The Effect of Adding Dopamine Infusion to Noradrenaline Infusion Combined With Restrictive Hydration on Renal Function and Tissue Perfusion during Open Abdominal Surgeries.

OBJECTIVES: This study was designed to assess the effect of adding dopamine infusion in addition to restrictive hydration combined with noradrenaline infusion on intraoperative renal function and serum lactate levels in comparison to restrictive hydration combined with noradrenaline infusion only and standard hydration during open abdominal surgeries. PATIENTS AND METHODS: One hundred and twenty patients were randomly assigned into three equal groups undergoing major open abdominal procedures. In Group I, dopamine infusion in addition to norepinephrine infusion were administered with restrictive hydration. In Group II, norepinephrine infusion was started before the induction of anesthesia with restrictive hydration. In Groups I and II, Ringer's solution was infused at a fixed rate of 2 mL.kg-1.h-1 until the end of surgery. In Group III, the conventional fluid replacement was introduced according maintenance, fluid deficit and third space loss. The outcome to be assessed was serial measurements of creatinine and serum lactate levels preoperatively, intraoperatively, and just postoperatively in addition to after 24 h.
RESULTS: Serum lactate level was significantly low in Groups I and II than that in Group III intraoperatively and postoperatively. In addition, urine output was significantly more in Group I and Group III than in Group II. Creatinine level was higher with significance in Group II than in Group I and III 24 h postoperatively.
CONCLUSION: Dopamine infusion, when added to norepinephrine infusion combined with restricted hydration, improved urine output and creatinine level. Tissue perfusion as indicated by serum lactate level was more adequate in Groups I and II than that in Group III.

INTRODUCTION

Perioperative fluid therapy is a cornerstone in major surgeries such as open abdominal procedures, which are associated with multiple physiological derangements. Such effects have a major impact on morbidity and mortality in addition to vital biomarkers including serum electrolytes (Na+ and K+), lactate, hematocrit and cardiac enzymes.[12]

Open abdominal surgery has always been associated with dehydration due to multiple factors such as fasting, bowel preparation and fluid shifts or third spacing.[34] The current practice of fluid replacement is based on maintenance, deficit and third-space losses with doses up to 15 mL.kg-1.h-1 fluids.[56]

A patient's physiologic and hemodynamic status defines the need for cardiovascular support via fluids, vasopressors and inotropes. The crucial hemodynamic goal includes maintaining blood volume and perfusion pressure, hence preserving cardiac output, tissue blood flow and adequate oxygen delivery.[7] Fluid therapy is a principle line for hemodynamic support because decreased circulating volume occurs during the induction of anesthesia and surgical trauma. Optimizing oxygen delivery and removal of metabolic bioproducts may need combining fluids, vasopressors and cardiovascular support.[7]

There are no specific means to measure circulating volume or methods to assess how optimal pressure, flow and oxygenation for surgical patients can be achieved. Even though mean systemic filling pressures can be estimated, they give only a partial picture of cardiac output. Given the absence of readily attainable regional measures of perfusion, evaluation of global perfusion by measuring base deficit, lactate, central and mixed venous oxygen saturation (ScvO2 and SvO2) may be beneficial.[8]

Whether standard or restrictive amounts of fluids can improve perioperative outcome and perfusion is debatable. Some studies proved the success of restrictive regimen, whereas others found no benefit between both.[9] Individualizing targets for restoration and optimization of circulating volume, pressure and perfusion must be determined for each patient.[10]

Elevated blood lactate levels in emergency and elective surgical patients alert the physician that the patient is at risk of increased morbidity and decreased chances of survival. Prompt therapeutic measures to restore the balance between oxygen demand and supply are warranted in such patients.[11]

This study aims to assess the effect of dopamine infusion when added to restrictive hydration combined with noradrenaline on renal function and serum lactate level as an index of tissue perfusion in major open abdominal procedures.

PATIENTS AND METHODS

This randomized, controlled, double-blinded study was conducted at Ain Shams University hospital and Kasr Alaini hospital between October 2016 and June 2018. After obtaining approval from the Ethical Committee, informed consent was taken from all patients scheduled for major open abdominal surgeries. The study was registered in ClinicalTrials.gov ID NCT03780686.

