Guidelines for the management of chronic medication in the perioperative period: systematic review and formal consensus

Authors


L. Castanheira, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal. Tel.: 00351 963082157; fax: 00351 275 329 099; e-mail: lcastanheira@fcsaude.ubi.pt

Summary

What is known and Objective:  The worldwide volume of surgery is huge and the number of interventions performed is increasing as a result of advances in technological resources and refinement of medical teams’ expertise, in a progressively elderly and sick population. Consequently, half of the general surgical patients take medications unrelated to surgery. Evidence-based guidelines for perioperative medication management are therefore critically needed to improve safety in surgery. The purpose of this work was to develop practice recommendations for the management of chronic medication in the perioperative period.

Methods:  A systematic review and a formal consensus were performed. A search in Medline, Embase, ISI Web of Knowledge and Medscape were conducted in September 2008. Two independent investigators assessed the quality of selected studies. Evidence-based guidelines with strength classification were found for some therapeutic groups. Those guidelines were adopted and no further analysis was performed. For the other therapeutic groups, a formal consensus was used, based on a modified nominal group technique: 32 statements were formulated considering the literature retrieved. A selected panel of experts was asked by electronic mail to rate their level of agreement with each statement. Then, a meeting was convened and a second round survey was used to determine the final level of agreement. The statements which met the established criteria of consensus were developed into practice recommendations, supported by the results of the formal consensus and the evidence-based findings from systematic review.

Results and Discussion:  A total of 23 studies were included in the systematic review; three randomized controlled trials (RCTs), 13 cohorts, two case–controls and three clinic-cases. Twenty-two practice recommendations for the management of chronic medication in the perioperative period resulted from formal consensus.

What is new and Conclusion:  Epidemiological studies concerning the perioperative management of chronic medications are clinically heterogeneous and there are few RCTs available. However, the formal consensus method proved to be a helpful tool to integrate different strands of evidence for the development of practice guidelines.

What is known and objective

The volume of surgery is huge worldwide and the number of interventions performed is increasing, due to advances in technological resources and refinement of medical teams’ expertise, in a progressively elderly and sick population (1). Consequently, half of the general surgical patients take medications unrelated to surgery (2). Nevertheless, there is little evidence quantifying the risk of withdrawal or continuation of chronic medication in the perioperative period. Often, clinical decisions are empirical and inconsistent among clinicians. An observational study by Kennedy and colleagues found that taking a drug unrelated to surgery was associated with an increased relative risk of a post-operative complication by 2·7, compared with those who were not taking any drug. Of those patients, 5% suffered post-operative complications directly attributable to withdrawal of their chronic medication (2). These numbers strongly suggest that correct management of chronic medication in the perioperative period should become a substantial global public-health concern.

Evidence-based guidelines for perioperative medication management are therefore critically needed to improve patient safety in surgery. Although there are published guidelines, these are not consensual and do not present evidence level classification. The purpose of this work was to provide practice recommendations for the management of chronic medication in the perioperative period, using a formal consensus process to incorporate key evidence findings from both a systematic review and clinical expertise.

Methods

Study selection

A systematic review was conducted in September 2008. First, we identified literature published in the last 10 years, in English, Spanish and French languages. We searched Medline, Embase, ISI Web of Knowledge and Medscape electronic databases, using combinations of the following terms: ‘perioperative period’, ‘surgery’, ‘chronic medication’, ‘regular medication’, ‘drug related problems’, ‘adverse drug interactions’, ‘adverse drug events’, ‘adverse drug reactions’, ‘complications’, ‘drug therapy’, ‘drug withdrawal’, ‘polypharmacy’, ‘management of perioperative’, ‘anaesthesia’. These terms were conjugated with the Medical Subject Heading (MeSH) search for different therapeutic groups. Second, we screened titles and abstracts to exclude obviously non-eligible studies and then hand searched additional references from the references lists of relevant articles. All retrieved studies concerning chronic medication in the perioperative period were then included. Studies already pooled in meta-analysis, were excluded to avoid weighting duplicated data.

Additionally, we searched for published guidelines in electronic sites of evidence-based journals and several organizations, responsible for providing guidance on clinical practice (Table 1).

Table 1.   Electronic sites of evidence-based journals and specific organizations
Clinical evidencehttp://www.clinicalevidence.bmj.com
Canadian Agency for Drugs and Technologies in Healthhttp://www.cadth.ca
Evidence-based medicinehttp://www.ebm.bmj.com/
Institute for Clinical Systems Improve (ICSI)http://www.icsi.org
National Heart Lung and Blood Institute (NHLBI)http://www.nhlbi.nih.gov
National Institute for Health and Clinical Excellence (NICE)http://www.nice.org.uk
National Guideline Clearinghouse™ (NGC)http://www.guideline.gov
Scottish Intercollegiate Guideline Network (SIGN)http://www.sign.ac.uk.com
Skyscapehttp://www.skyscape.com
Therapeutic guidelineshttp://www.tg.org.au/?sectionid=11
Therapeutics initiativehttp://www.ti.ubc.ca
TRIPhttp://www.tripdatabase.com/
Up-to-datehttp://www.uptodate.com

Quality assessment and data extraction

The quality of selected studies was evaluated by two independent investigators using the Scottish Intercollegiate Guidelines Network levels of evidence (SIGN) (3). Data were summarized in tables outlining the following information: study design, surgery type, patient characteristics, comparison groups, outcome measures and effect size.

For some therapeutic groups, we found evidence-based guidelines with strength classification. Those guidelines were adopted and no further analysis was performed. For the other therapeutic groups, with insufficient or conflicting evidence, a formal consensus method was used to integrate the different sources of evidence.

Formal consensus

The formal consensus method used was based on a modified nominal group technique described by Rycroft-Malone (4). An interdisciplinary panel of eleven experts was invited by telephone and agreed to participate. This panel comprise specialists with recognized expertise in internal medicine, evidence-based medicine, surgery, anaesthesiology and pharmacy. Seven specialists completed all the rounds of the consensus process.

Thirty-two statements for the management of perioperative chronic medication were formulated, considering the literature retrieved by the systematic review and the other evidence-based resources outlined above. All statements were constructed in a similar manner to reduce bias. These statements were collated in a structured form and rated on a 1–9 Likert scale, where 1 represents the least agreement and 9 represents the most agreement level.

The panel was then surveyed by email and asked to rate their level of agreement with each individual statement, taking into account their clinical expertise and the realities of healthcare services in Portugal. Some of the studies classified above with the highest level of evidence were also sent for facultative support.

