡ 21 (7) 78 (14)‡ 1.7 (0.7) 21.3 (5.3) 3.6 (0.7)‡ 31 (10)‡ 20 (5)‡

*Data presented as mean (SD). RAP 5 right atrial pressure; PVRI 5 pulmonary vascular resistance index; SVRI 5 systemic vascular resistance index; Qva/Qt 5 intrapulmonary shunt. †Dosage, 17 6 7 mg/kg/min. ‡p , 0.05. 750

The administration of dobutamine allowed the clinical signs of hypoperfusion to be controlled in each of the patients exhibiting signs of peripheral circulatory failure. With regard to hemodynamic parameters, the infusion of dobutamine at a mean dosage of 17 6 7 mg/kg/min resulted in a sharp and statistically significant increase in CI, from 2.3 6 0.6 to 3.6 6 0.7 L/min/m2 (Table 2). SVI increased by almost twofold, while HR remained unchanged. Mean SAP was enhanced substantially, from 64 6 12 to 78 6 14 mm Hg. PAOP decreased markedly, from 23 6 4 to 15 6 6 mm Hg (p , 0.05), with a reduction in venous admixture, from 29 6 7% to 20 6 5% (p , 0.05). With regard to RV function parameters, dobutamine infusion evoked a substantial and significant increase in RVEF, from 24 6 7% to 42 6 9%; RVESVI decreased markedly and significantly, while RVEDVI remained unchanged (Table 3). Increases in CI with dobutamine infusion resulted

Table 3—Right Ventricular Parameters at Baseline and After Dobutamine Infusion* Parameters

Baseline

After Dobutamine Infusion

RVEDVI, mL/m2 RVESVI, mL/m2 RVEF, %

93 (29) 71 (27) 24 (7)

93 (27) 52 (16)† 42 (9)†

*Mean (SD) in eight patients. †p , 0.05. Clinical Investigations in Critical Care

Table 4 —Tissue Oxygenation Parameters at Baseline and After Dobutamine Infusion Parameters 2

Do2, mL/min/m V˙o2, mL/min/m2 O2ER, %

Baseline

After Dobutamine Infusion

368 (104) 125 (35) 34 (8)

676 (156)† 156 (38) 24 (6)†

*Mean (SD) in 10 patients who presented with shock. O2ER 5 oxygen extraction ratio. †p , 0.05.

in a marked and statistically significant elevation of Do2, from 368 6 104 to 676 6 156 mL/min/m2, and a substantial, albeit not significant, increase in V˙o2 (Table 4). Oxygen extraction decreased significantly with dobutamine infusion, from 34 6 8% to 24 6 6% (p , 0.05). Discussion The present study shows that dobutamine infusion improves the hemodynamic performance in patients presenting with severe scorpion envenomation. Dobutamine infusion evoked substantial increases in CI and SAP and lowered PAOP; RV function and tissue oxygenation variables were also improved. Cardiopulmonary disturbances consequent to severe scorpion envenomation have been studied extensively in recent years. Animal and clinical studies have allowed for a better understanding of the pathophysiology of cardiopulmonary dysfunction caused by scorpion venom.2–9,20,21 In animal models, a transient hyperkinetic phase, characterized by systemic hypertension with an increase in cardiac output and coronary perfusion, is rapidly followed by a hypokinetic phase in which hypotension, shock, and pulmonary edema represent the main clinical features of a hemodynamic profile dominated by a fall in cardiac output.6,20,21 However, the hyperkinetic phase has been documented only in recent experimental studies and has not been described in clinical reports.6,21 Heart failure was the main finding of clinical studies dealing with cardiocirculatory disturbances associated with severe scorpion envenomation.4,8,9 Hence, it appears that clinically severe scorpion envenomation is characterized by a hemodynamic profile of acute heart failure with a decrease in cardiac output (associated or not with peripheral signs of shock), elevated LV filling pressure, and hemodynamic pulmonary edema.22 Scorpion envenomation induces LV stunning, and the right ventricle is involved to the same extent as the left ventricle.2,5,9 The specific treatment of scorpion envenomation

