Introduction
Induced hypotension is defined as elective lowering of the arterial blood pressure in a deliberate and controllable manner for minimizing blood loss and improving the operative field visibility.[1]
Induced hypotension can be achieved by several pharmacological and nonpharmacological techniques. The nonpharmacological methods include patient positioning and intermittent positive pressure ventilation to control venous return. The pharmacological techniques include volatile anesthetics, direct-acting vasodilator drugs, ganglion blocking drugs, alpha-blockers, beta-blockers, combined alpha and beta-blockers, calcium channel blockers, magnesium sulfate, alpha-2 agonists, and prostaglandins.[2]
Surgical trauma causes extensive alterations in the hemostatic system leading to a hypercoagulable state. These alterations include increased coagulation activity and platelet aggregation that may be modified by surgical and anesthetic techniques.[3–6]
We hypothesize that induced hypotension may affect the hemostatic alterations that occurred during surgery.
The aim of the study was to assess and compare the changes in platelet aggregation, coagulation, and fibrinolysis status during normotensive and dexmedetomidine-induced hypotensive anesthesia in patients undergoing spine surgery.
Material and Methods
A prospective, randomized, controlled trial was carried out after obtaining approval from the Hospital Ethics Committee (31421/03/17 on March 2017), registration in the Pan African Clinical Trials Registry (PACTR201704002217398), and informed written patient consent. Adult patients aged 18-40 years, of either gender, with American Society of Anesthesiology (ASA) physical status I and II undergoing elective spine surgery were included in the study. The duration of the study was 6 months.
The exclusion criteria of the study included patients with a history of blood disorders, patients on anticoagulant therapy, patients with malignancy, renal, hepatic or cardiovascular diseases.
Patients on aspirin or cyclo-oxygenase 1 inhibitors were informed to stop the medications 2 weeks before the operation. Patients were randomly allocated into two groups using a computer-generated randomization sequence placed in a sealed opaque envelope.
Group I (Normotensive group): Patients received normotensive anesthesia.
Group II (Hypotensive group): Induced hypotension was performed using dexmedetomidine infusion at a loading dose of 1 μg/kg over 10 min followed by a maintenance infusion of 0.2–0.7 μg/kg/h titrated to keep the mean arterial blood pressure (MAP) between 55 and 65 mm Hg.
A preoperative venous blood sample was obtained for complete blood count (CBC), collagen-induced platelet aggregation, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level, antithrombin III and D-dimer.
On arrival to the operating room, an 18 gauge intravenous (IV) cannula was inserted. Patients were monitored using 5 lead ECG, pulse oximetry, noninvasive and invasive blood pressure, temperature probe, and end-tidal capnography. General anesthesia was induced using fentanyl 1 μg / kg, propofol 2 mg / kg, and cis-atracurium 0.15 mg / kg. Endotracheal intubation was performed and mechanical ventilation was adjusted to keep end-tidal CO2 between 30 and 35 mm Hg. Anesthesia was maintained using isoflurane 1–1.5% in a gas mixture of oxygen (40%) and air (60%), fentanyl 1 μg / kg / h and incremental doses of cis-atracurium (0.03 mg/kg). After induction of anesthesia, an arterial line was inserted in the radial artery and a central line was inserted in the internal jugular vein. Packed RBCs was used to keep hematocrit value above 27%. Our aim was to keep all patients normothermic with CVP of 6–10 cm H2O and urine output 0.5–1 mL/kg/h. MAP was be kept more than 75 mm Hg in the normotensive group and between 55 and 65 mm Hg in the hypotensive group. The hypotensive technique was started after patient stabilization in the prone position and before skin incision.
Patients who developed severe hypotension (MAP < 55 mm Hg) were managed by decreasing the dose of dexmedetomidine and rapid infusion of Ringer’s lactate. Ephedrine bolus (6 mg) was given as needed and these patients were excluded from the study. Bradycardia was defined as a heart rate (HR) less than 50 beat/min and was treated with intravenous atropine 0.01 mg/kg. Tachycardia was defined as increased HR more than 20% of the baseline and managed according to the cause; rapid intravenous fluid infusion in the case of hypovolemia and intravenous injection of fentanyl (1 μg/kg) in the case of inadequate analgesia.