All patients with American Society of Anesthesiologists physical status Classes I, II or III and aged from 18 to 75 years scheduled for major open abdominal surgeries (hemi-colectomy, total colectomy and resection anastomosis) were enrolled in the study.

Exclusion criteria were patients with coagulopathies, hepatic dysfunction, renal dysfunction, congestive heart failure (New York Heart Association scores ≥3) and peripheral vascular disease.

Patients were randomized using closed envelopes into the following three equal groups: Group I (restrictive hydration combined with noradrenaline infusion and dopamine infusion), Group II (restrictive hydration combined with noradrenaline infusion only) and Group III (standard hydration).

Group I comprised forty patients. In this group, dopamine (dopamine 40 mg/mL – 200 mg/5 mL, Hospira, UK) infusion was started at a rate of 2–5 ug.kg-1.min-1, according to satisfactory urine output, before induction of anesthesia. Norepinephrine (norepinephrine [base] 4 mg / 4 mL 1 mg/mL, Sulfites free, Aguettant Ltd, UK) infusion was started at a constant rate of 3 ug.kg-1.h-1 (0.06 ug.kg-1.min-1) after induction of anesthesia until the end of surgery.

Group II comprised forty patients. Before induction of anesthesia, norepinephrine infusion was started at a constant rate of 3 ug.kg-1.h-1 (0.06 ug.kg-1.min-1) until the end of surgery.

The main aim of norepinephrine infusion in both groups was to maintain mean arterial pressure (MAP) between 70 and 100 mmHg. Ringer's solution was infused at a fixed rate of 2 mL.kg-1.h-1 until the end of surgery (deferred hydartion). If hypotension confronted, it was managed accordingly by bolus crystalloids (250 mL) and bolus colloids (50 mL) or increasing the dose of norepinephrine.

Group III comprised forty patients. The conventional fluid replacement was introduced according to maintenance (each hour 4 mL.kg-1 for first 10 kg and 2 mL.kg-1 for second 10 kg and 1 mL.kg-1 for the next 10 kg to follow), fluid deficit (fasting hours x maintenance) replacement in first three hours and third space loss (estimated between 6-8 mL.kg-1.h-1). For clarification, a 70 Kg patient fasted 8 hours, calculation of fluids will be as follows: for maintenance fluid per hour, he needs 110 mL.h-1 (40 mL + 20 mL + 50 mL), so fasting hours fluid deficit will be 880 mL. In first hour, 550 mL to be infused (440 mL+110 mL), in second hour, 330 mL (220 mL+110 mL), in third hour, 330 mL (220 mL+110 mL) and for the fourth hour and next hours, the patient will be infused with 110 mL.h-1. During operation time, in addition to the previously mentioned fluids per hour, the patient will be infused with 6 - 8 mL.kg-1.h-1 to compensate for third space loss starting from the second intraoperative hour.

If hypotension was observed (MAP <60 mmHg), a bolus of 250 mL Ringer's solution was given and in case of persistent hypotension, this procedure was repeated with the addition of colloid 50 mL and bolus dose of intravenous (i.v.) ephedrine 5–10 mg.

Gelatin polysuccinate, 4% (Gelofusine, B. Braun Melsungen AG, D-34209 Melsungen, Germany) solution infused as a rescue medication if a MAP <60 mmHg persisted after the above-mentioned correction with Ringer's solution.

In all groups, if blood loss exceeded the allowed loss, packed red blood cell (PRBCs) units were transfused to keep hemoglobin level above 8 g.dL-1.

In all groups, blood samples were collected for creatinine, electrolytes and serum lactate estimation. The first one was preoperative before induction of anesthesia, the second was intraoperative after tumor resection (or 2 h after the induction of anesthesia) and the third one was just after transfer to the postoperative care unit (PACU). For creatinine and lactate levels, another blood specimen was withdrawn 24 h postoperatively. Urine output collected and the amount calculated and recorded since induction of anesthesia till the patient leaves the PACU.