A face-to-face meeting was convened on March 2009. Each expert was given the results of the first-round survey, with the median rating of the group and the corresponding interquartile range (IQR) for each statement. The statements were discussed in turn, focusing primarily on those that were the source of most disagreement. All the members were given the opportunity to explain their point of view and invited to add suggestion.

During the meeting, two investigators registered the relevant conclusions that came out from the discussion. The panel also recommended some adjustments of the statements to clarify their meaning.

A second round survey was then conducted by e-mail and statements were re-rated. This second rating was then used to determine the final level of agreement with each statement. If the median score of a statement was 7–9 with an IQR range less than 3, this was considered to be agreement or ‘consensus’ and the statement was developed into a practice recommendation. Likewise, if it did not reach this level of consensus it was rejected.

The recommendations strength was classified according to SIGN grades (3).

 

Results and discussion

As illustrated in Fig. 1, the initial search yielded 3544 citations. After screening by one reviewer, 249 were identified as ‘possibly eligible’ for inclusion. Hand searching of references from the relevant articles identified 99 additional citations.

Figure 1.

 Flow diagram of study selection process.

Of these, 325 were excluded after reviewing the full publication. The studies that evaluated β-blockers, statins and antithrombotic therapy during perioperative period were also excluded from systematic review since, for these therapeutic groups, clinical practice guidelines with strength classification were found. The American College of Cardiology/American Heart Association developed practice guidelines which define the management of chronic use β-blockers and statins in the perioperative period (5).

The American College of Chest Physicians (ACCP) published clinical practice guidelines for the perioperative management of antithrombotic therapy (6).

For some therapeutic groups, we found practice recommendations but these had no strength evidence classification and thus were not adopted, although they were used for comparative discussion.

Finally, a total of 23 studies were included in the systematic review. Data extracted from the studies and their evidence level are summarized in Table 2 for the different therapeutic groups.

Table 2.   Characteristics of included studies
Study [Reference] DesignSurgery Type PatientsComparison GroupsOutcome measuresEffect sizeELi
Calcium Channel Blockers (CCB)
(7) CohortCardiac surgery 6635 individualsCCB users
CCB non-users

In-hospital mortality

Major Bleeding
Odds ratio (95%CIii)
0·56 (0·33–0·94)
Piii = 0·028
1·01 (0·75–1·37) P = 0·94
2++
(8) Case-ControlGeneral and Vascular surgery 453 patients
All patients receiving chronic intercurrent medication continued this up to and including the morning of surgery, and recommenced as soon as feasible after the end of operation.
Cases: Patients with postoperative silent myocardial ischemia
Controls: Patients with no postoperative silent myocardial ischemia

CCB use
Odds ratio (95% CI)
1·95 (1·15-3·32) P = 0·015
2+
Angitensin converting enzyme inhibitors (ACEI) and Angiotensin Receptor Antagonist (ARA)
(9) RCTCardiac surgery
40 Patients
1- Continue with their regular ACEI up until the day of surgery

2- Have the ACEI discontinued on the day before surgery
Vasoactive drugs:
Glyceryl trinitrate in theatre (mg)
Glyceryl trinitrate in recovery (mg)

Glyceryl trinitrate total (mg)
Metaraminol during surgery (mg)

Numbers of patient requiring vasoactive drugs:
Meraminol after induction
Epinephrine after surgery
Norepinephrine after surgery
Epinephrine in recovery
Norepinephrine in recovery
Glyceryl trinitrate (<1 mg h−1) after surgery
Glyceryl trinitrate (<1 mg h−1) in recovery
Sodium nitroprusside in recovery


Systemic mean arterial pressure measured at intervals during the perioperative period

Systemic vascular resistance measured at intervals during surgery and the early postoperative period
Comparison of means
P < 0·05
P < 0·05

P < 0·05
P < 0·05

Comparison of number of patients
Nsiv
Ns
Ns
Ns
Ns

P < 0·05

P < 0·05
Ns

Comparison of means
P < 0·05



P < 0·05
1
(10) CohortGeneral Surgery
267 Patients
1- Patients who took their last dose of ACEI or ARA < 10 hours before anaesthesia
2- Patients who took their last dose of ACEI or ARA ≥ 10 hours before anaesthesia
Blood pressure (at or shortly after induction), unplanned intensive care unit, hemodynamic instability in the postanaesthesia care unit (arterial blood pressure or heart rate), acute renal impairment, transient ischemic attack, stroke, myocardial ischemia/infarction, and death
The only significant difference between de groups was moderate hypotension at 0–30 min after induction 1 vs 2








Any episode
1–60·4%; 2–46·3%
P = 0·02
Odds Ratio(95% CI) P 1·74/1·03–2·93) P = 0·04
2+
(11) RCTVascular Surgery
37 Patients
Group I - ARA discontinued on the day before surgery
Group II - ARA given 1h before aesthesia
Systolic arterial pressure



Episodes of hypotension

Number of patients with hypotension episodes
Duration of hypotension episodes


Need for vasoactive drugs
Group II < Group I at 5, 15, and 23 min after induction
P < 0·05
Group I – 1
Group II – 2 P < 0·01
Group I – 12
Group II – 19 P < 0·01
Group I – 3 ± 4 min
Group II – 8 ± 7 min P < 0·01
Group II > Group I –P < 0·02
1
(12) CohortVascular surgery
84 patients
ARA users
ACEI users
ARA was given until the morning of surgery, whereas the last administration of ACEI was 24 hours before surgery
Patients with hypotension
ARA users compared with ACEI users
Patients with refractory hypotension
ARA users compared with ACEI users
Ephedrine requirements until 30 minutes after the induction of anaesthesia
ARA users compared with ACEI users
Comparison of proportions
P ≤ 0·05


P ≤ 0·05

Comparison of means


P ≤ 0·001
2+
(13) CohortVascular surgery
80 patients
ACEI users (take in the surgery morning)
ACEI non-users
Systemic haemodynamic variables at 5 points during surgery (Heart rate; Mean arterial pressure; Cardiac Output; Mixed venous oxygen saturation; Systemic vascular resistance)
Total amount of noradrenaline infused
Number of patients requiring noradrenaline
Only the cardiac output was significantly greater in ACEI non-users_P < 0·05