relies on the administration of scorpion antivenin.13–16 Unfortunately, clinical evidence of its efficacy is lacking, particularly in severe forms of scorpion envenomation.17,18 Moreover, the benefit of scorpion antivenin has been seriously challenged by a recent experimental study20 showing that injection of scorpion antivenin following the injection of scorpion venom had no effect on the cardiovascular consequences of scorpion envenomation. Symptomatic treatment is therefore of utmost importance, and it is based simply on oxygen administration and the use of mechanical ventilation when acute respiratory failure occurs secondary to pulmonary edema. Indeed, mechanical ventilation has several advantages in the setting of congestive heart failure, and it could be opportune, because it improves LV load conditions with a decrease in both LV afterload and preload. Decreased LV preload might be beneficial, because lung congestion is a major feature of scorpion envenomation. Afterload reduction and increased intrathoracic pressure related to mechanical ventilation might even induce a slight increase in LV ejection fraction in the setting of congestive heart failure.23 In addition to the use of mechanical ventilation when indicated, the administration of dobutamine is worthy of consideration (at least from a physiologic point of view) in the treatment of congestive heart failure evoked by severe scorpion envenomation.24 –26 Moreover, some of published studies8,9,12 dealing with severe scorpion envenomation reported the use of dobutamine in the treatment of circulatory failure and pulmonary edema characterizing this condition. However, the physiologic effects of dobutamine administration on hemodynamic disturbances relevant to severe scorpion envenomation have not been previously reported. The data recorded in the present study show that dobutamine infusion successfully corrected hemodynamic parameters relevant to LV and RV functions. Moreover, the hemodynamic changes produced by dobutamine infusion were quite similar to those described in congestive heart failure.24 –26 These hemodynamic effects were associated with a simultaneous clinical improvement in all patients. Because systemic vascular resistance did not increase, increased SAP with dobutamine infusion was related mostly to an increase in CI in relation to an increase of SVI, rather than to a modification of HR. An increase in stroke volume might theoretically result from an enhanced LV contractility, an increase in LV preload, and/or a decrease in LV afterload. In our patients, LV afterload was not lowered; SAP increased despite a slight decrease in systemic vascular resistance. As for LV preload, we can assume that it did not increase, because PAOP, which generally CHEST / 116 / 3 / SEPTEMBER, 1999

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varies in parallel to LV volume, decreased in our study.27 Hence, we could speculate that the increased SVI resulted merely from an increased LV contractility; LV contractility has previously been shown2–5 to be markedly depressed in severe scorpion envenomation. Dobutamine infusion also induced a sharp decrease in PAOP, thereby ameliorating the LV filling pressure. This was associated with a decrease in intrapulmonary shunting as a consequence of an improvement in pulmonary congestion. With regard to RV function, the infusion of dobutamine induced a marked improvement in RV performance, as reflected by a significant increase of RVEF. Although changes in RVEF could be derived from alterations in ventricular load conditions as well as contractility modification, a large variation in RVEF of the magnitude observed in our study generally results from RV contractility modifications.28 RV preload (RVEDVI) was not modified, while RV afterload, evaluated by mean PAP, decreased slightly; this suggests that variation in RV load conditions played only a small role, if any, in the increase in RVEF. To our knowledge, the present study is the first report of a group of patients in whom tissue oxygenation parameters were analyzed at the same time as standard hemodynamics, helping to further characterize scorpion envenomation-related shock. In addition to the hemodynamic profile of biventricular heart failure, patients with clinical signs of circulatory shock have a significant decline in V˙o2 as a consequence of reduction in cardiac output and systemic Do2. The rise of the oxygen extraction ratio at baseline suggests that oxygen uptake is preserved at the tissue level. These findings are consistent with the tissue oxygenation pattern reported in cardiogenic shock. They are quite different from the data reported by Sofer et al21 in envenomated pigs, in which evidence of tissue dysoxia was demonstrated. It is noteworthy that, in the experimental study by Sofer et al,21 scorpion venom injection induced a hyperkinetic state with an increase in cardiac output and ejection fraction, while PAOP and SVI did not change—a pattern substantially different from the hemodynamic profile observed in our patients. The dobutamine-related improvement in the hemodynamic parameters resulted in improved peripheral tissue oxygenation as reflected by a sharp increase in Do2, which almost doubled; a statistically significant decrease in oxygen extraction; and an increase (not statistically significant) in V˙o2. This Do2-V˙o2 dependency should be regarded as a physiologic one reflecting a preexisting oxygen debt in the tissue of patients with peripheral circulatory failure.29 In conclusion, our data document the beneficial effects of dobutamine infusion on hemodynamic 752