All patients were allowed to drink clear fluids up to 4 hours before surgery if no contraindications. Afterwards, they were infused with lactated Ringer's solution 500 mL (2mL.kg-1.h-1) before arriving at the operation room to overcome hypovolemia frequently encountered with this category of patients. Premedication with IV midazolam (0.02 mg.kg-1) was administered once the patient arrived at the operation theater. Standard monitoring, connected to all patients, included continuous 5-lead electrocardiographic data, heart rate (HR), pulse oximetry and noninvasive blood pressure. Noninvasive cardiac output monitoring (esCCO NIHON KOHDEN, Japan) was connected to all patients for continuous cardiac output estimation. Just before the induction of anesthesia, a radial artery cannula was inserted in the nondependent hand. After performing Allen's test, the skin was sterilized with chlorhexidine 2% in 70% alcohol swab stick, lidocaine 1 ml 2% was infiltrated at the site of insertion, and then the cannula was inserted, checked, and connected for the measurement of invasive MAP. A central venous catheter (REF CS-14703 Multi-Lumen Central Venous Catherterization Set with Blue FlexTip Catheter ARROW, USA) was inserted into the internal jugular vein, under complete aseptic technique, using a portable ultrasound machine (Sonosite, M-Turbo Ultrasound System, FUJIFILM Sonosite, Inc., USA) which was performed after the induction of general anesthesia. A nasopharyngeal temperature probe was inserted. Bair Hugger™ warming blankets were laid under all patients for maintaining normothermia during the operation (Bair Hugger, 3M, United States). Anesthesia induction included propofol (2 mg.kg-1), fentanyl (1–2 ug.kg-1) and cisatracurium (0.15 mg.kg-1) to facilitate intubation. Endotracheal intubation was assisted by a glidescope (Verathon Medical, Canada, ULC). Maintenance of anesthesia was achieved with sevoflurane inhalation at a minimum alveolar concentration. Intraoperative blood pressure measurements including HR, oxygen saturation and estimated cardiac output were recorded continuously in all the three groups.

At the end of the operation, infusion of both dopamine and norepinephrine was tapered according to the patient's hemodynamic status, and the patients were awakened, extubated, and shifted to the PACU for complete recovery.

If there was any complication like excessive intraoperative bleeding or general patient's condition necessitate postoperative close monitoring, so the patient was kept intubated and shifted to intensive care unit (ICU), otherwise all other patients were shifted to intermediate care unit.

Statistical analysis

Data were coded and entered using the statistical package SPSS version 24 (IBM Corp., Armonk, NY, USA) and summarized using mean and standard deviation for quantitative variables and frequencies (number of cases) and relative frequencies (percentages) for categorical variables. Comparisons between groups were done using unpaired t-test when comparing two groups. ANOVA test was used to compare multiple groups. For comparing categorical data, Chi-square test was used. Fisher's exact test was used instead when the expected frequency is <5. P < 0.05 was considered statistically significant.

RESULTS

One hundred and twenty patients fulfilled the study's inclusion criteria. They were randomized and allocated into the following three groups: Group I (dopamine norepinephrine), Group II (restrictive hydration), and Group III (standard hydration), with forty patients in each group. Twelve patients excluded from the study after enrollment due to severe intraoperative complications. Therefore, Group I included 36 patients, Group II 37, and Group III 35 patients. Demographic data for patients in all the three groups are shown in Table 1.

Table 1

Demographic data and type of surgery for all the three groups

	Dopamine norepinephrine	Restricted group	Standard group	P
Total number	36	37	35
Age	64±16	63±17	62±15
Sex (male/female)	17/19	17/20	16/19
Body weight (kg)	78.7±8.9	79.4±9.7	81.1±9.5	0.543
ASA physical status
I	6	7	7
II	21	22	21
III	9	8	7
Operation type
Subtotal colectomy	2	1	0
Total colectomy	1	0	1
Hemicolectomy	1	0	2
Left hemicolectomy	5	6	6
Right hemicolectomy	12	11	9
Ileocecal resection	5	7	8
Sigmoidectomy	4	8	6
Resection anastomosis	6	4	3
Duration of surgery	176.84±23.28	174.91±29.56	178.24±27.13	0.869

Data presented as number or mean±SD. P>0.05 is statistically not significant. SD=Standard deviation, ASA=American Society of Anesthesiologists

There was no statistical difference with regard to MAP, HR, and Na+ and K+ levels in all groups [Table 2].