ACEI users > ACEI non-users P < 0·05
Ns
2+
(14) Clinic CaseA 75 years old man submitted first an endaterectomy of the right and 2 months later of the left internal carotid artery. He takes nicardipine and enalapril to treat hypertension.
1st Surgery– Enalapril was withdrawn the eve of surgery, but nicardipine was given before surgery. Blood pressure (BP) decreased 4 minutes after induction by more 30% below the preoperative value. Despite repeated IV ephedrine administration (up to 27 mg), BP decreased to 88/46 mmHg and heart rate 46 bpm. A bolus of 1 mg of terlipressin was administered IV 9 minutes after induction, BP increase to 118/53 mmHg 1 minute later and remained stable during the anaesthesia period.
2nd Surgery– 10 days prior to surgery, enalapril was withdrawn and replaced by ibersartan. Preoperative blood pressure was 150/70 mmHg. Three hours before surgery, irbesartan and nicardipine were given. Blood pressure decreased 3 minute after induction to 92/44 mmHg. Despite repeated IV ephedrine administrations (up to 18 mg), BP decreased on 5th minute to 47/30 mmHg. BP increased after IV phenylephedrine administrations to 88/66 mHg but decreased again to 79/46 mmHg despite the administration of IV ephedrine. 20 minutes after induction of anaesthesia, terlipressin 1 mg bolus was administered. BP increased after 1 minute to 102/50 mmHg but decreased again to 78/52 mmHg. Administrations of terlipressin, 1 mg were repeated on the 17th and on 35th minute after induction until BP increased to 118/72 mmHg and remained stable during the entire anaesthesia period. No neurological or cardiac postoperative complications occurred.
3
(15) Clinic CaseA 71 years old woman submitted to thyroid lobectomy. She was being chronically treated with ACEI, which were taken until the morning of surgery. After induction of anaesthesia, arterial hypotension refractory to crystalloid therapy developed and worsened in spite of administration of a gelatin-type colloid (Gelafundina®). The patient did not respond to ephedrine or dopamine and required stabilization with adrenalin in continuous perfusion for 12 hours. Later evolution was satisfactory and recovery took place without sequelae.3
CCB, ACEI and Nitrates
(16) Prospective CohortMajor vascular surgery
1693 patients, mean age 65 years
ACEI users
ACEI non users
CCB users
CCB non-users
In-hospital mortality in patients who use:

ACEI

CCB

Long-term mortality

ACEI

CCB
Logistic regression models
Odds ratio (95%CI)
0·69 (0·44–1·09) P = 0·09
0·92 (0·60–1·40) P = 0·76
Hazard Ratio (95%CI)
0·74 (0·59–0·92)
P = 0·008
0·80 (0·61–1·05) P = 0·12
2+
(17) CohortCardiac surgery
1593 Patients, mean age 63·8 years.
Cardioactive drugs was continued until the morning of surgery
Nitrates users
CCB users
ACEI users
Digoxin users

Nitrates non-users
CCB non-users
ACEI non-users
Digoxin non-users
In-hospital deaths in patients who use:
Nitrates
CCB
ACEI
Digoxin
Relative risk (95% CI)
3·8 (1·5–9·6)
1·1 (0·6–2·1)
0·8 (0·4–1·5)
0·7 (0·2–1·8)
2+
Diuretics
(18) CohortNoncardiac surgery
12381 operative cases
Group I - ACEI or ARA users
Ia) Diuretics users
Ib) CCB users
Ic) Diuretics and CCB users
Id) Diuretics and CCB non-users
Group II - ACEI and ARA non-users
IIa) Diuretics users
IIb) CCB users
IIc) Diuretics and CCB users
IId) Diuretics and CCB non-users
ACEI/ARA users withhold the medication the day of surgery
Mean number of episodes of hypotension < 70 mmHG



Mean number of episodes with a 40% decrease in systolic blood pressure



Mean number of episodes with a 50% decrease in systolic blood pressure


Mean number of vasopressor boluses administered



Postoperative myocardial infarction




Renal failure
Ia vs IIa P = 0·003
Ib vs IIb Ns
Ic vs IIc Ns
Id vs IId Ns

Ia vs IIa P = 0·02
Ib vs IIb Ns
Ic vs IIc Ns
Id vs IId Ns

Ia vs IIa P = 0·02
Ib vs IIb Ns
Ic vs IIc Ns
Id vs IId Ns
Ia vs IIa P = 0·02
Ib vs IIb Ns
Ic vs IIc Ns
Id vs IId Ns

Ia vs IIa Ns
Ib vs IIb Ns
Ic vs IIc Ns
Id vs IId Ns

Ia vs IIa Ns
Ib vs IIb Ns
Ic vs IIc Ns
Id vs IId Ns
2+
Hormone Replacement Therapy
(19) CohortVascular surgery
734 Women older than 54 years
Estrogen users
Estrogen non-users

Mortality
Perioperative cardiac morbidity
(myocardial infarction, unstable angina, atrial fibrillation, ventricular fibrillation, ventricular tachycardiac, cardiogenic shock or complete heart block)
Late complications (perioperative cardiac morbidity, infections morbidity, permanent cerebral vascular accident, gastrointestinal complications, multisystem failure, pulmonary embolus, ventilator support for more than 5 days, renal failure requiring dialysis, deep vein thrombosis and acute limb ischemia)
Early complications (repeat surgery for tamponade, aortic dissection or bleeding)


Length of stay
Odds ratio (95% CI)
0·38 (0·07–1·21)
0·52 (0·23–1·7)



0·42 (0·16–0·96)






0·98 - Estrogens users
1·11 - Estrogen non-users
7·0 ± 0·36 – Estrogen users
8·5 ± 0·95 – Estrogen
non-users
2
(20) CohortVascular surgery
4782 patients
1-HRT users
2-HRT non-users
3-Men
Postoperative outcomes (myocardial infarction, congestive heart failure, central nervous system complication, renal dysfunction, red blood cell transfusion, fresh frozen plasma transfusion, platelet transfusion, duration o hospital stay)
Mortality
1 vs 2
2 vs 3
1 vs 3
There were no significant differences in the incidence of postoperative outcomes in the 3 groups.
Odds ratio (95% CI) P
0·7 (0·2–2·1) 0·51
0·8 (0·5–1·2) 0·30
0·9 (0·3–2·5) 0·79
2++
(21) Case-controlOrthopedic surgery
318 patients
HRT or selective oestrogen receptor modulators users HRT or selective oestrogen receptor non-users
Postoperative thrombosis
Odds ratio (95%
0·68 (0·35-1·28)
2+
Tricyclic antidepressants
(22) RCTOrthopedic surgery
120 patients
1 - Tricyclic users who continued antidepressants before surgery
2 - Tricyclic users who discontinued antidepressants 72 h before surgery and then are resumed on the day after surgery
3 - Antidepressants non-users



Hypotension during anaesthesia
Arrhythmias during anaesthesia
Delirium or confusion
The day before operation
The day of the operation