The hypotensive agent was stopped before starting wound closure for hemostatic assessment of the surgical field after patient returned normotensive. At end of surgery, inhalation anesthetic was discontinued, and neuromuscular block was antagonized with neostigmine 0.05 mg/kg and atropine 0.015 mg/kg.
Blood samples were taken to assess collagen-induced platelet aggregation preoperatively (T1), 15 min after induction of anesthesia (T2), 60 min after skin incision (T3), 120 min after skin incision (T4), at the end of surgery (T5), 2 h (T6), and 24 h (T7) postoperatively.
Platelet aggregation was measured by using the platelet lumi-aggregometer (Chrono-Log Corporation 540, Coulter, USA). Platelet aggregation measurement is based on the change in the light transmittance of stirred platelet-rich plasma (PRP) after addition of the aggregating agent to the aggregometer cuvette. Blood samples were collected into tubes containing 3.8% sodium citrate. The collected blood was centrifuged at 160 g for 10 min for preparing the PRP. After preparing PRP, the remaining sample was centrifuged at 1200 g for 20 min for preparing platelet-poor plasma (PPP). The platelet count of PRP was adjusted to be between 200 and 350 × 109/L.[7] Platelet aggregation was induced by collagen 5 μg/mL.
Blood samples for the assessment of platelet count, PT, aPTT, fibrinogen, antithrombin III, and D-dimer were taken preoperatively, 2 h and 24 h postoperatively.
MAP and (HR) were documented preoperatively, at 15 min after induction of anesthesia, every 30 min after skin incision, at the end of surgery and 2 h postoperative. Intraoperative blood loss, intra-operative infused fluid, packed RBCs transfusion and intra-operative urine output were recorded.
Statistical analysis
The sample size was calculated depending on the changes of platelet aggregation (%) during surgery. Based on the results of our pilot study (the mean platelets aggregation was 87.7 3 ± 12.03% for the normotensive group and 76.27 ± 9.4% for the hypotensive group), at least 25 patients were needed at α error of 0.05, and study power of 95%. The sample size calculation was based on a two-sample independent t test (two sided). Sample size was calculated using G* Power3 program (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany).
We used SPSS 16 software (SPSS) for statistical analysis. The Shapiro-Wilk test and visual inspection of histograms were performed to verify the assumption of normality. Quantitative data were described as mean ± SD, and an independent-sample t test was used for comparison between both groups. The intragroup changes of the continuous data were analyzed utilizing the repeated measures analysis of variance. Categorical data were described as number or frequencies (%), and χ2 test or Fisher exact test was used for comparison between both groups as appropriate. The nature of the hypothesis testing was two-sided, and value of P value < 0.05 was considered statistically significant.
Results
In each group, 30 patients were enrolled [Figure 1]. There was no significant difference between groups regarding age, gender, weight, ASA physical status or type of surgery (P = 0.197, 0.417, 0.249, 0.519, and 0.614, respectively) [Table 1].
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Figure 1: CONSORT Flow Diagram of participants through each stage of a randomized trial
Table 1: Perioperative patient characteristics
Intraoperative blood loss was significantly higher in the normotensive group than the hypotensive group (P < 0.001 with confidence interval (CI) 385.8; 547.8). Seven patients in the normotensive group received intraoperative packed RBCs transfusion compared to no patients in the hypotensive group. Out of these seven patients, three patients needed a transfusion of one unit packed RBCs, while the other four patients needed two units each. In the two studied groups, postoperative hemoglobin concentration was significantly lower as compared to the pre-operative value (P < 0.05). The postoperative decrease of hemoglobin concentration was more pronounced in the normotensive group as compared to the hypotensive group (P < 0.001 with CI 0.75; 1.75 and 0.78; 1.75 at 2 h and 24 h postoperative, respectively).
Preoperative collagen-induced platelet aggregation values were not statistically different between the two groups (P = 0.611). In the normotensive group, collagen-induced platelet aggregation was progressively increased. It was significantly higher at 120 min after skin incision, at the end of surgery, and at 2 h and 24 h postoperatively compared to the preoperative value (P < 0.05) Figure 2.