Table 2

Preoperative hemodynamics and electrolytes for all the three groups

	Dopamine norepinephrine Group I	Norepinephrine-restrictive Group II	Standard hydration Group III	P
MAP (mmHg)	97.46±9.51	96.86±8.93	100.66±9.53	0.186
HR (beats/min)	79.74±10.08	81.87±12.19	80.17±10.17	0.678
Na+ (mEq.L-1)	139.23±3.41	138.67±3.97	137.97±2.84	0.308
K+ (mEq.L-1)	3.72±0.34	3.86±0.32	3.75±0.38	0.179

All values are presented as mean±SD, P>0.05 is statistically not significant. SD=Standard deviation, MAP=Mean arterial pressure, HR=Heart rate

MAP and HR were significantly high in Group I and Group II than that in Group III, while serum Na+ level was lower in Group I than that in Groups II and III [Table 3].

Table 3

Intraoperative hemodynamics and electrolytes for all the three groups

	Dopamine norepinephrine group	Norepinephrine-restrictive group	Standard hydration group	P
MAP (mmHg)	87±7.88	86.65±8.01	78.31±6.77*	<0.001
HR (beats/min)	93.51±8.24	92.23±8.79	86.74±9.20*	0.003
Na+ (mEq.L-1)	136.26±2.07*	138.54±2.41	137.17±2.24	<0.001
K+ (mEq.L-1)	3.78±0.30	3.64±0.42	3.69±0.23	0.187

*Statistical significance at P<0.05. All values are presented as mean±SD. SD=Standard deviation, MAP=Mean arterial pressure, HR=Heart rate

There was no statistical significance between the three groups with regard to MAP, HR, and Na+ and K+ levels in postoperative measurements [Table 4].

Table 4

Postoperative hemodynamics and electrolytes for all the three groups

	Dopamine norepinephrine group	Norepinephrine-restrictive group	Standard hydration group	P
MAP (mmHg)	97.46±9.51	96.86±8.93	100.66±9.53	0.186
HR (beats/min)	79.74±10.08	81.87±12.19	80.17±10.17	0.678
Na+ (mEq.L-1)	139.23±3.41	138.67±3.97	137.97±2.84	0.308
K+ (mEq.L-1)	3.72±0.34	3.86±0.32	3.75±0.38	0.179

All values are presented as mean±SD. P>0.05 is statistically not significant. SD=Standard deviation, MAP=Mean arterial pressure, HR=Heart rate

Serum lactate level was significantly higher in Group III than that in Groups II and III intraoperatively and postoperatively [Table 5].

Table 5

Preoperative, intraoperative, and postoperative serum lactate levels

	Dopamine norepinephrine	Restricted group	Standard group	P
Lactate level (mmol/L)
Preoperative	0.98±0.17	0.96±0.12	0.97±0.16	0.852
Intraoperative	1.30±0.15	1.31±0.22	1.50±0.24*	<0.001
Postoperative	1.31±0.17	1.34±0.21	1.56±0.28*	<0.001
24 h postoperative	1.10±0.13	1.12±0.11	1.14±0.16	0.458

All values are presented as mean±SD. *Statistical significance P<0.05. SD=Standard deviation

Creatinine level was higher in Group II than that in Groups I and III intraoperatively and postoperatively but without statistical significance, while it was higher with statistical significance 24 h postoperatively [Table 6].