Postoperative day
1
2
3
Comparison of groups
1 - 2 – 3
8% 5% 0%
5% 5% 3%

0% 0% 0%P = Ns
0% 15% 0%P = 0·01

3% 10% 0%P = Ns
10% 5% 3%P = Ns
0% 0% 0%P = Ns
1
(23) CohortOrthopedic surgery
70 patients
Tricyclic users (discontinued on the day of the operation and restarted the next day)
Antidepressants non-users
Postoperative Shivering

Tryciclic users
No depressed patients
Comparison of groups
8/35
2/35
P = 0·04
2+
(24) Clinic case57-years-old man submitted to cardiac surgery, that take chronic clomipramine had severe, refractory hypotension during anaesthesia. The authors hypothesize that preoperative postural hypotension may be a risk factor for tricyclic related hypotension during anaesthesia.3
(25) Clinic case61-years-old woman submitted to gynaecology surgery, that take chronic amitriptyline had severe, refractory hypotension during anaesthesia.3
Serotonin reuptake inhibitors (SSRIs)
(26) CohortOrthopedic surgery
520 individuals
1- Serotonergic antidepressants users
2- Non serotonergic antidepressants users
3- Antidepressants non-users
Need for blood transfusion
1 vs 3
2 vs 3
Odds ratio (95%CI)
3·71 (1·35–10·18)
0·74 (0·1–5·95)
2+
(27) CohortVascular surgery
4794 patients
SSRIs users
SSRIs non-users


All cause mortality

Rehospitalization

Composite end point (all cause mortality or rehospitalization)
Hazard ratio (95% CI) P-value
1·61 (1·17–2·21) P = 0·003
1·52 (1·30–1·77) P < 0·0001
1·46 (1·26–1·70) P < 0·0001
Kaplan-Meier mortality estimate
Nearly 10% absolute excess mortality in the SSRIs users
2+
(28)49-year-old women, submitted to cardiac surgery, which pre-operative medication included clonazepam 0·5 mg daily, seroquel 25 mg twice daily and paroxetine 40 mg daily for anxiety and depression in postoperative period, she woke confused and agitated. Her temperature was 40°C. Neurologic examination revealed myoclonic jerks, fine tremors of the extremities, dilated pupils, shivering, hyperactive reflexes and hypertonicity. A diagnosis of serotonin syndrome was made.3
Glucocorticoids
(29) CohortHand and wrist surgery
80 patients with rheumatoid arthritis, mean age 53 years
All patients received their regular medication throughout the perioperative period
A-Methotrexate only
B-Steroids only
C-Steroids and Methotrexate
D-Neither drug
Wound infections

A e C /B e D
B e C/A e D
Wound infection and dehiscence rates
A/B/C/D
Wound infection
-diabetic rheumatoid patient
-non diabetic rheumatoid patient
Comparison of proportions
P = 1·0
P = 0·21

Ns
Rate (CI 95%)
33% (9·7–70)
3·3% (1·3–8·1)
2

Calcium channel blockers

No study comparing withdrawal and continuation of Calcium channel blockers (CCB) in the perioperative period was found. The literature search identified only three cohort studies assessing the effects of CCB on mortality during post-operative period, and one case–control study about the effect of CCB on post-operative silent myocardial ischaemia (7–10). Of the three cohort studies, only Wijeysundera et al. (10), found that CCB were associated with significantly reduced in-hospital mortality, but where not associated with major bleeding. The other two cohort studies failed to show a beneficial effect of CCB on post-operative mortality (7, 9). The case–control study showed a higher incidence of post-operative silent myocardial ischaemia in patients receiving chronic CCB.

Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonist

Two randomized controlled trials (RCT) and one cohort study compared withdrawal with continuation of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARA) during the perioperative period (11–13). One cohort study compared the administration of ARA in the morning of surgery with administration of ACEI 24 h before surgery (14). Another study (15) compared ACEI/ARA users with no users. These five studies found that intake of ACEI/ARA in the morning of surgery negatively affects haemodynamic control. Three of those studies (11, 12, 14) concluded that stopping ACEI/ARA on the day of surgery was associated with a minor number of hypotensive episodes in the post-induction period. Pigott et al. (13) verified that patients who stopped ACEI, had higher levels of arterial blood pressure, consequently needing less vasoconstrictors administration during surgery, but often requiring vasodilator infusions to prevent hypertension in the early post-operative period. Lee et al. (15) and Brabant et al. (14) concluded that patients who took ACEI or ARA medication on the surgery morning had significantly higher needs of vasopressors during surgery. Additionally, two case reports described refractory hypotension in patients treated with ACEI/ARB on the surgery morning. Two other studies (7, 9) evaluated the effect of ACEI on post-operative mortality; one found no effect but the other (7) observed a post-operative long-term mortality reduction in ACEI users.

Nitrates

No study comparing withdrawal with continuation of chronic nitrates in the perioperative period was found. Weightman et al. (9) suggest that there is an association, independent of other recognized risk factors, between pre-operative treatment with nitrates and increased in-hospital mortality after coronary artery surgery.

Diuretics

No study comparing withdrawal with continuation of chronic diuretics in the perioperative period was found. One study evaluated the association between ACEI/ARA therapy and the haemodynamic control of patients undergoing non-cardiac surgery and concluded that chronic diuretic therapy is associated with more frequent hypotension episodes in ACEI/ARA-treated patients (16).

Hormone replacement therapy

No study comparing withdrawal with continuation of hormone replacement therapy (HRT) in the perioperative period was found. Two cohort studies evaluated morbidity and mortality in HRT users and HRT non-users (17, 18). The two studies concluded that HRT administration had no effect on mortality or morbidity rates in women undergoing vascular surgery. One case–control study found no association between perioperative HRT and post-operative thrombosis in patients undergoing major orthopaedic surgery (19).

Tricyclic antidepressants

One randomized controlled trial (20) compared withdrawal of tricyclic antidepressants with continuation in the perioperative period and concluded that the incidence of intraoperative hypotension and arrhythmias was lower in patients taking antidepressants, whether treatment was stopped pre-operatively or not. On the other hand, discontinuation of antidepressants was associated with increased incidence of delirium, confusion and depressive symptoms. One cohort study showed a significantly higher incidence of post-shivering in depressed patients (21). Two clinic cases described severe, refractory hypotension during anaesthesia associated with chronic tricyclic antidepressant therapy (22, 23).