Figure 2: Collagen- induced platelet aggregation (%) changes in the two studied groups (presented as mean ± SD). *Indicates significant difference between the normotensive group and the hypotensive group. †Indicates significant difference compared to preoperative value of the normotensive group
In the hypotensive group, collagen-induced platelet aggregation was insignificantly different throughout the study times compared to the preoperative value (P > 0.05). Comparison of collagen-induced platelet aggregation between the two groups revealed that platelet aggregation was significantly increased in the normotensive group at 120 min after skin incision, the end of surgery, 2 h and 24 h postoperative compared to the hypotensive group (P < 0.05) Figure 2.
Postoperative PT and aPTT were significantly prolonged while postoperative platelet count and antithrombin III were significantly decreased in the normotensive group as compared to its preoperative value (P < 0.05). In the hypotensive group, these hemostatic markers were insignificantly different compared to the preoperative value (P > 0.05). There was a statistically significant difference between both groups regarding the postoperative PT, aPTT, platelet count, and antithrombin III (P < 0.05) [Table 2].
Table 2: Blood coagulation tests in the three studied groups
At 2 h postoperative, fibrinogen level was significantly decreased in the normotensive group as compared to the preoperative value (P < 0.001). Fibrinogen level was significantly lower in the normotensive group compared to the hypotensive group (P = 0.003, CI, 9.85; 45.82). At 24 h postoperative, fibrinogen level was insignificantly increased in the two groups as compared to the pre-operative value (P > 0.05) and the comparison between both groups was insignificantly different (P = 0.173, CI –31.03; 5.7) [Table 2].
Postoperative D-dimer was significantly increased in the two groups compared to preoperative value (P < 0.05). It was significantly higher in the normotensive group as compared to the hypotensive group (P < 0.05) [Table 2].
Preoperative HR and MAP values were comparable between the two groups (P = 0.488 and 0.514, respectively). In the normotensive group, HR and MAP had no statistically significant changes throughout the period of the study as compared to the preoperative value (P > 0.05). HR and MAP decreased significantly during the period of induced hypotension in the hypotensive group compared to the preoperative value (P < 0.05). During the period of induced hypotension, the HR and MAP values were significantly lower in the hypotensive group compared to the normotensive group (P < 0.05) Figures 3 and 4.
Figure 3: Mean arterial blood pressure (mmHg) changes in the two studied groups (presented as mean ± SD). *Indicates significant difference between the normotensive group and the hypotensive group. †Indicates significant difference compared to preoperative value of the hypotensive group
Figure 4: Heart rate (beat/min) changes in the two studied groups. *Indicates significant difference between the normotensive group and the hypotensive group. †Indicates significant difference compared to preoperative value of the hypotensive group
Discussion
Our study revealed that collagen-induced platelet aggregation was significantly increased in the normotensive group at 120 min after skin incision, at the end of surgery and postoperatively while it decreased insignificantly during the induced hypotensive period in the hypotensive group and remained statistically insignificant till the end of surgery and during the first 24 h postoperative. As regarding the postoperative changes in the coagulation and fibrinolytic status, platelet count, fibrinogen, and antithrombin III levels were significantly decreased 2 h postoperative in the normotensive group but their decrease was not statistically significant in the hypotensive group. Postoperative D-dimer level significantly increased in the two groups, but its increase was higher in the normotensive group compared to the hypotensive group.