Table 6

Creatinine levels in all groups

	Dopamine norepinephrine group	Norepinephrine-restrictive group	Standard hydration group	P
Creatinine levels (mg.dL-1) preoperatively	1.31±0.24	1.32±0.25	1.29±0.28	0.881
Creatinine levels (mg.dL-1) intraoperatively	1.22±0.27	1.28±0.29	1.24±0.23	0.616
Creatinine levels (mg.dL-1) postoperatively	1.19±0.28	1.32±0.29	1.21±0.25	0.097
Creatinine levels (mg.dL-1) 24 h postoperative	0.93±0.17	1.26±0.20*	1.01±0.19	<0.001

All values are presented as mean±SD. P>0.05 is statistically not significant. *Statistical significance P<0.05. SD=Standard deviation

Total IV crystalloids, colloids, and PRBCs infused and total blood loss intraoperatively were higher with significance in Group III than those in Groups I and II. Total urine output was higher with statistical significance in Group I than that in Groups II and III [Table 7].

Table 7

Intraoperative total intravenous fluids infused, total urine output, total blood loss, and cardiac output

	Dopamine norepinephrine group	Norepinephrine-restrictive group	Standard hydration group	P
Total intravenous crystalloid volume	1352.32±65.37	1341.65±61.45	1795.43±127.34*	<0.001
Total colloid volume†‡	0 (0-50)	0 (0-50)	50 (0-100)*	0.014
PRBCs†‡	0 (0-250)	0 (0-250)	250 (0-250)*	0.027
Total blood loss	387.5±102.25	376.94±98.41	443.72±104.62*	0.0142
Total urine output at the end of the surgery (mL)	443.43±64.12	351.11±65.36*	406.81±51.82	<0.001
Cardiac output (L/min)
At the beginning of the surgery	4.42±0.40	4.47±0.35	4.38±0.47	0.645
Intraoperative (2 h after the start)	4.02±0.42	3.95±0.38	3.76±0.46٭	0.029
At the end of the surgery	4.26±0.32	4.23±0.35	4.16±0.41	0.491

Values are presented as mean±SD. †,‡Data presented as median (ranges), *Statistical significance P<0.05. PRBCs=Packed red blood cells, SD=Standard deviation

DISCUSSION

Renal impairment is a common, critical and serious complication following major surgeries, especially those with major fluid shift. To impede the development of such a dilemma, it needs more awareness and extra care from medical staff.

We selected dopamine infusion for adding to restrictive group with norepinephrine infusion because dopamine infusion in low dose stimulates D1 and D2 receptors with enhancement of diuresis and natriuresis.[12]

In our study, we demonstrated that dopamine infusion in diuretic dose when added to restrictive hydration combined with noradrenaline infusion resulted in more urine output intraoperatively with a significant reduction in creatinine level measured 24 h postoperatively when compared with restrictive group with norepinephrine infusion only and standard hydration group.

Dopamine effect on the kidney is dose dependent. At doses of 0.3–5 ug.kg-1.min-1, dopamine achieves rise in renal blood flow by acting on D1 vascular receptors. Furthermore, dopamine acts on D2 receptors situated on presynaptic nerve endings, constraining the discharge of noradrenaline and hence, promotes diuresis and natriuresis.[12] These effects are attained through the inhibition of Na+/K+-adenosine triphosphatase action.[13]

Excitation of D2 receptor, situated on the collecting tubules, by dopamine in low dose, leads to rise in prostaglandin E2 production, which in turn counteracts the action of antidiuretic hormones, amplifying free water diuresis.[1415]

On the other hand, norepinephrine engenders vasoconstriction by acting on α-adrenergic receptors, the effect that may elicit a downturned organ blood flow as a consequence of regional vascular bed constriction. In such a scheme, blood flow would lessen because of increment in intraorgan vascular resistance that exceeds the perfusion pressure, principally for the kidney.[1617] Literally, noradrenaline infusions have been disclosed to diminish renal and splanchnic blood flow when administered during normal circulation, hypotension due to hypovolemia and in cases of essential hypertension.[181920]

Muscles are the main source for lactate production, but also, lactate is created by most body tissues but in minute amount. Under usual circumstances, lactate is chiefly eliminated by the liver with minimal amount excreted through the kidney.[21] In normal aerobic environment, creation of lactate is bypassed through the production of pyruvate by the way of glycolysis. Meanwhile, when tissues are deprived of oxygen, the end product of glycolysis is lactate which is used as a substrate for gluconeogenesis.[22]