Serotonin reuptake inhibitors

No study comparing withdrawal of serotonin reuptake inhibitors (SSRIs) with continuation in the perioperative period was found. Two cohort studies (24, 25) compared different endpoints between SSRIs users and non-users. Movig et al. (24) concluded that the use of SSRIs is associated with increased risk of bleeding and subsequent need of blood transfusions during orthopaedic surgery. The other study verified that SSRI use before surgery was associated with a higher risk of long-term post-operative mortality and re-hospitalization (25). We also found one clinical case of serotonin syndrome following cardiac surgery, in a woman who had paroxetine in the pre-operative period (26).

Glucocorticoids

Only one study assessing the chronic use of steroids in the perioperative period was found. This cohort study found no statistically significant risk of wound infection or breakdown in patients taking steroids, methotrexate or both (27).

Formal consensus.  From the second round rating, nine of the 32 statements did not meet the established criteria of consensus/agreement (median score from 7 to 9 and IQR less than 3) (Table 3). The remaining statements were developed into practice recommendations, supported by the results of the formal consensus process and the evidence-based findings from the systematic review.

Table 3.   Statements of formal consensus
  1. *Statements did not meet the established criteria of consensus.

  2. †Did not make sense.

Calcium channel blockers (CCB)
For patients currently taking CCB and scheduled for surgery, CCB should be continued until the day of surgery, inclusively. After surgery, CCB should be restarted with oral intake.
       1 6 
Disagree123456789Agree
Median – 9 Interquartile range – 0
If the patient cannot take oral medications, it may be necessary intravenous (IV) substitution, if poor haemodynamic condition occurs (hypertension or arrhythmia).
       232 
Disagree123456789Agree
Median – 8 Interquartile range – 1
Angiotensin-converting enzyme inhibitors (ACEI)
For patients currently taking ACEI scheduled for surgery, ACEI should be withdrawn on the morning of surgery. After surgery, ACEI should be restarted with oral intake.
        25 
Disagree123456789Agree
Median – 9 Interquartile range – 0·5
*For patients currently taking ACEI for the management of hypertension and scheduled for surgery, ACEI should be continued until the day of surgery inclusively. After surgery, ACEI should be restarted with oral intake.
 21    121 
Disagree123456789Agree
Median – 7 Interquartile range – 6·5
If the patient cannot take oral medications, it may be necessary IV substitution, namely if poor haemodynamic condition occurs (hypertension or heart failure). However, as there is no IV form available, consider parental β-blockers or CCB.
       213 
Disagree123456789Agree
Median – 8 Interquartile range – 2
Angiotensin receptor antagonist (ARA)
For patients currently taking ARA and scheduled for surgery, ARA should be withdrawn on the morning of surgery. After surgery, ARA should be restarted with oral intake.
       1 6 
Disagree123456789Agree
Median – 9 Interquartile range – 0
Nitrates
For patients currently taking nitrates and scheduled for surgery, nitrates should be continued until the day of surgery, inclusively. After surgery, nitrates should be restarted with oral intake.
         7 
Disagree123456789Agree
Median – 9 Interquartile range – 0
Diuretics
For patients currently taking diuretics and scheduled for surgery, diuretics should be withdrawn on the day of surgery and restarted with oral fluid intake.
       223 
Disagree123456789Agree
Median – 8 Interquartile range – 1·5
α2-Agonists
For patients currently taking α2-agonists and scheduled for surgery, α2-agonists should be continued until the day of surgery, inclusively. After surgery, α2-agonists should be restarted with oral intake.
       214 
Disagree123456789Agree
Median – 9 Interquartile range – 1·5
Digoxin
For patients currently taking digoxin and scheduled for surgery, digoxin should be continued until the day of surgery, inclusively. After surgery, digoxin should be restarted with oral intake.
     111 4 
Disagree123456789Agree
Median – 9 Interquartile range – 2·5
*If the patient has instable arrhythmia or heart failure, consider possible IV administration.
 1  1  123 
Disagree123456789Agree
Median – 8 Interquartile range – 3·5
Niacin, fibrates, cholestyramine and colestipol
For patients currently taking niacin, fibric acid derivatives or bile sequestrants and scheduled for surgery, this medications should be discontinued 1 day before surgery and restarted with oral fluids intake.
      1 15 
Disagree123456789Agree
Median – 9 Interquartile range – 0·5
Oral contraceptives (OC)
*For patients currently taking OC and scheduled for surgery, OC should be stopped 4 or 6 weeks before surgery.
 22     12 
Disagree123456789Agree
Median – 3 Interquartile range – 5
If the patient is submitted to procedures with low to moderate risk of thromboembolism, OC should be continued until the day of surgery, inclusively.
If the patient is submitted to procedures with high risk of thromboembolism, OC should be continued until the day of surgery, inclusively, and the patient should have thromboprophylaxis in the perioperative period.
  1  1 122 
Disagree123456789Agree
Median – 8 Interquartile range – 2·5
*After surgery, OC should be restarted with oral intake.
 311   1 1 
Disagree123456789Agree
Median – 2 Interquartile range – 4
OC should be restarted after surgery, at the time the patient has the first menstruation and recovers mobility.
       1 6 
Disagree123456789Agree
Median – 9 Interquartile range – 0
Hormone replacement therapy (HRT)
*For patients currently taking HRT and scheduled for surgery, HRT should be stopped 4 or 6 weeks before surgery.
 1   1 113 
Disagree123456789Agree
Median – 8 Interquartile range – 3
*If the patient is submitted to procedures with low to moderate risk of thromboembolism, HRT should be continued until the day of surgery, inclusively.
If the patient is submitted to procedures with high-risk thromboembolism, HRT should be continued until the day of surgery, inclusively, and the patient should have thromboprophylaxis in the perioperative period.
 2    1111 
Disagree123456789Agree
Median – 6 Interquartile range – 6
*After surgery, HRT should be restarted with oral intake.
 4 1 1  1  
Disagree123456789Agree
Median – 1 Interquartile range – 3
HRT should be restarted after surgery when the patient recovers mobility.
       1 6 
Disagree123456789Agree
Median – 9 Interquartile range – 1
Tricyclic antidepressants (TCAs)
For patients currently taking TCAs and scheduled for surgery, TCAs should be continued until the day of surgery, inclusively. After surgery, TCAs should be restarted with oral intake.
   1    15 
Disagree123456789Agree
Median – 9 Interquartile range – 0·5
Serotonin reuptake inhibitors (SSRIs)
For patients currently taking SSRIs and scheduled for surgery, SSRIs should be continued until the day of surgery, inclusively. After surgery, SSRIs should be restarted with oral intake.
  1     33 
Disagree123456789Agree
Median – 8 Interquartile range – 1
If the patient is submitted to procedures with a high risk of operative bleeding, SSRIs should be withdrawn according to their half-life. After surgery, SSRIs should be restarted with oral intake.
      1132 
Disagree123456789Agree
Median – 8 Interquartile range – 1
Monoamine oxidase inhibitors (IMAO)
For patients currently taking IMAO and scheduled for surgery, if IMAO-safe technique anaesthesia is used, IMAO should be continued until the day of surgery, inclusively. If IMAO-safe technique anaesthesia cannot be used, IMAO should be discontinued 2 weeks before surgery. After surgery, IMAO should be restarted with oral intake.
 1    1212 
Disagree123456789Agree
Median – 7 Interquartile range – 2
Insulin
For patients currently taking subcutaneous insulin and scheduled for surgery, the usual dose should be administered in the day before surgery. In the perioperative period, glucose levels should then be assessed and adequate doses of rapid acting insulin should be administered. The normal insulin schedule should be restarted with oral food intake.
      1123 
Disagree123456789Agree
Median – 8 Interquartile range – 1·5
Oral hypoglycemics (OH)
For patients currently taking OH and scheduled for surgery, OH should be stopped, according to their half-life. After surgery, OH should be restarted with oral intake. If diabetes is poorly controlled insulin should be administered in the perioperative period.
        16 
Disagree123456789Agree
Median – 9 Interquartile range – 0
Non-steroidal anti-inflammatory drugs (NSAIDs)
*For patients currently taking NSAIDs and scheduled for surgery, NSAIDs should be withdrawn before surgery, according to their half-life. After surgery NSAIDs should be restarted with oral intake.
 11    113 
Disagree123456789Agree
Median – 8 Interquartile range – 4·5
*For patients currently taking NSAIDs and scheduled for surgery, NSAIDs can be continued during the perioperative period.
 11    3 2 
Disagree123456789Agree
Median – 7 Interquartile range – 3·5
Thyroid hormones
Patients taking thyroid hormones, should take the usual dose until the morning of surgery. After surgery, medication should be restarted with oral intake.
      1  6 
Disagree123456789Agree
Median – 9 Interquartile range – 0
Antithyroid agents
Patients taking antithyroid agents should take the usual dose until the morning of surgery. After surgery, medication should be restarted with oral intake.
       1 6 
Disagree123456789Agree
Median – 9 Interquartile range – 0
Glucocorticoids
For patients currently taking glucocorticoids and scheduled for surgery, glucocorticoids should be continued until the day of surgery, inclusively. After surgery, glucocorticoids should be restarted with oral intake.
 1      15 
Disagree123456789Agree
Median – 9 Interquartile range – 1·5
If the patient is taking more than 5 mg/day of prednisolone (or equivalent), or might have some degree of hypothalamic–pituitary–adrenocortical axis suppression, supplemental hydrocortisone doses should be given.
       223 
Disagree123456789Agree
Median – 8 Interquartile range – 1·5