parameters relevant to either LV or RV performance. This lends further support to the hypothesis that depressed ventricular contractility, rather than a change in load conditions, accounts for the hemodynamic disturbances that follow severe scorpion envenomation. Further studies are needed in order to shed light on the effects of a strategy based on dobutamine infusion on relevant clinical end points, such as mortality, duration of mechanical ventilation, and length of ICU stay. References 1 Goyffon M, Vachon M, Broglio N. Epidemiological and clinical characteristics of the scorpion envenomation in Tunisia. Toxicon 1982; 20:337–344 2 Gueron M, Ilia R, Sofer S. The cardiovascular system after scorpion envenomation: a review. J Toxicol Clin Toxicol 1992; 30:245–258 3 Gueron M, Adolph RJ, Grupp IL, et al. Hemodynamic and myocardial consequences of scorpion venom. Am J Cardiol 1980; 45:979 –986 4 Abroug F, Boujdria A, Belghith M, et al. Cardiac dysfunction and pulmonary edema following scorpion envenomation. Chest 1991; 100:1057–1059 5 Abroug F, Ayari M, Nouira S, et al. Assessment of left ventricular function in severe scorpion envenomation: combined hemodynamic and echo-Doppler study. Intensive Care Med 1995; 21:629 – 635 6 Tarasiuk A, Sofer S, Huberfelo S, et al. Hemodynamic effects following injection of venom from the scorpion Leirus quinquestriatus. J Crit Care 1994; 9:134 –140 7 Margulis M, Sofer S, Zalstein E, et al. Abnormal coronary perfusion in experimental scorpion envenomation. Toxicon 1994; 32:1675–1678 8 Abroug F, Nouira S, Boujdaria R, et al. Cardiac dysfunction and pulmonary edema following scorpion envenomation [letter]. Chest 1992; 102:1308 –1309. 9 Nouira S, Abroug F, Haguiga H, et al. Right ventricular dysfunction following severe scorpion envenomation. Chest 1995; 108:682– 687 10 Karnad DR. Hemodynamic patterns in patients with scorpion envenomation. Heart 1998; 79:485– 489 11 Rahav G, Weiss AT. Scorpion sting-induced pulmonary edema: scintigraphic evidence of cardiac dysfunction. Chest 1990; 97:1478 –1480 12 Gueron M, Margulis G, Ilia R, et al. The management of scorpion envenomation 1993 [letter]. Toxicon 1993; 31:1071– 1083 13 Gateau T, Bloom M, Clark R. Response to specific Centruroides sculpturatus antivenom in 151 cases of scorpion stings. J Toxicol Clin Toxicol 1994; 32:165–171 14 Dehesa-Davila M, Possani LD. Scorpionism and serotherapy in Mexico. Toxicon 1994; 32:1015–1088 15 Freire-Maia L, Campos JA, Amaral CF. Approaches to the treatment of scorpion envenoming. Toxicon 1994; 32:1009 – 1014 16 Ismail M. The treatment of the scorpion envenoming syndrome: the Saudi experience with serotherapy. Toxicon 1994; 32:1009 –1014 17 Sofer S, Shahak E, Gueron M. Scorpion envenomation and antivenom therapy. J Pediatr 1994; 124:973–978. 18 Bawaskar HS, Bawaskar PH. Treatment of cardiovascular manifestations of human scorpion envenoming: is serotherapy essential? J Trop Med Hyg 1991; 94:156 –158 Clinical Investigations in Critical Care

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