The increased platelet aggregation and the changes of the coagulation and fibrinolytic activities that were detected in the normotensive group can be explained by the effect of surgical tissue trauma causing an increase in the concentrations of blood coagulation factors at the site of vascular damage and increased secretion of stress hormones leading to increased blood coagulability and platelet aggregation.[3,8] So there are two important alterations of the hemostatic system; the first is the tendency toward hypercoagulability,[9] and the second is an initial enhancement of fibrinolysis, followed by a decline in fibrinolytic activity.[10]
Coagulation activation was indicated by the reduction of antithrombin III, platelet count, and decreased fibrinogen level. Antithrombin causes inactivation of several activated factors, including factors X, IX, XII, and thrombin. By inactivating the previously mentioned factors, thrombin production is reduced. Antithrombin also binds with thrombin and thereby blocks thrombin’s interaction with fibrinogen.[11] Fibrinogen is an acute-phase protein produced by the liver. The significantly decreased fibrinogen level in the normotensive group at 2 h postoperative is due to early activation of fibrinolysis. The increased fibrinogen level that occurred 24 h postoperative in both studied groups may reflect the close association between stress and coagulation activation.[12]
D-dimer is a cross-linked fibrin degradation product, which is produced as a result of fibrin breakdown. D-dimer levels are commonly elevated in response to surgery or trauma. It indicates the presence of an intravascular clot that has undergone lysis.[11] Postoperative D-dimer level was increased in the two groups with a more pronounced increase in the normotensive group than the hypotensive group. Increased D-dimer level may be due to surgical trauma and fibrinolysis activation.[13] The difference in the postoperative D-dimer level between the normotensive and the hypotensive groups reflects the lower consumption of coagulation factors in the induced hypotensive group. These hemostatic system changes were documented in previous studies.[11,14–18]
In a trial to modify the hemostatic response, we investigated the effect of induced hypotensive anesthesia on platelet aggregation, coagulation, and fibrinolytic status. Platelet aggregation is affected by many anesthetic and hypotensive agents.[19,20] However, dexmedetomidine may have no or negligible effect on platelet aggregation and hemostasis.[21]
In hypotensive group, platelet aggregation insignificantly decreased during the induced hypotensive period and remained statistically insignificant till the end of surgery and during the first 24 postoperative hours. So, the induced hypotension prevented the increase in platelet aggregation and attenuated the alteration of the hemostatic system that was noticed in the normotensive group. The decreased platelet aggregation due to induced hypotension may be explained by the vasodilatation properties and the reduced vessel wall shear stress.[22,23]
The effects of induced hypotension on the coagulation and fibrinolytic status may be attributed to prevention of increased platelets aggregation that lead to better preservation of coagulation factors[24] together with less blood loss, lower need for packed RBCs transfusion and less hemodilution leading to better preservation and less consumption of platelets and coagulation factors.
Dietrich et al.[22] evaluated the effects of sodium nitroprusside-induced hypotension on platelet function and on adrenoceptors in 40 patients (divided into two groups; controlled and hypotensive groups) undergoing nasal septum, tympanoplasty, or sphenoid sinus surgery. They documented that spontaneous platelet aggregation only increased in the control group intra-operatively and on the day after surgery while epinephrine-induced platelet aggregation only increased in the controls on the day after surgery. They concluded that induced hypotension using sodium nitroprusside attenuates epinephrine-induced and spontaneous platelet aggregation. On the day after hypotension, the postoperative increase in platelet aggregation did not occur in the induced hypotension group. Heesen et al.[25] in their study on 30 patients (randomly allocated into control and sodium nitroprusside-induced hypotension groups) undergoing nasal septum operations, documented that platelet function was not changed significantly in the induced hypotension group. They concluded that platelet aggregation was significantly increased in the control group, which was probably counteracted in the sodium nitroprusside-induced hypotensive patients. Felfernig-Boehm et al.[24] in their study on 30 patients undergoing orthognathic surgery; compared the effects of normotensive and hypotensive general anesthesia on platelet aggregation, plasma coagulation parameters and blood loss. Patients were randomly allocated into three groups: Normotensive group, remifentanil-induced hypotension group and nitroglycerin-induced hypotension group. They reported that during induced hypotension, platelet aggregation decreased significantly as compared to the normotensive group. Postoperative platelet count, prothrombin activity, fibrinogen, and antithrombin III significantly decreased while aPTT and thrombin time increased after normotensive anesthesia whereas they were not significantly changed in the hypotensive groups. They concluded that induced hypotension decreases platelet aggregation and subsequently prevents the subclinical consumption of coagulation system. The beneficial effects of hypotensive anesthesia on hemostatic system were investigated in other previous studies.[26–28] Our study has some limitations. In addition to the limited duration of the study, we didn’t study patients with preexisting coagulation disorders.
Conclusion
Intraoperative and postoperative platelet aggregation significantly increased in the normotensive group with significant alterations of the coagulation markers. Dexmedetomidine-induced hypotensive anesthesia prevented the increased platelet aggregation that occurred in the normotensive group with better preservation of platelet and coagulation factors.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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