Our results clearly show that there is a lack of experimental randomized evidence on perioperative risk management of chronic medication. Sometimes, this evidence is controversial and not completed with observational studies. Consequently, the 23 practice recommendations developed for the management of chronic medication in the perioperative period are supported mainly by observational cohort studies and formal consensus. For some therapeutic groups, for which no studies were found, physiologic and pharmacologic plausibility was considered to justify the recommendation.

Calcium channel blockers

Patients currently taking CCB and scheduled for surgery, should continue CCB until the day of surgery, inclusively. After surgery, CCB should be restarted with oral intake. Strength of recommendation: C

Rationale: This recommendation is supported by the formal consensus (median score 9, IQR 0) and by extrapolated evidence from a cohort study (10), with evidence level of 2++. This study did not compare withdrawal with suspension of CCB in perioperative period, but found no association between CCB chronic use and major bleeding in patients submitted to vascular surgery. It also concluded that CCB use was associated with significantly reduced in-hospital mortality.

Seven recommendations (28–34) were published in accordance with our recommendation.

If the patient cannot take oral medications and poor haemodynamic condition occurs (hypertension or arrhythmia), intravenous (IV) substitution of CCB may be necessary. Strength of recommendation: D

Rationale: This recommendation is only supported by the formal consensus (median score 8, IQR 1). The consensus panel agreed that an episode of hypertension might require IV administration of CCB if the patient cannot take oral medication.

Angiotensin converting enzyme inhibitors and angiotensin receptor antagonist

In patients currently taking ACEI or ARA scheduled for surgery, the medication should be withdrawn on the morning of surgery. After surgery, ACEI should be restarted with oral intake.

Strength of recommendation: C

Rationale: This recommendation is supported by the formal consensus (median 9, IQR 0·5), by evidence from two cohort studies (strength of evidence 2+) (12, 14) and by evidence from two clinic cases (strength of evidence 3) (35, 36).

Several studies show that continuing chronic ACEI or ARA up to the time of surgery results in increased incidence of hypotension episodes and increased need of vasoconstrictors in the perioperative period, but possibly a reduced incidence of post-operative hypertension (11–15). Two clinic cases also described refractory hypotension associated with ACEI or ARA use (35, 36).

These results and two published guidelines (30, 34) are in accordance with our recommendation. The formal consensus panel agreed that the better approach is to withdrawal ACEI and ARA before surgery, because a hypertension episode it is easier to reverse than a hypotensive episode.

Nevertheless, some authors (31, 32) recommend continuing ACEI in hypertensive patients during the perioperative period, because in the study of Comfere et al. (12) patients who omitted their ACEI required vasodilators administration more often to control hypertension in the early post-operative period.

If the patient cannot take oral medications and poor haemodynamic condition occurs (hypertension or heart failure), IV substitution of ACEI or ARA may be necessary. However, as there is no IV form available, consider parental β-blockers or CCB administration.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 8, IQR 2). Again, the formal consensus experts agreed that an episode of hypertension might require IV administration if the patient cannot take oral medication.

Nitrates

Patients currently taking nitrates and scheduled for surgery, should continue nitrates until the day of surgery, inclusively. After surgery, nitrates should be restarted with oral intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 9, IQR 0). Moreover, one cohort study found an association between pre-operative treatment with nitrates and increased in-hospital mortality after coronary artery surgery (9). However, the authors do not recommend withdrawal of nitrates before coronary artery surgery because of possible rebound coronary vasoconstriction and worsening of myocardial ischaemia. Three recommendations were published in accordance with our recommendation (30, 34, 37).