In this study, serum lactate levels increased with statistical significance in standard group than in dopamine norepinephrine group and norepinephrine-restricted group which means that norepinephrine improves tissue perfusion. In addition, the increment in lactate level was corrected within 24 h postoperatively, but this intraoperative effect may lead to bad outcome such as increased incidence of postoperative complications with extended hospital stay.[23]

Wenkui Y investigated the response of a restricted intravenous fluid regimen tailored by serum lactate level with a standard liberal regimen on co-morbidities after major elective surgery for gastrointestinal (GI) malignancy. It was found that a fluid-restricted regimen may lead to fluid insufficiency and low tissue perfusion in up to 28% of patients. In comparison to the present study, a restrictive fluid regimen (combined with noradrenaline infusion) resulted in a lower level of serum lactate as opposed to the standard regimen. Inadequate tissue perfusion can be detected early and so corrected immediately, with adjustment of i.v. fluid administration if there is a close monitoring of serum lactate levels intraoperatively and in the early postoperative period.[24]

The value of serum lactate levels strongly correlates with poor outcomes. Some literature claiming that variations in blood lactate levels, particularly in the first 24 h, were significantly combined with postoperative morbidity and mortality in patients subjected to elective major abdominal surgery. In a study by Shenghua et al. on patients who underwent elective major abdominal surgery, blood lactate was determined postoperatively at 6-h intervals during the first 24 h. The accuracy of lactate levels to predict both overall and major complications increased postoperatively from 0 h to 24 h.[25]

Another study by Meregalli et al., which evaluated serial blood lactate levels as predictors of outcome, concluded that elevated blood lactate levels are associated with a higher mortality rate and postoperative complications in hemodynamically stable surgical patients.[26]

One of the main vital goals of major abdominal surgeries is to maintain gut perfusion with concern to glycolytic flux in an attempt to lower lactate levels. Glycolytic flux could be modulated by insulin administration, but such treatment is controversial and may have unwarranted effects on glucose homeostasis.[27] Lactate elimination in GI surgery patients could be enhanced by boosting oxygen delivery with a combination of i.v. fluids and inotropes. However, results of such “goal-directed” therapy after major surgery are conflicting[28] and probably benefit only those patients with the highest risk profile.[29] In addition, pursuing lactate normalization at all costs in the absence of other signs of tissue hypoperfusion may expose patients to the toxicity of overresuscitation without any clear benefit. Nevertheless, lactate-driven adjustment of i.v. fluid administration intraoperatively and in the early postoperative period allowed early detection and correction of inadequate tissue perfusion and significantly decreased the overall complication rate after elective surgery for GI malignancy.

Regarding resuscitation policy in elective surgery, a number of factors were found implicated in the lactate/outcome relationship. These include the use of artificial colloids which can augment the risk of peri-operative hemorrhage by more than 50%,[30] while a sustained positive fluid balance in the early postsurgical period may significantly increase infectious complications and mortality in critically ill surgical patients.[31] Furthermore, the grade of intestinal mucosal damage and corresponding high lactate concentrations have been found to be directly correlated with the duration of surgery.[32]

Limitations

The effect of adding dopamine to restrictive hydration in combination with norepinephrine infusion needs more thorough studies to detect its ultimate results on vascular system, bleeding, postoperative hospital stay, intestinal motility, gut, and tissue perfusion. Such a huge study was beyond our capabilities. Other studies may be performed to investigate the effect of adding minimal infusion dose of norepinephrine and/or dopamine in combination with standard hydration in major abdominal surgeries.

CONCLUSION

Despite our limitations, we could conclude that, dopamine infusion, when added to norepinephrine infusion combined with restricted hydration, improved urine output and creatinine level when compared to norepinephrine infusion alone. Tissue perfusion as indicated by serum lactate level was more adequate in both groups (dopamine norepinephrine group and norepinephrine-restricted group) than in standard group.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.