Diuretics

Patients currently taking diuretics and scheduled for surgery, should withdraw diuretics on the day of surgery and restart with oral fluid intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median score 8, IQR 1·5) and by extrapolated evidence from a cohort study (16), with evidence level of 2+. This cohort study (16) concluded that chronic diuretic therapy is associated with more frequent hypotension in ACEI/ARA-treated patients, compared with ACEI/ARA non-users, in spite of holding diuretic and ACEI/ARA therapy in the morning of surgery.

The systemic vasodilatation induced by the anaesthetic drugs may cause hypotension in patients taking diuretics. In the consensus meeting, the expert panel agreed that it is easier to reverse a possible episode of hypertension than hypovolaemia and hypokalaemia. However, in cases of heart failure, the patient may need IV diuretics. Four recommendations were published in accordance with our recommendation (29, 32–34).

α2-Agonists

Patients currently taking α2-agonists and scheduled for surgery, should continue α2-agonists until the day of surgery, inclusively. After surgery, α2-agonists should be restarted with oral intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (media 9, IQR 1·5). The formal consensus panel agreed that α2-agonists should be continued in the perioperative period, because they are usually prescribed in hypertensive cases of difficult control. On the other hand, abrupt withdrawal of these agents can precipitate rebound hypertension. Potential benefits of continuing α2-agonists perioperatively include decrease in the stress response to surgery procedures and the reduction of anaesthetic doses because of their sedative, anxiolytic, analgesic and anti-shivering properties (32). Three recommendations were published in accordance with our recommendation (29, 32, 34).

Digoxin

Patients currently taking digoxin and scheduled for surgery, should continue digoxin until the day of surgery, inclusively. After surgery, digoxin should be restarted with oral intake.

Strength of recommendations: D

Rationale: This recommendation is supported by the formal consensus (media 9, IQR 2·5). Pre-operative discontinuation of digoxin is not recommended given the risk of complication of the underlying disease and because the drug would need to be stopped some days before surgery owing its long half-life. Five recommendations were published in accordance with our recommendation (28, 30, 33, 34, 37). The Drug and Therapeutics Bulletin highlighted that in cases of arrhythmia IV administration of antiarrhythmics might be necessary (38). During the meeting, some experts agreed with our statement, that IV administration might be necessary if the patient has instable arrhythmia or heart failure. However, this practice did not meet the established criteria of consensus.

Niacin, fibrates, cholestyramine and colestipol

Patients currently taking niacin, fibric acid derivatives or bile sequestrants and scheduled for surgery, should discontinue these medications one day before surgery and restart them with oral fluids intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 9, IQR 0·5). Niacin and fibrates are known to cause myopathy and rhabdomyolysis, a risk increased by surgery (32). On the other hand, the formal consensus panel agreed that these are not essential therapy. Three recommendations were published in accordance with our recommendation (32–34).

Oral contraceptives

If the patient is submitted to procedures with low to moderate risk of thromboembolism, oral contraceptives (OC) should be continued until the day of surgery, inclusively.

If the patient is submitted to procedures with high risk of thromboembolism, OC should be continued until the day of surgery, inclusively, and the patient should have thromboprophylaxis in the perioperative period.

OC should be restarted after surgery, when the patient has the first menstruation and recovers mobility.

Strength of recommendation: D

Rationale: These recommendations are supported by formal consensus, median 8, IQR 2·5 and median 9, IQR 0, respectively. The decision to continue or to stop OC before surgery must balance the risk of unwanted pregnancy against the risk of thromboembolism.

Some recommendations (37, 39) and the formal consensus panel agree that, ideally, OC should be stopped at least 4 weeks before the surgery (32), but the benefits and the risks of perioperative thromboembolism vs. perioperative pregnancy should be discussed with each patient.

Some experts defend that the risk of giving anaesthesia to a pregnant woman is higher than the risk of thromboembolism. Therefore, OC should be continued and the need for thromboprophylaxis therapy considered.

Tricyclic antidepressants

Patients currently taking tricyclic antidepressants (TCAs) and scheduled for surgery, should continue TCAs until the day of surgery, inclusively. After surgery, TCAs should be restarted with oral intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 9, IQR 0·5). Also we found one randomized controlled trial (20), although with evidence level 1, where the patients on chronic TCA had a lower incidence of intraoperative hypotension and arrhythmias, independently of whether treatment was ceased pre-operatively or not. On the other hand, discontinuation TCAs was associated with increased incidence of delirium, confusion and depressive symptoms. Four published recommendations were in agreement with our recommendation (29, 32, 33, 40).

Serotonin reuptake inhibitors

Patients currently taking SSRIs and scheduled for surgery, should continue SSRIs until the day of surgery, inclusively. After surgery, SSRIs should be restarted with oral intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 8, IQR 1). As the wash-out period of SSRIs may be as long as 3 weeks and clinical benefit from readministration may take several weeks, stopping SSRIs could lead to exacerbation of mood disorders. Four published recommendations are in agreement with our recommendation (32, 33, 37, 41).

If the patient is submitted to procedures with high risk of operative bleeding, SSRIs should be withdrawn according to their half-life. After surgery, SSRIs should be restarted with oral intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 8, IQR 1) and by a cohort study (24) (evidence level of 2+). This cohort study concluded that the use of SSRIs is associated with an increased risk of bleeding and subsequent need for blood transfusion during orthopaedic surgery (24). One published recommendation agrees with our recommendation (32).

Monoamine oxidase inhibitors

For patients currently taking monoamine oxidase inhibitors (MAOI) and scheduled for surgery, if MAOI-safe technique anaesthesia is used, MAOI should be continued until the day of surgery, inclusively. If MAOI-safe technique anaesthesia cannot be used, MAOI should be discontinued 2 weeks before surgery. After surgery, MAOI should be restarted with oral intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 7, IQR 2). MAOI use leads to accumulation of biogenic amines in the central and autonomic nervous systems. During anaesthesia, concomitant administration of sympathomimetic agents, like ephedrine, can result in massive release of stored norepinephrine and subsequent severe hypertension. In addition, administration of dextromethorphan and meperidine (pethidine) with MAOI can cause serious serotonin syndrome (32). Our recommendation is in accordance with these facts. Three other published recommendations also agree with our recommendation (32, 37, 40).

Insulin

Patients currently taking subcutaneous insulin and scheduled for surgery, should administer the usual dose in the day before surgery. In the perioperative period, glucose levels should then be assessed and adequate doses of rapid acting insulin should be administered. The normal insulin schedule should be restarted with oral food intake.

Strength of recommendation: D

Rationale; This recommendation is supported by the formal consensus (median 8, IQR 1·5). We found several insulin protocols (31, 33, 40, 42–44) in the literature for the perioperative management of insulin diabetic patients; however, there is no comparison study between protocols. Therefore, this topic was discussed in the formal consensus meeting.

Oral hypoglycaemics

Patients currently taking oral hypoglycaemics (OH) and scheduled for surgery, should stop OH, according to their half-life. After surgery, OH should be restarted with oral intake. If diabetes is poorly controlled, insulin should be administered in the perioperative period.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 9, IQR 0). Sulphonylureas should be suspended 24–48 h before surgery, according to their half-life and renal function of the patient, to avoid hypoglycaemia. Metformin should be discontinued 48 h before anaesthesia to avoid lactic acidosis in situations of impaired tissue oxygenation (43). Inhibitors of α-glycosidases act on intestinal absorption of carbohydrates and therefore are not necessary during restricted food intake of the perioperative period (43). Ten published recommendations agree with our recommendation (28, 29, 31, 33, 37, 40, 42–45).

Thyroid hormones

Patients taking thyroid hormones should take the usual dose until the morning of surgery. After surgery, medication should be restarted with oral intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 9, IQR 0). Thyroid hormones regulate important functions such as cardiac contractility, vascular tone, water and electrolyte balance and normal function of the central nervous system. It is now widely accepted than an euthyroid state marked by adequate levels of thyroid hormones is necessary to obtain the best possible results from any kind of surgical intervention (46). Three published recommendations agree with our recommendation (31, 33, 40).

Antithyroid agents

Patients taking antithyroid agents should take the usual dose until the morning of surgery. After surgery, medication should be restarted with oral intake.

Strength of recommendation: D

Rationale: This recommendation is supported by the formal consensus (median 9, IQR 0). As with hypothyroidism, hyperthyroidism affects many body systems and influence surgical outcomes. In addition, patients with hyperthyroidism are at increased risk of thyroid storm, a potentially life-threatening condition that presents with fever, tachycardia, and confusion and may quickly lead to cardiovascular collapse and death. It can occur in the inadequately treated or undiagnosed hyperthyroid patient during, or soon after, surgery (42, 47). Two published recommendations agree with our recommendation (28, 33).

Glucocorticoids

Patients currently taking glucocorticoids and scheduled for surgery, should continue glucocorticoids until the day of surgery, inclusively. After surgery, glucocorticoids should be restarted with oral intake.

Strength of recommendation: D

If the patient is taking more than 5 mg/day of prednisone (or equivalent), or might have some degree of hypothalamic–pituitary–adrenocortical axis (HPA) suppression, supplemental hydrocortisone doses should be given.

Strength of recommendation: D

Rationale: These recommendations are supported by the formal consensus, median 9, IQR 1·5 and median 8, IQR 1·5, respectively. Physiologic stress inherent to surgery procedure activates HPA axis and increases corticotrophin (ACTH) and cortisol secretion. Exogenous glucocorticoids can suppress the HPA axis and the patient on chronic glucocorticoids may not produce sufficient levels of ACTH and cortisol to meet physiologic needs. Therefore, adrenal insufficiency with hypotension and shock may occur (42). To prevent this life-threatening complication, supplemental glucocorticoids (‘stress dose’ steroids) should be given perioperatively to those patients with documented or presumed HPA axis suppression. Prednisone (or equivalent) in a single morning dose of 5 mg does not cause clinically significant suppression of the HPA axis (42). Five published recommendations agree with our recommendations (33, 42, 48–50).

Our results bring out several controversies regarding the perioperative management of HRT and of non-steroidal anti-inflammatory drugs. Consequently, the result of the experts panel was not consensual. Therefore, additional investigation is required to support a practical recommendation.

Hormone replacement therapy

Extrapolated evidence form one cohort study (17) (evidence level 2++) and from one case–control study (19) (evidence level 2+) recommend continuation of HRT in the perioperative period with strength classification of C. However, the formal consensus panel defended withdrawal of HRT before surgery, because of higher risk of thromboembolism with this therapy compared with OC. Oestrogen dosages in HRT are higher and the target population is older. Moreover, suspension of HRT can reverse the symptoms of menopause but does not present the risk of unwanted pregnancy. On the other hand, the Portuguese clinical practice pre-operative consultation schedule does not allow withdrawal of HRT 4–6 weeks prior to surgery.

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) have antiplatelet effects, leading to increased risk of surgical bleeding. Selective cyclo-oxygenase-2 inhibitors have minimal effects on platelet activity but, like other NSAIDs, have the potential for causing renal dysfunction (28, 30, 51). Thus, five published recommendations agree that NSAIDs should be withdrawn before surgery, according to their half-life (28, 30, 37, 40, 51). On the other hand, during the formal consensus meeting some experts argued that it does not make sense to withdraw NSAIDs before surgery and after surgery then administer analgesics to control pain. Consequently, there was not agreement in the formal consensus.

As with any systematic review, this study has limitations. Although a comprehensive literature search was carried out, publication bias could be questioned due to language and publication year limits. However, the recommendations were developed on the basis of a number of different evidence sources and we believe that formal consensus was valuable and helpful clarifying some lack of evidence and contradictory findings.

Efforts were made to minimize bias by having two investigators independently undertake the study quality assessment and data extraction. Studies were relatively heterogeneous with respect to patient population, study design, treatment regimen and studied end-points. Knowing that the quality of a systematic review is always a reflection of the quality of included studies, our recommendations have limited strength of evidence (maximum evidence level C), but most of them agree with prior published recommendations.

The formal consensus panel comprised a multidisciplinary group with recognized expertise. However, only seven of the 11 specialists completed all rounds of the consensus process. A direct pre- and post-meeting comparison of the round ratings was not performed because some of the statements changed in their wording during the meeting in the light of clarifying comments of the participants.

What is new and conclusion

The formal consensus method implemented proved to be a practical and helpful method to integrate different strands of evidence for the development of evidence practice guidelines. Epidemiologic studies concerning the perioperative management of chronic medications are clinically heterogeneous and there are few randomized clinical trials available. Consequently, for some therapeutic groups, it was not possible to achieve consensus and define a practical recommendation.

Despite the limitations of this study, we believe that it makes an important contribution for the perioperative management of chronic medication and helps to clarify some of the rationale supporting each decision.

Nevertheless, further epidemiologic studies are needed to increase strength of evidence of the developed practice recommendations and to support the development of new recommendations.

Acknowledgements

We acknowledge the following individuals for contributing their expertise to this study as panel members: Alexandre Teixeira, MD; António Araújo, MD; António Vaz Carneiro, MD, PhD; Daniela Coelho, MD; Maria de Lurdes Castro, MD; Paulo Carrola, sMD; Rosário Mesquita, PharmD.

Ancillary